Pediatric Psychopharmacology for Depressive and Anxiety Disorders
Abstract
Anxiety and depressive disorders are the most common psychiatric illnesses among children and adolescents. These disorders are associated with impairments in social, family, and educational functioning. This article summarizes the evidence base for psychopharmacologic interventions; the developmental pharmacology of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs); and pharmacokinetic and pharmacodynamic differences between youths and adults that call for differences in dosage and affect response and tolerability. The authors also review the efficacy and tolerability of SSRIs and SNRIs in children and adolescents with depressive and anxiety disorder diagnoses, as well as data related to duration of therapy and SSRI/SNRI discontinuation in this population. Taken together, the current evidence suggests that SSRIs are the first-line psychopharmacologic intervention for youths with depressive and anxiety disorders, with SNRIs having a more limited role. These medications are safe and well tolerated, although emerging data and developmental pharmacologic concepts may help clinicians to choose from available SSRIs and to improve the efficacy and tolerability of these medications in children and adolescents.
Anxiety and depressive disorders are the most common psychiatric illnesses affecting children and adolescents. These disorders are associated with impairments in social, family, and educational functioning. To date, both psychopharmacologic and psychotherapeutic interventions have robust support for youths with depressive and anxiety disorders, although the combination of a selective serotonin reuptake inhibitor (SSRI) and psychotherapy produces superior functional and clinical outcomes compared with monotherapy. Importantly, pharmacotherapy for these conditions of youths requires an understanding of pediatric pharmacokinetics and pharmacodynamics and of efficacy and tolerability data on these interventions. Beyond this, effectively treating children and adolescents who have depression and/or anxiety requires clinicians to synthesize knowledge from multiple studies to inform medication selection, dosage, evaluation of response (or partial response), and treatment duration. In this review, we summarize how pharmacokinetic and pharmacodynamic differences between youths and adults subtend differences in dosing, response, and tolerability. In addition, we review the efficacy and tolerability of SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) for the treatment of depressive and anxiety disorders among children and adolescents, as well as data related to treatment duration and medication discontinuation.
Pharmacologic Considerations in Treating Depression and Anxiety Among Children and Adolescents
Pediatric Pharmacokinetics
In general, metabolic capacity at birth is less than in adults and increases to levels seen in adults by approximately 2 years of age. In peripubertal patients, metabolism may be greater than that commonly observed among adults. Furthermore, during childhood and adolescence, hepatic metabolism and renal function change, and from childhood to adolescence, distribution also changes, thus affecting the pharmacokinetics of many medications in youths. Finally, in children (and to a lesser extent in adolescents), total body water is increased as a result of lower relative body fat compared with adults. These differences affect the distribution of many medications and the accumulation of lipophilic medications (and their metabolites).
Absorption and Bioavailability
Absorption is influenced by the route of administration of a medication and, for orally administered medications, is influenced by gastric pH and the presence of food in the stomach. Bioavailability—the fraction of the drug that reaches systemic circulation—is influenced by concurrently administered medications and first-pass metabolism.
Metabolism and Pharmacogenetics
Many psychotropic medications are metabolized by the cytochrome P450 enzymes CYP3A4, CYP2C19, or CYP2D6 in the liver. The activity of CYP2D6 is fairly constant from 1 year of age through adulthood, but the activity of CYP2C19 and CYP3A4 may be increased in children compared to adults (1). In addition, in younger children, hepatic clearance of drugs may be increased, because hepatic blood flow is increased compared with adults.
Variants in the genes encoding the metabolizing enzymes (e.g., CYP2C19 and CYP2D6) influence the enzyme activity, so that patients can be poor metabolizers (with no activity), intermediate metabolizers, normal metabolizers, rapid metabolizers, or ultrarapid metabolizers (1, 2). Dosage recommendations that are based on these metabolizer types are available from the Clinical Pharmacogenetics Implementation Consortium and the Dutch Pharmacogenetics Working Group, and some are included on U.S. Food and Drug Administration (FDA) medication labels. CYP2C19 and CYP2D6 enzyme activity determines the systemic concentration of some SSRIs, which can be normalized with dose adjustments, by using lower doses for patients who are poor metabolizers and higher doses for those who are ultrarapid metabolizers. These differences in P450 activity have been evaluated in pediatric patients with regard to SSRI dosing and suggest that, to normalize exposure, clinicians might consider variation in CYP450 activity (Figure 1). Importantly, variation in SSRI exposure has been linked with differences in tolerability in prospective studies for fluvoxamine (3) and escitalopram (4), as well as for fluoxetine and citalopram (5). Finally, recent studies of combinatorial testing involving multiple pharmacokinetic and pharmacodynamic genes have failed to predict response (6). Thus, the current evidence base for SSRIs and SNRIs suggests that individual genes should be used to adjust medication dosage rather than using combinatorial pharmacogenetic testing for medication selection (2, 7).
