The COVID-19 pandemic has created several challenges across the United States resulting in the mental health of adolescents ages 12 to 18 being in a particularly vulnerable state.

Just a few years ago, in 2017, approximately 3.2 million or 13% of US adolescents reported at least one major depressive episode,1 and a separate earlier survey showed that 32% of US adolescents were diagnosed with an anxiety disorder, 8% of which were severe.2 As the pandemic continues, there is a need to identify those presenting or at risk for depression or anxiety-related disorders as these numbers are likely higher. In fact, a recent survey identified an increase in positive depressive symptom screenings from 5.0% pre-pandemic to a mid-pandemic rate of 6.2%. Positive suicide risk screening rates had also increased from 6.1% to 7.1% in adolescents.3 Herein, we review current treatment recommendations for prescribing clinicians, including the initiation and switching of antidepressants in the adolescent population.

Signs and Symptoms of Depression and Anxiety in Adolescents

Signs of adolescent depression and anxiety may be readily recognized. Common indicators for major depressive disorder (MDD) include fatigue, insomnia, sleeping more, irritability, weight gain or loss, decline in academics, and/or difficulties in family relationships.4 Presentation of anxiety disorders can vary depending on their subcategory. A diagnosis should be made between clinician and patient based on symptoms.5

Associated risks for adolescent depression and/or anxiety have been anticipated as the COVID-19 pandemic continues. Motivating factors (ie, not wanting to get others sick, peer pressure, fear of judgment) for US adolescents to engage in social distancing have been associated with increased symptoms of anxiety and/or depression.6 Within the LGBTQ+ adolescent population, social distancing has presented unique challenges. Reported stressors from this population have included general mental health decline from pandemic restrictions, an unsupportive household, and/or lack of access to a supportive resource for outreach (eg, therapist, mentor).7

Current Guidelines for Treating Depression and Anxiety in Adolescents

Guidelines from the American Academy of Pediatrics (AAP) state that adolescents should be screened annually for depression with a formal self-report screening tool, namely, the PHQ-9 adapted to adolescents. Identification of patients with increased depressive risk factors – such as family history, other psychiatric disorders, and/or previous depressive episodes – should be assessed and monitored for any developments.4

Regarding anxiety disorders, no formal recommendations have been established by the American Academy of Child & Adolescent Psychiatry (AACAP). If concerns arise for anxiety symptoms, it is advised that clinicians conduct general social-emotional screenings in an appropriate child-serving environment.5

Treatment for both adolescent depression and anxiety can include antidepressant pharmacotherapy and psychotherapy.5,8 Although antidepressants are utilized for other indications (eg, migraine, other mental health disorders), this review is specific to anxiety and depression.

Treatments for Depression in Adolescents

Pharmacotherapy

The American Psychological Association (APA) recommends fluoxetine as first-line pharmacotherapy for adolescents with MDD.8 The AAP also recommends escitalopram for first-line pharmacotherapy, although evidence is deemed insufficient by the APA.8,9 Both medications are part of the selective serotonin reuptake inhibitors (SSRIs) class of antidepressants and are the only two SSRIs that are FDA approved for adolescents for the management of MDD.10,11 Specifically, fluoxetine has an FDA-approved MDD indication for children and adolescents while escitalopram is approved for ages 12 and older.8,9

When comparing fluoxetine to psychotherapy, the APA states that no evidence has established a recommendation of one therapy over the other.8 If fluoxetine is not a feasible therapy for adolescents with MDD, conditional use of other medications must be assessed between patient and provider. There is insufficient evidence for recommending alternative medication or psychotherapy (see below).8

Due to safety concerns, the APA recommends against using clomipramine, imipramine, mirtazapine, paroxetine, and venlafaxine in this population unless remaining alternatives have been exhausted.8

Psychotherapy

The APA also recommends either cognitive-behavioral therapy (CBT) or interpersonal psychotherapy for adolescents (IPT-A) for initial psychotherapy.8 In fact, through the development of Guidelines for Adolescent Depression in Primary Care (GLAD-PC), the AAP provides recommendations for comprehensive treatment of MDD in adolescents. The multifactorial analysis of RCTs and Clinical Global Impression (CGI) scores of antidepressant response rates enables a provider to make appropriate treatment decisions. Results from the Treatment of Adolescent Depression Study (TADS, 2007) demonstrated an improved response with fluoxetine use, in combination with CBT or as monotherapy compared to placebo.12

Treatments for Anxiety Disorders in Adolescents

Pharmacotherapy

Regarding anxiety disorders, including generalized anxiety disorder (GAD), AACAP recommends SSRIs as first-line pharmacotherapy in adolescents, particularly in more severe presentations. SSRIs have been routinely used in clinical practice for anxiety disorders in adults, however, no FDA approval has been issued for this indication in adolescents. Medication choice  should therefore include consideration of patient-specific pharmacokinetics, tolerability, affordability, and adverse effect profile evaluation.

