Evidence-Based Reviews

Antidepressants for pediatric patients

Current Psychiatry. 2019 September;18(9):26-30,32-36,41-42,42A-42F

References

1. Williams SB, O’Connor EA, Eder M, et al. Screening for child and adolescent depression in primary care settings: a systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2009;123(4):e716-e735. doi: 10.1542/peds.2008-2415.
2. Kessler RC, Avenevoli S, Ries Merikangas K. Mood disorders in children and adolescents: an epidemiologic perspective. Biol Psychiatry. 2001;49(12):1002-1014.
3. Lewinsohn PM, Clarke GN, Seeley JR, et al. Major depression in community adolescents: age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry. 1994;33(6):809-818.
4. Weissman MM, Wolk S, Goldstein RB, et al. Depressed adolescents grown up. JAMA.1999;281(18):1707-1713.
5. Fergusson DM, Woodward LJ. Mental health, educational, and social role outcomes of adolescents with depression. Arch Gen Psychiatry. 2002;59(3):225-231.
6. Keenan-Miller D, Hammen CL, Brennan PA. Health outcomes related to early adolescent depression. J Adolesc Health. 2007; 41(3): 256-62.
7. Shaffer D, Gould MS, Fisher P, et al. Psychiatric diagnosis in child and adolescent suicide. Arch Gen Psychiatry. 1996;53(4):339-348.
8. Centers for Disease Control and Prevention. National Vital Statistics System. Deaths, percent of total deaths, and death rates for the 15 leading causes of death in 5-year age groups, by race and sex: United States, 1999-2015. https://www.cdc.gov/nchs/nvss/mortality/lcwk1.htm. Published October 23, 2017. Accessed May 2, 2019.
9. Merikangas KR, He JP, Burstein M, et al. Lifetime prevalence of mental disorders in US adolescents: results from the National Comorbidity Survey Replication-Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49(10):980-989.
10. Wittchen HU, Nelson CB, Lachner G. Prevalence of mental disorders and psychosocial impairments in adolescents and young adults. Psychol Med. 1998;28(1):109-126.
11. Foley DL, Goldston DB, Costello EJ, et al. Proximal psychiatric risk factors for suicidality in youth: the Great Smoky Mountains Study. Arch Gen Psychiatry. 2006;63(9):1017-1024.
12. Cheung A, Sacks D, Dewa CS, et al. Pediatric prescribing practices and the FDA black-box warning on antidepressants. J Dev Behav Pediatr. 2008 29(3):213-215.
13. Walkup JT. Antidepressant efficacy for depression in children and adolescents: industry- and NIMH-funded studies. Am J Psychiatry. 2017;174(5):430-437.
14. Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173(2):174-183.
15. Varigonda AL, Jakubovski E, Taylor MJ, et al. Systematic review and meta-analysis: early treatment responses of selective serotonin reuptake inhibitors in pediatric major depressive disorder. J Am Acad Child Adolesc Psychiatry. 2015;54(7):557-564.
16. Strawn JR, Welge JA, Wehry AM, et al. Efficacy and tolerability of antidepressants in pediatric anxiety disorders: a systematic review and meta-analysis. Depress Anxiety. 2015;32(3):149-157.
17. March JS, Biederman J, Wolkow R, et al. Sertraline in children and adolescents with obsessive-compulsive disorder: a multicenter randomized controlled trial. JAMA. 1998;280(20):1752-1756.
18. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753-2766.
19. Kennard BD, Silva SG, Tonev S, et al. Remission and recovery in the Treatment for Adolescents with Depression Study (TADS): acute and long-term outcomes. J Am Acad Child Adolesc Psychiatry. 2009;48(2):186-195.
20. Cipriani A, Zhou X, Del Giovane C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet. 2016;388(10047):881-890.
21. Cohen JA, Mannarino AP, Perel JM, et al. A pilot randomized controlled trial of combined trauma-focused CBT and sertraline for childhood PTSD symptoms. J Am Acad Child Adolesc Psychiatry. 2007;46(7):811-819.
22. Robb AS, Cueva JE, Sporn J, et al. Sertraline treatment of children and adolescents with posttraumatic stress disorder: a double-blind, placebo-controlled trial. J Child Adolesc Psychopharmacol. 2010;20(6):463-471.
23. Diehle J, Opmeer BC, Boer F, et al. Trauma-focused cognitive behavioral therapy or eye movement desensitization and reprocessing: what works in children with posttraumatic stress symptoms? A randomized controlled trial. Eur Child Adolesc Psychiatry. 2015;24(2):227-236.
24. Aiyer R, Barkin RL, Bhatia A. Treatment of neuropathic pain with venlafaxine: a systematic review. Pain Med. 2017;18(10):1999-2012.
25. Barrickman LL, Perry PJ, Allen AJ, et al. Bupropion versus methylphenidate in the treatment of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1995;34(5):649-657.
26. Monuteaux MC, Spencer TJ, Faraone SV, et al. A randomized, placebo-controlled clinical trial of bupropion for the prevention of smoking in children and adolescents with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2007;68(7):1094-1101.