FIGURE 1. Pharmacokinetics of escitalopram in adolescentsa,b
a For each CYP2C19 metabolizer phenotype, the dashed line in the violin plots indicates predicted concentration 12 hours after a 20 mg/day dose, with the dotted lines indicating the maximum concentration (CMAX) and the trough concentration (C0).
b Adapted with permission from Strawn et al. Pediatric therapeutic drug monitoring for selective serotonin reuptake inhibitors. Front Pharmacol 2021; 12:749692.
SSRIs
SSRIs in Pediatric Anxiety Disorders
To date, sertraline (8, 9), fluoxetine (10, 11), escitalopram (4), fluvoxamine, and paroxetine (12) have been evaluated for the treatment of anxiety disorders among children and adolescents. Meta-analyses (13, 14) have shown SSRIs to be superior to other medications for pediatric anxiety disorders. However, SSRIs are more likely to lead to discontinuation because of adverse events (AEs) compared with SNRIs, and SSRIs are more likely than SNRIs to produce activation among children and adolescents with anxiety disorders (15).
The largest study of an SSRI for pediatric patients with anxiety disorders, the Child/Adolescent Anxiety Multimodal Study (CAMS) (9), compared sertraline (N=133), cognitive-behavioral therapy (CBT) (N=139), combination therapy (CBT+sertraline) (N=140), and placebo (N=76). CAMS included youths with separation, generalized, and/or social anxiety disorders. More than half of patients receiving sertraline (55%) exhibited improvement, as reflected by Clinical Global Impression-Improvement (CGI-I) scores, compared with 81% of youths receiving CBT+sertraline. This study also provided important data regarding the probability of response, which can help to guide clinicians in terms of when to switch treatment. For example, sertraline-treated youths who did not improve by the eighth week of treatment were unlikely to benefit when treated with sertraline for an additional 4 weeks (16). Thus, this study informs us as to the optimal duration of an SSRI trial.
SSRIs in Pediatric Depressive Disorders
Fluoxetine and escitalopram have demonstrated superiority to placebo among youths with major depressive disorder and are FDA-approved for treating the disorder among youths. Beyond fluoxetine and escitalopram, several other SSRIs have demonstrated efficacy for youths with major depressive disorder.
The Treatment for Adolescents with Depression Study (TADS) represents one of the largest trials to examine SSRIs for adolescents with major depressive disorder (N=439). In this study, patients were randomized to receive fluoxetine monotherapy (10–40 mg/day), CBT monotherapy, CBT+fluoxetine (10–40 mg/day), or placebo. Following 12 weeks of treatment, patients who received CBT+fluoxetine were significantly more improved compared with patients who had received either CBT or fluoxetine monotherapy. Additionally, fluoxetine monotherapy was superior to CBT monotherapy, and all active treatments were superior to placebo.
Whereas TADS was critical to establishing the evidence base for interventions for major depressive disorder among youths, limited guidance was available for clinicians treating patients who did not respond to an initial SSRI, until the completion of the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study. In TORDIA, adolescents (ages 12–18, N=334) with depression that did not respond to an adequate dosage of an SSRI over at least 8 weeks were randomized one of four treatments over 12 weeks (17). Importantly, these patients had, on average, a more chronic course of depression than those enrolled in TADS. In TORDIA, patients could switch to a different SSRI (paroxetine, citalopram, or fluoxetine); a different SSRI+CBT; venlafaxine extended-release (ER); or venlafaxine ER+CBT. CBT+medication switch (to another SSRI or to venlafaxine ER) was associated with a modest decrease in depressive symptoms compared with simply changing medication. The two arms with CBT+medication had higher response rates (55%) than a medication switch alone (41%). In the original analysis, no differences in final outcomes were detected between switching to venlafaxine ER relative to another SSRI, but patients who were switched to a second SSRI had less suicidal ideation than those switched to venlafaxine (18) and had fewer AEs (5). Additionally, when tolerability and efficacy of the SSRIs were considered together, adolescents treated with citalopram and fluoxetine fared better than those treated with paroxetine.
