Treatment-Resistant Juvenile Depression—A Quicksand?

Abstract

Though research in juvenile depression is advancing, evidence examining effective treatments for Treatment-resistant juvenile depression remains at large limited. There is a dire need for more studies to help guide clinicians navigating these challenging cases.

Major Depressive disorder (MDD) is common in youth with lifetime prevalence in adolescence similar to adults.¹ It is tied to significant psychosocial morbidity including academic failure, unemployment, pregnancy and heightened suicidality.

Of those diagnosed with MDD, circa 40% will not respond to initial treatment. Even in responders, recurrence is very commonplace.

To start with, there is no consensus on an operational definition for treatment-resistant juvenile depression (TRJD). This is particularly problematic for clinicians trying to clinically appraise evidence-base and inform treatment decisions for their child/adolescent population (CAP) patients.

Four definitions were proposed in literature. A systematic review by Boyaln² et al—failure to respond to 2 evidence-based adequate trials of SSRIs AND psychotherapy. In TORDIA (Treatment Of Resistant Depression In Adolescents) trial—failure to respond to 8-week trial of an SSRI. Cullen³ et al. in an open-label trial of ketamine in adolescents with TRD—failure to respond to 2 antidepressants. Dwyer⁴ et al. in a research review—failure to respond to one evidence-based antidepressant OR psychotherapy (either in 2 separate trials or combined). Two failed trials of evidence-based antidepressants AND psychotherapy is designated Treatment-Refractory Depression.

Three antidepressants are (US) FDA approved for MDD in CAP population- viz. fluoxetine (8 ys), escitalopram (12 ys), and, (historically) doxepin (12 ys). All carry a black-box warning of suicidality in CAP population.⁵

Using evidence-based treatment in the acute management of depression in CAP population may lower the risk of development of TRJD.

Based on consensus guidelines and evidence-base, SSRIs are recommended first-line. Early response is a predictor of positive outcomes and long-term recovery.

If trial is not effective, possible diagnostic, medical, or psychosocial contributing factors need to be ruled out/in. Revisiting diagnosis (e.g., bipolar depression), ensuring compliance, parsing out comorbidities (psychiatric, substance use, medical), and digging for psychosocial adversities (bullying, abuse, parental mental illness, etc) are all important considerations in workup of TRJD. AACAP does not endorse routine pharmacogenetic testing for TRJD at time of writing this report.

Next, a switch to another evidence-based SSRI is advised. This can bring about a response rate of 50%. Of note, placebo response is quite high in CAP population up to 50%. Adding psychotherapy is recommended based on TORDIA trial. A literature review by Weersing⁶ et al. showed CBT as possibly efficacious for children with depression and CBT/IPT-A as well-established effective treatments in adolescents with depression.

Literature on augmentative or combinatorial strategies for TRJD is scant.

A case series examined the efficacy of quetiapine augmentation (median dose of 200 mg/d) showed a 70% response rate.⁷ This approach is fraught by vulnerability of CAP to AAP-related metabolic syndrome.⁸

A recent randomized sham-controlled trial of TMS in 103 adolescents (aged 12–21) with TRJD, demonstrated no significant difference between the two groups primary outcome measure- change in Hamilton Depression Rating Scale from baseline to endpoint.⁹

A retrospective chart review examining the efficacy of ECT in 54 adolescents with TR mood disorders (including unipolar and bipolar depression), showed a response rate of 55.8% with a mean number of treatments of 13.7.¹⁰ Prolonged seizures were common, and long-term side effects were memory loss limited to time around ECT treatment.

An open-label study examined the efficacy of IV ketamine in 13 adolescents (aged 12–18 ys) receiving 6 infusions (0.5 mg/kg) over 2 weeks³ Response was seen in 5. Though sounds potential, recommending ketamine for TRJD with limited safety and efficacy data in CAP population sounds premature at this point of time.

Adjunctive L-methylfolate for TRJD in 10 adolescents showed an improvement in depression, anxiety and irritability in 80%.¹¹ Dose ranged from 2–15 mg/d. It was well tolerated. Of note, 80% of cases had a single mutation in 2 MTHFR gene variants.

Of complementary alternative treatments, omega-3 fatty acids, albeit well tolerated have mixed results.¹² Interestingly, Vit C (1000 mg/d) adjuventia to fluoxetine (10–20 mg/d) outperformed fluoxetine+ placebo with no tolerability issues.¹³ Studies examining add-on Vit D and Zinc were negative.

Though research in juvenile depression is advancing, evidence examining effective treatments for TRJD remains at large limited. There is a dire need for more studies to help guide clinicians navigating these challenging cases.