27. Biederman J, Baldessarini RJ, Wright V, et al. A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy. J Am Acad Child Adolesc Psychiatry. 1989;28(5):777-784.
28. Spencer T, Biederman J, Coffey B, et al. A double-blind comparison of desipramine and placebo in children and adolescents with chronic tic disorder and comorbid attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2002;59(7):649-656.
29. DeVeaugh-Geiss J, Moroz G, Biederman J, et al. Clomipramine hydrochloride in childhood and adolescent obsessive-compulsive disorder--a multicenter trial. J Am Acad Child Adolesc Psychiatry. 1992;31(1):45-49.
30. Caldwell PH, Sureshkumar P, Wong WC. Tricyclic and related drugs for nocturnal enuresis in children. Cochrane Database Syst Rev. 2016;(1):CD002117.
31. Varigonda AL, Jakubovski E, Bloch MH. Systematic review and meta-analysis: early treatment responses of selective serotonin reuptake inhibitors and clomipramine in pediatric obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 2016;55(10):851-859.e2. doi: 10.1016/j.jaac.2016.07.768.
32. Walkup J, Labellarte M. Complications of SSRI treatment. J Child Adolesc Psychopharmacol. 2001;11(1):1-4.
33. Leo RJ, Lichter DG, Hershey LA. Parkinsonism associated with fluoxetine and cimetidine: a case report. J Geriatr Psychiatry Neurol. 1995;8(4):231-233.
34. Strawn JR, Prakash A, Zhang Q, et al. A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2015;54(4):283-293.
35. Bernstein GA, Borchardt CM, Perwien AR, et al. Imipramine plus cognitive-behavioral therapy in the treatment of school refusal. J Am Acad Child Adolesc Psychiatry. 2000;39(3): 276-283.
36. Safer DJ, Zito JM. Treatment-emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents. J Child Adolesc Psychopharmacol. 2006;16(1-2):159-169.
37. Reinblatt SP, DosReis S, Walkup JT, et al. Activation adverse events induced by the selective serotonin reuptake inhibitor fluvoxamine in children and adolescents. J Child Adolesc Psychopharmacol. 2009;19(2):119-126.
38. Goldsmith M, Singh M, Chang K. Antidepressants and psychostimulants in pediatric populations: is there an association with mania? Paediatr Drugs. 2011;13(4): 225-243.
39. Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 2011;72(2):156-167.
40. Allain N, Leven C, Falissard B, et al. Manic switches induced by antidepressants: an umbrella review comparing randomized controlled trials and observational studies. Acta Psychiatr Scand. 2017;135(2):106-116.
41. McClellan J, Kowatch R, Findling RL. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(1):107-125.
42. Dobry Y, Rice T, Sher L. Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors. Int J Adolesc Med Health. 2013; 25(3):193-199.
43. Schwartz AR, Pizon AF, Brooks DE. Dextromethorphan-induced serotonin syndrome. Clin Toxicol (Phila). 2008;46(8):771-773.
44. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry. 2007;164(9):1356-1363.
45. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339.
46. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007;297(15):1683-1696.
47. Sharma T, Guski LS, Freund N, et al. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ. 2016;352: i65. doi: https://doi.org/10.1136/bmj.i65.
48. Olfson M, Shaffer D, Marcus SC, et al. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry. 2003;60(10):978-982.
49. Garland JE, Kutcher S, Virani A, et al. Update on the Use of SSRIs and SNRIs with children and adolescents in clinical practice. J Can Acad Child Adolesc Psychiatry. 2016;25(1):4-10.
50. Bridge JA, Barbe RP, Birmaher B, et al. Emergent suicidality in a clinical psychotherapy trial for adolescent depression. Am J Psychiatry. 2005;162(11):2173-2175.
51. Birmaher B, Brent D, Bernet W, et al. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503-1526.
52. Ravizza L, Maina G, Bogetto F, et al. Long term treatment of obsessive-compulsive disorder. CNS Drugs. 1998;10(4):247-255.
53. Hosenbocus S, Chahal R. SSRIs and SNRIs: a review of the discontinuation syndrome in children and adolescents. J Can Acad Child Adolesc Psychiatry. 2011;20(1):60-67.
54. Bloch MH, McGuire J, Landeros-Weisenberger A, et al. Meta-analysis of the dose-response relationship of SSRI in obsessive-compulsive disorder. Mol Psychiatry. 2010;15(8):850-855.
55. Issari Y, Jakubovski E, Bartley CA, et al. Early onset of response with selective serotonin reuptake inhibitors in obsessive-compulsive disorder: a meta-analysis. J Clin Psychiatry. 2016; 77(5):e605-e611. doi: 10.4088/JCP.14r09758.
56. Brent D, Emslie G, Clarke G, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA. 2008;299(8):901-913.