A recent reanalysis (19) of the TORDIA data, with contemporary statistical approaches, found that among patients not receiving CBT, SSRIs produced greater and faster improvement in depressive symptoms compared with venlafaxine ER. However, for patients treated with CBT, SSRIs and venlafaxine ER produced similar improvements in anxiety and depression.
SNRIs
SNRIs in Pediatric Anxiety Disorders
Two studies have evaluated venlafaxine in youths experiencing generalized anxiety disorder (GAD) (20) and social anxiety disorder (21), and duloxetine has been examined in children and adolescents with GAD (22). Additionally, atomoxetine was superior to placebo in reducing anxiety symptoms among pediatric patients with attention-deficit hyperactivity disorder (ADHD) and co-occurring generalized, separation, and/or social anxiety disorders (23). These studies generally suggested benefit compared with placebo. However, as a class, SNRIs produce less improvement and slower improvement than SSRIs (13). This finding is noteworthy given that the only FDA-approved pharmacologic treatment for an anxiety disorder, in children and adolescents, is an SNRI (22), which are generally considered second line.
SNRIs in Pediatric Depressive Disorders
In patients with depression, however, most studies of SNRIs, including desvenlafaxine (24), levomilnacipran, and duloxetine (25), have failed to separate from placebo in randomized controlled trials of youths with depression. Additionally, efficacy and tolerability differences have been demonstrated among youths with SSRI-resistant depression, as discussed earlier. At this time, SNRIs are neither first- nor second-line interventions for youths with depression.
Tolerability of SSRIs and SNRIs Among Pediatric Patients
SSRI and SNRI tolerability relates to their side effect profiles (26) and class-specific side effects. Side effects are not uncommon with SSRIs and SNRIs among youths and represent a significant concern for many practitioners (27). For the general psychiatrist, it is important to consider general tolerability and related proxies (e.g., discontinuation secondary to AEs), activation, and the FDA warning related to suicidal thinking and behavior.
General Tolerability
A recent meta-analysis of 18 trials of pediatric patients with obsessive-compulsive disorder (OCD) and anxiety disorders (N=2,631), who were treated with seven medications (16 SSRI and four SNRI trials), found that, compared with placebo, SSRIs were associated with a greater likelihood of sedation (p=0.002), insomnia (p=0.001), abdominal pain (p=0.005), and headache (p=0.04), as well as activation (p=0.003). Additionally, activation was more common with SSRIs (versus SNRIs, p=0.007). Neither SSRIs nor SNRIs were associated with treatment-emergent suicidality (see below).
Some side effects are difficult to evaluate secondary to variation in antidepressant exposure (i.e., plasma concentrations), overlapping disorder-specific symptoms (e.g., anorexia, increased appetite, anergia and/or fatigue), or developmental changes in pediatric patients. One such example is weight gain. In one naturalistic study (28) of SSRI-treated youths, citalopram and escitalopram were associated with increased body mass index and fat mass index, and weaker associations were observed for fluoxetine, but not for sertraline. However, one recent study (29) has suggested that weight gain related to escitalopram and/or citalopram in children and adolescents is related to CYP2C19 metabolism, with slower metabolizers having greater reported weight gain compared with faster metabolizers. Regarding SNRIs, effects on weight have been mixed, although some studies have suggested decreased weight among patients treated with duloxetine, and this information has now been added to the package labeling on the basis of the registration trial (22) of duloxetine in children and adolescents with GAD.
Discontinuation as a Result of AEs
Several studies (14, 30) suggest that SSRIs are associated with greater likelihood of AE-related discontinuation, compared with placebo, in pediatric anxiety and depressive disorders. Moreover, in anxiety disorders, because of discontinuation due to AEs, SNRIs appear to be more tolerable relative to other classes of medications. Finally, in a large network meta-analysis (31) that compared individual SSRIs and SNRIs for depressive disorders among children and adolescents, fluoxetine was superior to duloxetine in terms of discontinuations caused by AEs, compared with patients receiving placebo.