It is worth noting that a meta-analysis conducted by the Department of Psychiatry and Behavioral Neuroscience at the University of Cincinnati demonstrated that all SSRIs included in randomized placebo-controlled trials were efficacious in reducing anxiety symptoms among adolescents with a large effect size [Cohen’s d 0.62 (95%CI, 0.34 to 0.89)].13 The improvement in symptom reduction and response to treatment with SSRI use seen in the Agency for Healthcare Research and Quality (AHRQ) meta-analysis support these conclusions.5,14

Fluoxetine may be a suitable treatment preference for managing anxiety in adolescents due to once-daily dosing capabilities and its longer half-life. Dosing and treatment onset information is similar for generalized anxiety disorder and depression in adolescents.

Cognitive Behavioral Therapy

AACAP recommends CBT as a first-line psychotherapy in mild to moderate presentations of anxiety. If CBT is unavailable or inaccessible for patients, SSRI pharmacotherapy may be considered. AACAP also suggests a combination therapy of SSRI and CBT, which may be preferred to reduce acute symptoms in severe and functionally impaired patients or in those who have a partial response to individual therapy. Recommendations for alternative psychotherapies have not been established due to insufficient evidence.5

SSRI Initiation and Switching

Initial SSRI treatment for anxiety and depression may not be effective for all patients. As a first-line recommendation for SSRIs, clinicians may interchange the medication within the class. However, recommendations regarding antidepressant switching are not clearly defined in the adolescent population. The conservative method is to taper and discontinue the first SSRI before initiating the alternative SSRI. Cross-tapering is an alternative approach that would avoid the washout phase and these associated risks. The risk of discontinuation syndrome during tapering and the risk of serotonin syndrome during cross-titration should be evaluated by the primary care provider and/or prescriber in consideration with efficacy, tolerability, and cost when antidepressant switching is implemented. Patients should be closely monitored for safety concerns when either strategy of antidepressant switching is implemented.5,8

Initiation of fluoxetine and escitalopram for adolescent depression should be at low dosages with appropriate titration. Starting fluoxetine at 10 mg daily with dose increases of 10 mg to 20 mg every 1 to 2 weeks (max 60 mg/day), and escitalopram starting at 10 mg daily with increases of 5 mg daily every 1 to 2 weeks (max 20 mg/day) are both first-line pharmacologic recommendations supported by the GLAD-PC guidelines for depression in adolescents.9 The APA recommends fluoxetine be considered first over escitalopram, due to a lack of evidence supporting other treatment options are superior to fluoxetine.4 Response rates can be varied among adolescents due to limitations in symptom presentation and recognition. If symptom improvement is not seen within 6 to 8 weeks, consultation with a mental health specialist should be considered.9

Treatment-Resistant Depression in Teens

When it comes to treatment-resistant depression, additional studies, such as the Treatment of SSRI-Resistant Depression in Adolescents study (TORDIA), display limited response in adolescents who switch to non-SSRI therapy (eg, venlafaxine) or a second SSRI for treatment-resistant depression (TRD). However, higher response rates have been seen when antidepressant switching occurs in combination with CBT. Adolescents who switched to a second SSRI or SNRI in combination with CBT showed a 54.8% response rate versus 40.5% in those switched to a second antidepressant alone (95% CI: 47%-62%; P = 0.009).9,15

If switching, alternative antidepressants such as sertraline, citalopram, paroxetine, or venlafaxine have been explored as additional options for adolescent depression. However, limited data exists suggesting other antidepressants with similar response rates to escitalopram or fluoxetine have adequate safety profiles. Newer antidepressants such as vortioxetine, desvenlafaxine, or vilazodone demonstrate little improvement in depression symptoms when compared to placebo therapy. However, the improvement these newer generation antidepressants offer in adolescents appears to be small and associated with increased costs.16 The SSRI response rates seen across RCTs in a meta-analysis from the GLAD-PC guidelines is shown below in Table I.9,15

Table I. Adolescent Antidepressant Response Rates based on Clinical Global Impression Scale for MDD.9

