As pediatricians, we are acutely aware of the increase in depression in our teen patients. Lifetime prevalence is now approaching 20%, and we are doing our best to help.
Dr. Barbara J. Howard
The Guidelines for Adolescent Depression in Primary Care (GLAD-PC, 2018) has advice on screening and primary care provider (PCP) management, verifying our role in care. But GLAD-PC also advises “referral to a mental health specialist” in patient scenarios we see multiple times per week. Even when patients are willing and able to go, mental health specialists are in short supply or have months-long waiting lists. What should we do to help the more severely depressed adolescent when immediate referral is not possible? What should we expect of specialist care for what is called treatment-resistant or treatment-refractory depression (TRD)?
To know what to do for a youth with TRD, first you need to know what constitutes an adequate trial of treatment. After diagnosis of major depressive disorder (MDD) from a validated screening tool or an interview based on DSM-5 criteria and an appropriate assessment (as described in GLAD-PC), patients and parents need education on symptoms, course, prognosis including suicide risk, and treatment options. Known TRD risk factors, besides longer or greater depression severity, anhedonia, and poor global functioning, can benefit from being specifically addressed: trauma, bullying, comorbid anxiety or substance use, subsyndromal mania, insomnia, hypothyroidism, nutritional deficiencies from eating disorders, certain genetic variants, LGBTQ identification, family conflict, and parental depression. Screening and assessment for suicidal ideation/attempts is needed initially and in follow-up as MDD increases risk of suicide 30 times.
PCPs can manage mild depression with regular visits every 1-2 weeks for active support for 6-8 weeks. Advise all depressed youth on healthy eating, adequate sleep and exercise, pleasurable activities, and refraining from substance use. With a full response (50%+ reduction in symptom score from baseline), monthly monitoring for symptoms, suicidality, and stressors (phone/televisits suffice) should continue for 6-24 months as half recur. Monitoring with ratings by both youth and parent are recommended and may be required by insurers. Scores below cutoff suggest “remission,” although functioning must be considered. Youth report symptoms best but parents may better report improved functioning and affect that can precede symptom reduction.
If there is no initial response (< 25% decrease in symptom score) or a partial response (25%-49% decrease), PCPs should begin treatment as for moderate depression with either a selective serotonin reuptake inhibitor (SSRI) or psychotherapy. Use of both has the best evidence; cognitive behavior therapy (CBT) and interpersonal psychotherapy for adolescents are equally effective.
Side effects from SSRIs are almost universal with GI upset, headaches, and sexual dysfunction most common, but activation (increased agitation or irritability) may occur. Educate patients about these and encourage tolerating them as they tend to subside in weeks, allowing continuation of these most effective medicines. Activation rarely indicates true mania, which would require stopping and referral.
Moderate depression with only comorbid anxiety may be addressed by PCPs with problem-focused supportive counseling and SSRIs, but mental health consultation or referral also are appropriate. Fluoxetine starting at 5-10 mg/day has best evidence and Food and Drug Administration approval for MDD from age 8. Starting at a higher dose may increase risk of suicidal ideation. Alternatively, escitalopram is FDA approved for MDD at age 12 starting at 10 mg/day, although meta-analyses do not distinguish effectiveness within the SSRI class. Although benefit usually appears within 2 weeks, a trial of at least 4 weeks should be used to assess effect.
If after 4 weeks, the SSRI is tolerated but has little or no response, reassess the diagnosis, try a different SSRI, e.g. sertraline, and add CBT (combined SSRI+CBT has an advantage). To switch SSRIs, reduce the first every 1-2 weeks (by 10-20 mg for fluoxetine; 5-10 for escitalopram) to reduce side effects. If overlapping, the replacement SSRI may start midway in the wean at low dose with patients educated about serotonin syndrome. If instead there was a partial response to the initial SSRI, progressively increase the dose (by 10 mg for fluoxetine or 5 mg for escitalopram monthly) as indicated by symptom change up to the maximum (60-80 mg fluoxetine or 20 mg escitalopram), if needed, and maintain for another 4 weeks. Alternatively, or in addition, start psychotherapy or ask to change current therapy, as therapy focus makes a difference in effect. Initial CBT focus on anxiety acts fastest when anxiety is comorbid.
Once a regimen produces a response, maintain it for 16-20 weeks, the longer for more severe depression. Although three-fourths of mildly to moderately depressed youth are late responders, emerging near 6 weeks, a rapid initial response is associated with better outcome. The recommended 8 weeks on a final tolerated dose constituting an adequate trial before changing may be shortened to 6 weeks in severe unremitting cases. Youth not remitting by 12 weeks should be offered alternative treatment. Referral is recommended for moderately severe depression with comorbidity or severe depression but also for unresponsive moderate depression or by family or clinician preference.
Treatment-resistant depression is defined as “clinically impairing depression symptoms despite an adequate trial of an evidence-based psychotherapy and an antidepressant with grade A evidence (fluoxetine, escitalopram, or sertraline),” sequentially or together; treatment-refractory depression comprises the above with failure on at least two antidepressants, with at least one being grade A. Unfortunately, TRD occurs in 30%-40% of children and remission is only 30%. Low adherence based on pill counts (> 30% missed) or with therapy (fewer than nine visits) should be considered in treatment failures.
With manageable factors addressed, the next step for TRD is treatment augmentation. The best evidence-based augmentation for TRD is CBT; 55% of those receiving CBT responded within 12 weeks. TRD augmentations and interventions with evidence in adults have either no evidence of effect in children (SNRIs, lithium), no randomized controlled trials, or support only from small suggestive studies, e.g., antipsychotics, 16 g/day omega-3 fatty acid supplementation, folic acid supplementation, repetitive transcranial magnetic stimulation, electroconvulsive therapy, or ketamine. Prompt referral to a child psychiatrist is essential for youth classified as TRD as earlier more aggressive treatment may avoid the long-term morbidity of chronic depression.
Fortunately, a meta-analysis of studies showed that PCP medication management visits with monitoring could improve outcomes, even for TRD.
Dr. Howard is assistant professor of pediatrics at Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She had no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to MDedge News. E-mail her at pdnews@mdedge.com.
Reference
Dwyer J et al. Annual research review: Defining and treating pediatric treatment-resistant depression. J Child Psychol Psychiatry. 2020 March;61(3):312-32.