Activation
Activation represents a hyperarousal event characterized by specific symptoms, including an increase in activity, disinhibition, impulsivity, insomnia, restlessness, hyperactivity, and irritability (32). However, these symptoms frequently co-occur, and this overlap complicates the assessment and measurement of activation. To date, activation appears to be more common with SSRIs compared with SNRIs and is greater for SSRIs compared with placebo. Additionally, studies (3, 4) have suggested that activation is related to pharmacokinetic variables, including exposure and maximal concentrations (CMAX). Given these findings, strategies generally include decreasing the dose of the antidepressant (32); this strategy—in one prospective study (3) and in clinical practice—resolves activation-related AEs in most children treated with SSRIs.
Suicidal Thinking and Behavior
In 2004, an FDA advisory committee reviewed results of a fixed-effects meta-analysis of 24 controlled clinical trials of nine antidepressants, which included approximately 4,400 pediatric patients. The cumulative risk for spontaneously reported suicidal thinking or behavior (often referred to as “suicidality”) was approximately 4% of those receiving medication versus approximately 2% for children and adolescents receiving placebo. As a result, the FDA issued a boxed warning that antidepressant use among children, adolescents, and young adults was accompanied by an increased risk for suicidal thinking and behavior. However, multiple meta-analyses have failed to replicate the original FDA analyses, with the inclusion of nearly two decades of additional data incorporated. That said, the “risk” of suicidality with these medications appears to fluctuate on the basis of the disorder being treated, which likely reflects the underlying intrinsic risk associated with the disorder (e.g., major depressive disorder versus anxiety disorders). Furthermore, there may be differences in this risk among specific SSRIs. To this end, one meta-analysis (14) found differences in suicidality, with sertraline potentially having less treatment-emergent suicidality, whereas paroxetine had higher rates of suicidality compared with placebo. Some SSRIs are differentially associated with both higher and lower rates of suicidality compared to placebo, with class-wise comparisons (e.g., SSRI versus placebo) finding no significant differences, which calls into question the boxed warning as applied to all antidepressants regardless of indication and specific medication (33).
Duration of Pharmacotherapy
Several studies that have examined relapse, as well as open-label continuation and some follow-up studies, have provided partial guidance regarding treatment duration. For children and adolescents with depressive disorders, current data suggest high and sustained remission rates are associated with longer treatment durations (e.g., approximately 9–12 months) (18, 34, 35). One study (36) reported a lower recurrence rate with a 52-week maintenance phase compared with earlier discontinuation; the current data support acute antidepressant treatment for 6–12 months as an initial strategy for depression among pediatric patients.
Among children and adolescents with generalized, separation, and/or social anxiety disorders, the benefits of SSRI treatment—regardless of whether administered with CBT—are robust at 9 months, and open-label extension studies of SSRIs and SNRIs for pediatric patients suggest similar findings at 6–7 months (22, 37).
The current data suggest 12 months of SSRI treatment for youths with depression, whereas for youths with generalized, separation, and social anxiety disorders, 6–9 months of SSRI treatment may be sufficient (38). Many clinicians extend treatment to 12 months on the basis of extrapolations of data from adults with anxiety disorders. Such extended treatment periods may decrease the risk of long-term morbidity and recurrence, and the goal of treatment is ultimately remission, rather than brief duration of antidepressant pharmacotherapy.
Discontinuation of Pharmacotherapy
When antidepressants are to be discontinued, the timing of discontinuation should be considered with regard to the adolescent’s psychosocial milieu. Shamseddeen and colleagues (39) found that adolescents who end treatment during summer vacation were nearly twice as likely to have adequate treatment response. Thus, clinicians should consider planning antidepressant discontinuation during lower stress periods, recognizing the importance of incorporating nondisorder-dependent factors (e.g., school, separation-related events) into the discontinuation strategy. However, clinicians should be reminded that, for the anxious or depressed child, some “low stress periods” for healthy youths (e.g., family vacations, summer camp) may be suffused with stress and anxiety that could be mistakenly attributed to medication discontinuation.