Box 1

Interventional treatments

Continuing severe depression is associated with reduced educational attainment and quality of life, as well as increased risk of substance abuse and suicide,^1,2 which is the second leading cause of death in individuals age 10 to 24 years.³ Given the substantial morbidity and mortality associated with adolescent depression, interventional psychiatry treatments are under-researched and underutilized in pediatric patients. Interventional antidepressants in adults include electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and, most recently, ketamine.

Electroconvulsive therapy is the most effective therapy available for depression in adults, alleviating depressive symptoms in treatment-refractory patients and outperforming both pharmacotherapy⁴ and rTMS.⁵ Despite its track record of effectiveness and safety in adults, ECT continues to suffer considerable stigma.⁴ Cognitive adverse effects and memory problems in adults are generally self-limited, and some aspects of cognition actually improve after ECT as depression lifts.⁶ The combination of stigma and the concern about possible cognitive adverse effects during periods of brain development have likely impeded the rigorous testing of ECT in treatment-refractory pediatric patients. Several case series and other retrospective analyses suggest, however, that ECT has strong efficacy and limited adverse effects in adolescents who have severe depression or psychotic symptoms.^7-9 Despite these positive preliminary data in pediatric patients, and a large body of literature in adults, no controlled trials of ECT have been conducted in the pediatric population, and it remains a rarely used treatment in severe pediatric mental illness.

Repetitive transcranial magnetic stimulation is a technique in which magnetic stimulation is used to activate the left dorsolateral prefrontal cortex (DLPFC), a target thought to be important in the pathophysiology of MDD. Repetitive transcranial magnetic stimulation is FDAapproved to treat medication-refractory major depressive disorder (MDD) in adults, and has been shown to be effective as both a monotherapy¹⁰ and an adjunctive treatment.¹¹ The estimated number needed to treat (NNT) for rTMS ranges from 6 to 8, which is quite effective, although less so than ECT (and probably initial pharmacotherapy).⁵ Similar to ECT, however, there are no large randomized controlled trials (RCTs) in children or adolescents. Pilot RCTs¹² and open trials¹³ suggest that DLPFC rTMS may be effective as an adjunctive treatment, speeding or augmenting response to a selective serotonin reuptake inhibitor in adolescents with MDD. Larger trials studying rTMS in pediatric patients are needed. While rTMS is generally well tolerated, disadvantages include the time-consuming schedule (the initial treatment is typically 5 days/week for several weeks) and local adverse effects of headache and scalp pain.

