Treatment-resistant depression in children and adolescents

Introduction

Treatment-resistant depression in children and adolescents is defined as clinically significant depression that has not responded to treatment with a selective serotonin reuptake (SSRI) for at least 8 weeks by the TORDIA (Treatment of SSRI-Resistant Depression in Adolescents) trial ( ). define treatment-resistant depression in youth as clinically significant depression that fails to respond to an adequate treatment trial of one evidence-based antidepressant or one adequate psychotherapy trial, either in two separate treatment trials or used in combination. They further define treatment-refractory depression as two failed trials of evidence-based antidepressant treatment and a failed adequate psychotherapy trial. A ketamine study in adolescents defined treatment-resistant depression as a failure to respond to at least two antidepressant medications ( ). Based on a systematic review of interventions for treatment-resistant depression in adolescents, proposed that treatment-resistant depression be defined as failure to respond to two evidence based trials of SSRI antidepressants of adequate dose and duration in combination with psychotherapy. The lack of a consistent definition for treatment-resistant depression in children and adolescents is problematic and can be confusing for clinicians trying to critically appraise the evidence and find appropriate treatments for their patients.

Depression in youth

A diagnosis of major depressive disorder in children and adolescents is made using the same Diagnostic and Statistical Manual, 5th edition (DSM 5) diagnostic criteria for adults, with the exception of irritability as a possible mood state in children and teens, even in the absence of depressed mood ( ). The lifetime prevalence of depression in adolescents has been reported to be approximately 12% ( ). National Survey on Drug Use and Health data has shown an increase in the prevalence of major depressive disorder from 8.1% to 13.2% among adolescents aged 12–17 years, from the year 2005 to the year 2017 ( ). This represents an increase of 52% in the prevalence of major depressive disorder in adolescents over the course of 12 years. Of the children and adolescents diagnosed with major depressive disorder, about 40% will not respond to initial treatment ( ).

Even in youth who do respond to the first treatments used, recurrence of depressive symptoms is also a significant problem. In a study examining long term outcomes of 140 adolescents with depression receiving treatment with therapy and/or medication, 93% of youth experienced full remission from their initial depressive episode, but most went on to experience recurrence of depression (53%) and development of a nonmood disorder (79%). Only 15% were reported as having no subsequent depressive episodes or nonmood disorders at follow-up (mean 6 years) ( ).

Depression in adolescence has been shown to be associated with significant psychosocial morbidity, including failure to finish school, unemployment, and pregnancy/parenthood in a metaanalysis of long-term outcome studies ( ). Suicide is a greater risk in patients who experience symptoms of depression prior to adulthood, and about 50% of depressed adults experience symptom onset before the age of 18 ( ). Suicide is now the second leading cause of death in individuals aged 10–34 years ( ). Research examining the association of suicidality in youth with treatment-resistant depression shows that youth with reduced right superior temporal gyrus volume may have a greater risk of suicide attempts, suggesting a possible biological marker to help assess risk in this population ( ).

More severe illness and the presence of suicidality are associated with poor response to treatment in children and adolescents with depression. Children with comorbid psychiatric disorders, increased levels of hopelessness, and increased family stress also have a higher risk of poor treatment response. Children with better global functioning prior to treatment may respond better to treatment, as well as children with depressive episodes that are shorter in duration ( ). Early treatment response has been shown to be a predictor of positive outcomes in pediatric depression and may also predict long-term response and recovery. In a metaanalysis of randomized placebo-controlled studies in children and adolescents, the greatest benefits of SSRIs occurred early in treatment and were minimal after 4 weeks ( ). The Treatment of Adolescents with Depression (TADS) study showed that early responders at 12 weeks of treatment were more likely to achieve full recovery at 3-year follow-up ( ).

Treatment-resistant depression studies

The TORDIA trial examined the efficacy of SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), and cognitive behavior therapy (CBT) in the treatment of pediatric SSRI treatment-resistant depression ( ). The study included 334 patients aged 12–18 years with treatment-resistant depression, defined as no response to at least 8 weeks of treatment with an SSRI at a dosage of at least 40 mg of fluoxetine or its equivalent. The participants were randomized to receive one of four different treatments for the course of the 12-week study. The four treatment groups included switching to a different SSRI, switching to a different SSRI plus CBT, switching to venlafaxine, or switching to venlafaxine plus CBT. Response was defined as a Clinical Global Impression-Improvement score (CGI-I) ≥ 2 ( ) and a reduction in the Children’s Depression Rating Scale-Revised (CDRS-R) ( ) score of at least 50% from baseline. Switching to either medication and adding CBT produced the highest response rate (54.8%). The response rate in the SSRI group (47%) did not differ significantly from the venlafaxine group (48.2%), but more adverse effects were observed in the venlafaxine group. Increased diastolic blood pressure and pulse and skin problems were observed at a significantly higher rate when compared to the SSRI group. Switching to a second SSRI and adding CBT is recommended in youth who have failed their first antidepressant trial, as SSRIs may have fewer adverse effects.