Although the optimal duration of antidepressant treatment for youths with depressive or anxiety disorders remains controversial, the overarching goal of treatment is remission. Any discussion of treatment discontinuation is predicated on the patient having achieved remission of depressive or anxiety symptoms; remission indicates clinical relief is linked to functional recovery (18). If remission is not achieved with acute treatment with either antidepressant monotherapy or antidepressant medication plus psychotherapy, clinicians should consider changing antidepressants. Such a change should not be delayed excessively in hopes of a late response to the initial SSRI (which is unlikely after an 8-week trial) (16). Moreover, a switch in SSRI among nonresponders has been associated with benefit (37, 40). In fact, the results of the TORDIA study (41) remind clinicians that, following a switch in antidepressant, “eventual remission is evident within the first 6 weeks in many, suggesting that earlier intervention among nonresponders could be important” (Figure 2).
FIGURE 2. Reduction in Children’s Depression Rating Scale—Revised scores among patients in the Treatment of Resistant Depression in Adolescents (TORDIA) studya,b
a Possible scores on the Children’s Depression Rating Scale range from 17 to 113, with higher scores indicating more severe depressive symptoms. In general, a score≥40 corresponds with moderate to severe depression.
b Reproduced with permission from Emslie et al. (41).
To date, one study has examined relapse as it relates to SSRI discontinuation among adolescents. In that study (42), relapse occurred more commonly and earlier for patients who discontinued fluoxetine relative to those who continued SSRI treatment. Of clinical importance, most of the relapse occurred within the first 3 months of discontinuing treatment (Figure 3)—despite the long half-life of fluoxetine. This finding has important implications for monitoring of patients when SSRIs are discontinued. Finally, fluoxetine in conjunction with CBT has been shown to reduce risk of relapse in youths with major depressive disorder (42).
FIGURE 3. Time to relapse for youths with depression randomly assigned to continue fluoxetine or switch to placebo following acute fluoxetine treatmenta,b,c
a Relapse was defined as either a one-time score≥40 on the Children’s Depression Rating Scale—Revised (CDRS–R) with worsening (>2 weeks) or clinician determination that “full relapse would be likely without altering treatment.”
b Possible scores on the Children’s Depression Rating Scale range from 17 to 113, with higher scores indicating more severe depressive symptoms. In general, a score≥40 corresponds with moderate to severe depression.
c Reproduced with permission from Emslie et al. (35).
Conclusions
Anxiety and depressive disorders represent the most common psychiatric illnesses affecting children and adolescents. There is a substantial evidence base for psychopharmacologic interventions. However, successful use of psychopharmacologic interventions for pediatric depressive and anxiety disorders requires that clinicians attend to developmental pharmacology and the pharmacokinetic and pharmacodynamic differences between youths and adults. These differences have implications for differences in dosing, response, and tolerability in pediatric patients compared with adults. Taken together, the evidence suggests that SSRIs are the first-line psychopharmacologic intervention for youths with depressive and anxiety disorders, with SNRIs having a more limited role. These medications are generally safe and well tolerated, although emerging data and developmental pharmacologic concepts may help clinicians to choose from available SSRIs more effectively and to improve the efficacy and tolerability of these interventions in youths.
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Published in print: Spring 2022
Published online: 22 April 2022
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The National Institutes of Health had no role in the drafting or writing of the manuscript or in the decision to publish in this journal.
Funding Information
Drs. Strawn and Ramsey were supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD099775). Dr. Strawn has received research support from AbbVie and the National Institutes of Health (National Institute of Child Health and Human Development [NICHD], National Institute of Environmental Health Sciences, National Institute of Mental Health); he has received material support from Myriad Genetics and royalties from the publication of three texts (Springer); he has served as an author for UpToDate, as an associate editor for Current Psychiatry, and has received honoraria from the American Academy of Child and Adolescent Psychiatry, American Academy of Pediatrics, CMEology, and the Neuroscience Education Institute; he reports providing consultation to the Food and Drug Administration and Intracellular Therapeutics. Dr. Ramsey has received research support from NICHD; she has received an educational grant from and has provided consultation to BTG Specialty Pharmaceuticals. Dr. Vaughn reports no financial relationships with commercial interests.
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