Ketamine, which traditionally is used as a dissociative anesthetic, is a rapidly emerging novel treatment in adult treatment-refractory MDD. It acts quickly (within hours to days) and cause significant improvement in difficult symptoms such as anhedonia¹⁴ and suicidal ideation.¹⁵ In adult studies, ketamine has a robust average effect size of >1.2, and an NNT ranging from 3 to 5 in medication-refractory patients.^16,17 Ketamine is a glutamatergic modulator, acting outside of the monoamine neurochemical systems traditionally targeted by standard antidepressants.¹⁶ The efficacy of ketamine in treatment-refractory adults is impressive, but the effects of a single treatment are ephemeral, dissipating within 1 to 2 weeks, which has led to significant discussion surrounding optimal dosing strategies.¹⁶ Although small RCTs in pediatric patients are currently underway, at this time, the only evidence for ketamine for pediatric MDD is based on case series/report data^18,19 which was positive.

For all of these interventional modalities, it is critical to refer children with treatmentrefractory disorders to interventionists who have appropriate experience and monitoring capabilities.

References
1. Weissman MM, Wolk S, Goldstein RB, et al. Depressed adolescents grown up. JAMA.1999;281(18):1707-1713.
2. Fergusson DM, Woodward LJ. Mental health, educational, and social role outcomes of adolescents with depression. Arch Gen Psychiatry. 2002;59(3):225-231.
3. Centers for Disease Control and Prevention. National Vital Statistics System. Deaths, percent of total deaths, and death rates for the 15 leading causes of death in 5-year age groups, by race and sex: United States, 1999-2015. Centers for Disease Control and Prevention. https://www.cdc.gov/nchs/nvss/mortality/lcwk1.htm. Published October 23, 2017. Accessed May 2, 2019.
4. UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and metaanalysis. Lancet. 2003;361(9360):799-808.
5. Berlim MT, Van den Eynde F, Daskalakis ZJ. Efficacy and acceptability of high frequency repetitive transcranial magnetic stimulation (rTMS) versus electroconvulsive therapy (ECT) for major depression: a systematic review and meta-analysis of randomized trials. Depress Anxiety. 2013;30(7):614-623.
6. Semkovska M, McLoughlin DM. Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis. Biol Psychiatry. 2010;68(6):568-577.
7. Jacob P, Gogi PK, Srinath S, et al. Review of electroconvulsive therapy practice from a tertiary child and adolescent psychiatry centre. Asian J Psychiatr. 2014;12(1):95-99.
8. Zhand N, Courtney DB, Flament MF. Use of electroconvulsive therapy in adolescents with treatment-resistant depressive disorders: a case series. J ECT. 2015;31(4):238-245.
9. Puffer CC, Wall CA, Huxsahl JE, et al. A 20 year practice review of electroconvulsive therapy for adolescents. J Child Adolesc Psychopharmacol. 2016;26(7):632-636.
10. Berlim MT, van den Eynde F, Tovar-Perdomo S, et al. Response, remission and drop-out rates following high-frequency repetitive transcranial magnetic stimulation (rTMS) for treating major depression: a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials. Psychol Med. 2014;44(2):225-239.
11. Liu B, Zhang Y, Zhang L, et al. Repetitive transcranial magnetic stimulation as an augmentative strategy for treatment-resistant depression, a meta-analysis of randomized, double-blind and sham-controlled study. BMC Psychiatry. 2014;14:342.
12. Huang ML, Luo BY, Hu JB, et al. Repetitive transcranial magnetic stimulation in combination with citalopram in young patients with first-episode major depressive disorder: a double-blind, randomized, sham-controlled trial. Aust N Z J Psychiatry. 2012;46(3):257-264.
13. Wall CA, Croarkin PE, Sim LA, et al. Adjunctive use of repetitive transcranial magnetic stimulation in depressed adolescents: a prospective, open pilot study. J Clin Psychiatry. 2011;72(9):1263-1269.
14. Lally N, Nugent AC, Luckenbaugh DA, et al. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. 2014;4:e469. doi: 10.1038/tp.2014.105.
15. Ballard ED, Ionescu DF, Vande Voort JL, et al. Improvement in suicidal ideation after ketamine infusion: relationship to reductions in depression and anxiety. J Psychiatr Res. 2014;58:161-166.
16. Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172(10):950-966.
17. McGirr A, Berlim MT, Bond DJ, et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015;45(4):693-704.
18. Dwyer JB, Beyer C, Wilkinson ST, et al. Ketamine as a treatment for adolescent depression: a case report. J Am Acad Child Adolesc Psychiatry. 2017;56(4):352-354.
19. Cullen KR, Amatya P, Roback MG, et al. Intravenous ketamine for adolescents with treatment-resistant depression: an open-label study. J Child Adolesc Psychopharmacol. 2018;28(7):437-444.