The TORDIA trial showed that remission at week 24 was associated with early response ( ). When comparing the participants who were in remission at 24 weeks with those who were not, the remitted group had significantly less severe symptoms by week 6 of the study. Early response to treatment may be predictive of remission at a much earlier stage than the recommended acute treatment duration of 12 weeks. An analysis of the TORDIA data using a Bayesian hierarchical model showed that switching to an SSRI vs venlafaxine produced a greater response and quicker time to response ( ). When examining these results in youth with significant comorbid anxiety, however, venlafaxine performed as well as the SSRIs, suggesting clinicians may consider switching to an SNRI earlier in treatment after a failed response to an initial SSRI in children with treatment-resistant depression and comorbid anxiety.

Long-term follow-up in the TORDIA trial showed that by 72 weeks, about 61% of the participants had achieved remission, with no difference between treatment groups in remission rate or time to remission ( ). Certain factors were associated with a lower chance of remitting, including substance use, severity of depression, and more impairment in functioning at baseline. Anhedonia was shown to be a predictor of poor recovery with SSRIs, with longer time to remission and fewer depression-free days when compared to other depressive symptoms ( ). Treatment nonadherence was found to be a common cause of treatment nonresponse ( ). A history of nonsuicidal self-injury and hopelessness were significant predictors for suicide attempts throughout the study ( ). Venlafaxine was associated with more treatment-emergent suicidality when compared to the SSRI group, a finding which further strengthened the recommendation to try a second SSRI prior to switching to an SNRI ( ).

Substance use was fairly common in the TORDIA trial, with about 28% of participants reporting repeated substance use (between three and nine times in the previous month), and youth who had lower substance use at baseline or who decreased their substance use during the study showed better response to treatment during the study ( ). Parent conflict was an important factor in response to treatment in the TORDIA trial ( ). Higher parent-reported conflict predicted lower rates of remission, though there was no effect seen on treatment response. Youth who received more than nine CBT sessions had a higher rate of response than those who had nine or less sessions, emphasizing the importance of an adequate number of sessions for treatment-resistant depression in youth ( ). Overall, the TORDIA trial showed a response rate of about 50% when switching to a second SSRI. With approximately 40% of depressed youth not responding to initial treatment (from acute depression treatment studies), this means that approximately 20% of depressed youth (half of initial nonresponders) will not respond to the first two treatments tried. There is inadequate evidence guiding clinicians in treatment decisions for these remaining youth.

Augmentation of antidepressants with antipsychotic medications has shown some benefit in adult depression studies, but there is currently very little evidence examining their efficacy in children and adolescents with depression, and no randomized controlled trials in this population. A case series examining the efficacy of quetiapine (median dose 200 mg/day) augmentation in 10 adolescents with treatment-resistant depression showed a 70% response rate (CGI-I ≥ 2) ( ). A case report described improvement in depressive symptoms with adjunctive clozapine for an adolescent with treatment-resistant depression ( ). Large, randomized controlled treatment studies are needed before recommending this as an evidence-based augmentation strategy in children and adolescents with depression. The potential side effects with antipsychotics are concerning, and children and adolescents seem to be at an increased risk of experiencing cardiometabolic side effects with the second-generation antipsychotics ( ). Other augmentation strategies using medications may include lithium, bupropion, and mirtazapine, but are based on adult studies, with no randomized controlled trials showing efficacy or safety of these strategies in the pediatric population ( ).

The FDA has approved repetitive transcranial magnetic stimulation (rTMS) as a treatment for treatment-resistant depression in adults, but it is not approved for use in the pediatric population. A randomized controlled trial examining the efficacy of TMS for treatment-resistant depression in adolescents included a double-blind design using a sham TMS treatment for the control group ( ). The trial included 103 adolescents, aged 12–21 years, with treatment-resistant depression. This was a 6-week study, with a total of 30 treatments given as monotherapy. Participants were randomized to receive left prefrontal 10 Hz TMS or sham TMS treatment (including a sham coil that appeared identical to the active coil, an acoustically matched profile, and a mild percussive sensation to mimic active treatment). The primary outcome measure was change in the Hamilton Depression Rating Scale (HAM-D-24) ( ) from baseline to endpoint. There was no significant difference between the active TMS treatment group and sham TMS treatment group on the primary outcome measure, with change in scores being − 11.1 and − 10.6, respectively. There were also no significant differences between TMS and sham TMS in response (41.7% and 36.4%, respectively) or remission rates (29.2% and 29.0%, respectively). Participants in the active treatment group reported side effects, including headaches, eye pain, nausea, and facial twitching, which were observed significantly more than in the sham treatment group.

A recent systematic review showed 14 studies examining the efficacy of TMS in adolescents with depression, eight of which were open-label, multisubject trials ( ). The other six studies were post hoc analyses of the open label studies and one 3-year follow-up of an open trial. The eight open-label studies included a total of 142 adolescents with depression, all of which showed TMS having some effect on reducing symptoms of depression. The review concluded the studies were of either poor or fair quality, with a high risk of bias. A recent randomized sham-controlled trial compared active TMS and sham TMS in 103 adolescents aged 12–21 with treatment-resistant depression. Each group received 30 daily treatments over 6 weeks. There was no significant difference between the two groups on the primary outcome measure, a change in the Hamilton Depression Rating Scale from baseline to endpoint ( ). More large randomized controlled trials are needed before routinely recommending TMS for adolescents with treatment-resistant depression.

There are no randomized controlled trials examining the efficacy of electroconvulsive therapy (ECT) in children and adolescents with depression. A retrospective chart review examined the efficacy of ECT in 54 adolescents with treatment-resistant mood disorders, including unipolar and bipolar depression ( ). The youth received their first ECT treatment course prior to the age of 18. Response was defined as a Clinical Global Impressions (CGI) score ≤ 2 and was assessed after initial treatment and at 1-year follow-up. The mean number of treatments was 13.7 for initial treatment and the response rate was 52.8%. The study showed that 82% of the youth were considered responders at 1-year follow-up, with a reduction in suicidal ideation and self-injurious behaviors. Prolonged seizures were common during ECT (74%) and long-term side effects were memory loss limited to the time surrounding ECT treatment. A retrospective observational study including 190 adolescents and young adults, aged 16–25 years, examined the efficacy of ECT for multiple psychiatric diagnoses, including 128 subjects with treatment-resistant depression and showed significant improvement on self-reported depressive symptoms as a group (the study did not report on percent of responders separately) ( ). A case series of 13 adolescents aged 15–18 years with treatment-resistant depression showed a mean of 14 ECT sessions to be effective for reducing depressive symptoms in 10 of the 13 (77%) participants ( ).

A retrospective study of ECT in adolescents with treatment-resistant depression showed an average improvement of 46% in the participants’ symptoms, with a third of participants experiencing at least 60% improvement in symptoms ( ). A retrospective case report showed significant improvement in 83% of adolescents (aged 14–17 years) with treatment-resistant depression receiving ECT. The study included six subjects, and ECT was well-tolerated by the adolescents in the study ( ). Side effects of ECT can include transient cognitive impairment, headache, prolonged seizures, and nausea. The American Academy of Child and Adolescent Psychiatry developed practice parameters for the use of ECT in adolescents ( ). The recommendation is that ECT should be considered for severe, persistent, and significantly disabling depression in adolescents who have failed at least two adequate trials of appropriate psychopharmacological agents along with other appropriate treatments.

Ketamine is another treatment being used in adults with treatment-resistant depression, but there are no randomized controlled studies in children and adolescents. An open-label study examined the efficacy of intravenous ketamine in 13 adolescents aged 12–18 years with treatment-resistant depression ( ). The participants were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Response (≥ 50% reduction in CDRS-R score from baseline to endpoint) was seen in five (38%) of the adolescents, with relapse occurring within 2 weeks in two of these responders. Adverse effects reported included transient blood pressure changes, transient (within 1 h) dissociative symptoms, dysphoria, and nausea. A systematic review on ketamine treatments for use in adolescents included the above study and two case reports in adolescents with treatment-resistant depression ( ). Ketamine was shown to improve depressive symptoms in some patients. The authors concluded that ketamine may have potential for treatment-resistant depression in youth but considering ketamine in treatment guidelines for adolescents with treatment-resistant depression is premature, given the limited evidence of efficacy and safety in this patient population. A commentary on esketamine use in adolescents raised concerns about repetitive and chronic exposures to esketamine in this patient population ( ). Animal studies of esketamine on developing brains show permanent negative effects on the neurodevelopmental process in the prefrontal cortex, which is a risk that could be heightened in children and adolescents with genetic risk factors for schizophrenia. Ketamine and esketamine lack sufficient efficacy and safety data to recommend for use in children and adolescents with treatment-resistant depression.

Adjunctive l -methylfolate was examined as a potential treatment for treatment-resistant depression in 10 adolescents (mean age 14) in a case series ( ). Eighty percent of patients had a single mutation among two methylene tetrahydrofolate reductase (MTHFR) gene variants, indicative of reduced MTHFR activity. The dose of l -methylfolate ranged from 2 to 15 mg/day. In the study, 80% of participants showed improvement in symptoms of depression, irritability, and anxiety. l -Methylfolate was well-tolerated. More rigorous studies are required in this patient population before l -methylfolate augmentation can be recommended for adolescent treatment-resistant depression.

A medication consensus treatment guideline was developed for major depressive disorder in youth ( ) but has not been updated. The recommendation was initial treatment with an SSRI, and then switching to a second SSRI if no response. This recommendation is now consistent with the findings of the TORDIA study. If there is a partial response to treatment with an SSRI, augmentation with a second antidepressant may be considered, although this has not been studied in children and adolescents. If there is no response to the second SSRI tried, an alternate antidepressant from a different class (venlafaxine, bupropion, mirtazapine, duloxetine) is recommended. Desvenlafaxine and vilazodone have now been studied in youth with depression and may be considered in the list of alternate antidepressants. If there is still no response, the clinician should reassess symptoms. Newer antidepressants should be used with caution due to limited safety and efficacy data in children and adolescents.