SSRI Drug Response Rate Placebo Response Rate
Fluoxetinea 56% 33%
Paroxetine 66% 48%
Citalopram 51% 53%
Sertraline 63% 53%
Escitaloprama 64% 53%

a:FDA approved for adolescent depression

Antidepressants and Adverse Effect Management

The decision to utilize drug therapy for the management of depression or anxiety in adolescents is not without risk. As such, use of an SSRI should be an informed decision among the healthcare provider, patient, and caregivers. Common adverse effects associated with the most utilized drug therapies (fluoxetine, escitalopram, sertraline, paroxetine) are presented in Table II. These effects are mainly sourced from clinical studies in adults; however, studies assessing fluoxetine and escitalopram for depression in adolescents have noted adverse reactions similar to those seen in adult studies. It should be assumed that all drugs within the SSRI class have similar profiles related to gastrointestinal and sexual adverse effects.10,11,17,18 Adverse effects such as nausea, headaches, and behavioral activation were noted to be most common in adolescents treated with duloxetine, venlafaxine, and paroxetine.9 Some antidepressants have been linked to weight loss or lack of weight gain (eg, fluoxetine) in adolescents, but studies were often a short duration of assessment. These findings may also be related to the adverse GI effects noted upon initiation of therapy. Weight gain associated with long-term use of antidepressants may be a concern for adolescents, so healthy eating and lifestyle habits are important to stress.19

The most concerning adverse effect of antidepressants is the emergency of new or worsened suicidality. Estimated risks seem to be at twice the rate of those on placebo, occurring in 4% of those who receive medication.9,10,11,17,18 However, improvement in suicidality with drug therapy is possible. Analyses have noted an inverse relationship between suicide and use rates of SSRI prescriptions in adolescents and that most adolescents who die by suicide do not test positive for antidepressants in toxicology reports.9,20 Paroxetine and venlafaxine may have a higher risk of this effect as compared to other serotonergic antidepressants.9,16

Pregnancy-Related Complications

All female adolescents should be educated on the risks of neonatal complications associated with use of SSRIs during the third trimester of pregnancy. Risks of birth defects upon exposure during the first trimester are inconclusive.10,11,17,18 Pregnancy exposure registries exist.21

Drug interactions should also be a consideration for adolescents who take other medications. Other serotonergic drugs (eg, triptans, tricyclic antidepressants, amphetamines, St. John’s wort, etc.) should be avoided or utilized cautiously due to the risk of serotonin syndrome. The use of alcohol should be avoided.10,11,17,18

Mitigation strategies

Mitigation strategies include symptom monitoring and education to the adolescent and guardian.4,9 In addition, development of a safety plan is particularly important for serious adverse effects such as the increased risk of worsened depression and suicidal ideation in adolescents and young adults.10,11,17,18,22,23 Monitoring for adverse effects is particularly important upon initiation of therapy for several months and with any dose increases or dose reductions.10,11,17,18

Table II. Safety Considerations for Commonly Utilized Antidepressants.10,11,17,18,22

Drug Common Adverse Effectsa Drug Interactions
Fluoxetineb

Abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, yawning

Other effects noted in adolescentsc: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, menorrhagia

Potent CYP2D6 inhibitor; avoid use or monitor and consider dose reductions of all CYP2D6 substrates

 

Escitalopramb

Insomnia, ejaculation disorder, nausea, increased sweating, fatigue and somnolence, decreased libido, anorgasmia

Other effects noted in adolescentsc: insomnia, back pain, urinary tract infection, vomiting, nasal congestion

Paroxetinec Headache, fatigue, nausea Potent CYP2D6 inhibitor; avoid use or monitor and consider dose reductions of all CYP2D6 substrates
Sertraline Nausea, diarrhea, tremor, dyspepsia, reduced appetite, hyperhidrosis, ejaculation failure, decreased libido CYP2D6 inhibitor; avoid use or monitor and consider dose reductions of all CYP2D6 substrates
Mitigation Strategies
  • For GI effects, encourage to take with food (especially sertraline)
  • Monitor weight and growth

a:Common AEs are not specific to adolescent population
b:These reactions have been reported in more than 5% of patients and at least twice the incidence of those who received placebo in clinical studies
c:These reactions have been reported in more than 2% of patients and at a higher incidence than those who received placebo in clinical studies.

Professional Takeaways

Ongoing education with guardians and regular evaluation for depression and/or anxiety is necessary in adolescent patients with depression and/or anxiety. Communication is particularly important amidst the ongoing pandemic and within the LGBTQ+ community.

The decision to utilize an SSRI for the treatment of depression and/or anxiety in adolescent patients should be shared between the patient, guardian, and provider. Factors affecting treatment should be efficacy, tolerability and safety, and cost. In particular, the risk of worsened depression and suicidality should be mitigated and monitored, particularly upon initiation of therapy. When interchanging from one drug therapy to another, it is advised to closely monitor the patient as treatment continues and to avoid the risks for discontinuation symptoms.

It is important to consider the use of multiple treatment strategies, consisting of non-pharmacologic and pharmacologic components when managing both MDD and general anxiety disorder. Complex disease states such as these often require unique, patient-specific treatment regimens to optimize clinical improvement. A delicate balance between effective treatment and safe use limits many provider treatment strategies in practice. Further evaluation of additional pharmacologic treatment options in adolescent psychiatric conditions is needed.

See also, school-related anxiety and COVID.

References
Last Updated: Sep 13, 2021