Specifics about Depression Pharmacotherapy
Selective Serotonin Reuptake Inhibitors (SSRIs) are first-line pharmacotherapy for pediatric depression. Two SSRIs are FDA-approved for the treatment of depression in pediatric patients: Fluoxetine (Prozac) is approved for depression in children ages 8 and above, and Escitalopram (Lexapro) is approved for depression in adolescents aged 12 and above. Other SSRIs, such as Sertraline (Zoloft), are also commonly used off-label for pediatric depression.
The GLAD-PC guidelines suggest Fluoxetine as the first-line recommendation among SSRIs due to several factors, including FDA approval (and age of approval) and half-life (Fluoxetine’s long half-life can decrease the effects of missed doses). Due to Fluoxetine’s FDA approval, multiple successful medication trials, and long half-life, Fluoxetine is recommended as the first choice in the absence of other considerations or contraindications. However, it is important to note that Fluoxetine is a strong inhibitor of CYP450 2D6 and therefore has the potential for drug-drug interactions. When drug-drug interactions are a consideration, Escitalopram is a good choice due to its minimal effects on CYP enzymes.
While not FDA approved for depression, several other SSRIs are frequently used off-label, particularly in cases with comorbid anxiety disorders. For example, Sertraline and Fluvoxamine (Luvox) are FDA approved for pediatric OCD, and there is also good evidence for the efficacy in anxiety disorders (Sertraline was used in the Child/Adolescent Anxiety Multimodal Study) and some evidence for the efficacy of Sertraline for depressive symptoms. Additional considerations when selecting an SSRI include whether there has been a family history of response or lack of response to a particular medication.
In most cases, SSRIs are well tolerated, and the most common side effects of SSRIs tend to be mild and/or self-limited (Miller & Campo, 2021). Common side effects of SSRIs include headaches, gastrointestinal discomfort, sedation or insomnia, sexual dysfunction, and dry mouth. Activation, which can present as insomnia, disinhibition, or restlessness, is more common in pediatric and adolescent patients than in adult patients. Activation more commonly occurs with higher starting doses and/or rapid dose escalation; this is one factor guiding recommendations to start at low doses and titrate gradually. More rare and severe in nature than activation is mania (symptoms can include markedly decreased need for sleep, irritability, expansive mood or grandiosity, or risky behavior); it is recommended that family history of bipolar disorder or mania be ascertained prior to starting medications. Other rare but serious side effects include serotonin syndrome, characterized by fever, hyperthermia, restlessness, muscle twitching, and confusion, and QTc prolongation most commonly associated with citalopram, for which an EKG should be considered. If side effects are mild, GLAD-PC guidelines recommend waiting 2-7 days to see whether they are transient. For persistent side effects, medication can be continued at the same dose if side effects are mild, or the dose can be reduced if side effects are moderate.
Importantly, in 2004, the FDA issued a black box warning that antidepressants may increase the risk of suicidal thinking and behavior in youth up to age 24, particularly in the first month after starting medication. A subsequent meta-analysis of data from trials of antidepressant treatment in adolescents showed a small but significant risk difference of 0.7 percentage points for suicidal ideation or attempts between those receiving antidepressants compared to those treated with placebo. However, more recent studies have not found significant differences, and an additional consideration is the risk of suicidal ideation and behavior associated with untreated pediatric and adolescent depressive symptoms.
Second Line Medications and Approaches When Initial Trial of Medication is Unsuccessful
As up to 40% of adolescents do not respond to initial medication treatment, the Treatment of Resistant Depression in Adolescents (TORDIA) study evaluated several approaches to this scenario, including switching to another SSRI or switching to another class of medication such as the Selective Norepinephrine Reuptake Inhibitor (SNRI) Venlafaxine. In this study, patients who switched to a different SSRI had similar responses to those who switched to an SNRI, and those receiving the SNRI reported more side effects. As such, it is recommended to switch to a different SSRI first rather than switch classes of medications. In cases where there is a partial response to medication, adding a second medication from a different class, or augmenting, is sometimes considered; however, there is less data for this strategy in pediatric populations compared to adult populations. Agents that are sometimes considered for augmentation include Bupropion, Lithium, and Atypical Antipsychotics. In these cases, consultation with a specialist is recommended.