Box 2

Talking to families when starting antidepressants for pediatric patients

Efficacy

Selective serotonin reuptake inhibitors are the most effective pharmacologic treatment we have for pediatric depression, OCD, and anxiety
More than one-half of children who are prescribed SSRIs have a significant improvement, regardless of condition
Based on current estimates, we need to treat 4 to 6 children with an SSRI to find one that will improve who would not improve with placebo
The clinical benefits of SSRIs generally take a while to accrue; therefore, it is advisable to take the medication for at least 2 to 3 months before concluding that it is ineffective
In addition to medication, evidence-based psychotherapies provide significant benefit for pediatric depression, OCD, and anxiety

Tolerability

Most commonly prescribed pediatric antidepressants have been used safely in children for 2 to 3 decades. The safety profiles of SSRIs are among the best of any medications used for children and adolescents
While many children get better when taking these medications, it’s important that we also talk about potential adverse effects. Some children will experience sleep problems (either sleepier than usual or difficulty sleeping), changes in energy levels, headache, gastrointestinal upset, and dry mouth. These are most likely at the beginning of treatment, or when we increase the dose; they usually are time-limited and go away on their own
Often adverse effects occur first and the benefits come later. Because it may take at least a few weeks to start to see the mood/anxiety benefits, it’s important for us to talk about any adverse effects your child experiences and remember that they usually are short-lived

Suicidality

The FDA placed a “black-box” warning on antidepressants after pediatric studies found a small but statistically significant increased risk of reporting suicidal thoughts or behaviors over the short-term compared with placebo
The increased risk of spontaneously reporting suicidal ideation was quite small. Studies suggested that one would need to treat 100 to 140 children to see 1 child report suicidal ideation compared to placebo. Suicidal ideation is a common symptom in children with depression and anxiety
Studies found no increased risk when suicidal ideation was systematically assessed using structured rating scales
In the studies evaluated, there were no completed suicides by patients taking medication or placebo
Population studies show that higher rates of antidepressant prescriptions are associated with lower rates of attempted and completed teen suicide, which underscores that in general, these medicines treat the underlying causes of suicidality
No scientific consensus exists on whether these medications are truly associated with an increased risk of new-onset suicidal ideation, or if this association is due to other factors (eg, improvement in anxiety and depressive symptoms that make patients more comfortable to report suicidal ideation spontaneously)
Regardless, the FDA recommends frequent monitoring of children for suicidal thoughts when these medications are started. This should be done anyway in children experiencing depression and anxiety, and it’s why we will plan to have more frequent appointments as the medication is initiated

OCD: obsessive-compulsive disorder; SSRIs: selective serotonin reuptake inhibitors

References

Mindfulness-based relapse prevention tied to lower anxiety, depression

Antidepressants for pediatric patients

References

Pages

Next Article: