This open-label study (n=13) probed into the efficacy and tolerability of intravenous ketamine in adolescents with treatment-resistant depression (TRD), and investigated clinical response predictors using the Children’s Depression Rating Scale-Revised (CDRS-R) and the Clinician-Administered Dissociative States Scale (CADSS). It supported the potential of ketamine in the treatment of adolescent patients with TRD and a dose-response relationship but called for larger sample size and overcoming limitations such as the open-label design and further research.

Abstract

“Background: Novel interventions for treatment-resistant depression (TRD) in adolescents are urgently needed. Ketamine has been studied in adults with TRD, but little information is available for adolescents. This study investigated efficacy and tolerability of intravenous ketamine in adolescents with TRD, and explored clinical response predictors.

Methods: Adolescents, 12–18 years of age, with TRD (failure to respond to two previous antidepressant trials) were administered six ketamine (0.5 mg/kg) infusions over 2 weeks. Clinical response was defined as a 50% decrease in Children’s Depression Rating Scale-Revised (CDRS-R); remission was CDRS-R score ≤28. Tolerability assessment included monitoring vital signs and dissociative symptoms using the Clinician-Administered Dissociative States Scale (CADSS).

Results: Thirteen participants (mean age 16.9 years, range 14.5–18.8 years, eight biologically male) completed the protocol. Average decrease in CDRS-R was 42.5% (p = 0.0004). Five (38%) adolescents met criteria for clinical response. Three responders showed sustained remission at 6-week follow-up; relapse occurred within 2 weeks for the other two responders. Ketamine infusions were generally well tolerated; dissociative symptoms and hemodynamic symptoms were transient. Higher dose was a significant predictor of treatment response.

Conclusions: These results demonstrate the potential role for ketamine in treating adolescents with TRD. Limitations include the open-label design and small sample; future research addressing these issues are needed to confirm these results. Additionally, evidence suggested a dose–response relationship; future studies are needed to optimize dose. Finally, questions remain regarding the long-term safety of ketamine as a depression treatment; more information is needed before broader clinical use.”

Authors: Kathryn R. Cullen, Palistha Amatya, Mark G. Roback, Christina Sophia Albott, Melinda Westlund Schreiner, Yanan Ren, Lynn E. Eberly, Patricia Carstedt, Ali Samikoglu, Meredith Gunlicks-Stoessel, Kristina Reigstad, Nathan Horek, Susannah Tye, Kelvin O. Lim & Bonnie Klimes-Dougan

Summary

Ketamine is a novel intervention for treatment-resistant depression in adolescents.

Introduction

Adolescents with depression often do not respond to their first intervention, and only half of nonresponders respond to the second treatment. Hence, novel treatment strategies are urgently needed.

Ketamine is an N-methyl-d-aspartate receptor antagonist that has been used extensively for procedural sedation and analgesia in adults and children. It has recently been explored as a novel treatment for TRD in adults, but no information is yet available on the efficacy or tolerability of ketamine in adolescents.

The current study examined the effects of six serial infusions of intravenous ketamine, given over 2 weeks, as an acute intervention for treatment-resistant depression in adolescents. It found that treatment was associated with reduced depression symptoms and a longer duration of response than previously reported for adults.

Participants

Adolescents with treatment-resistant depression were recruited through community postings and clinical referrals. They had to be aged 12-18 years, have a current diagnosis of Major Depressive Disorder, and have failed at least two antidepressant medications.

Pretreatment clinical assessment

Following informed consent and assent, participants were evaluated using the Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version (K-SADS-PL). They completed self-report measures, including the Beck Depression Inventory-II (BDI-II) and the Temporal Experience of Pleasure Scale (TEPS).

Ketamine infusions and ongoing assessments

Participants who met inclusion/exclusion criteria were scheduled for six open-label ketamine infusions over the course of 2 weeks. The dose was based on ideal body weight for the first 5 participants, but was changed to use actual body weight for the remaining participants. Vital signs, depression symptoms, and a follow-up assessment were collected at baseline, 1 hour, and 2 hours post-infusion. A 6-month follow-up assessment was conducted 1 day following the final infusion.

Outcome measures

The primary outcome measure was percent change in depression symptoms as measured by the CDRS-R, and remission was defined as a CDRS-R score £28.

Statistical analyses

We conducted descriptive analyses of demographic and clinical data, conducted paired t-tests on the primary and secondary outcome measures, and conducted linear regression analyses to explore response predictors.

Improvement in depression symptoms

Five participants (38%) met criteria for response; three of these participants were also in remission posttreatment, two of whom were still in remission at 6-weeks; two of the other two participants relapsed at 1 and 2 weeks, respectively.

Adverse effects

Transient blood pressure changes were observed, but no significant changes in heart rate, respiratory rate and oxygen saturation were observed. Two participants reported feeling uncomfortable during the infusion, three reported nausea, and one participant reported hand pain.

Exploratory analyses: predictors of clinical response at posttreatment

Significant predictors of response included actual ketamine dose and BMI, and dosing strategy (actual versus ideal body weight). Trauma history had a trend-level effect in predicting clinical response, but age, sex, intelligence quotient, number of past medications, age of depression onset, duration of current episode, or baseline severity were not.

Discussion

Ketamine research has generated considerable excitement because of its rapid-acting antidepressant effects in adults with TRD. In this study, ketamine was used as a treatment for adolescent TRD, and the treatment was generally well tolerated.

In this adolescent study, ketamine produced a lower response than in adult TRD studies. This could be because the adolescent population has a different pathophysiology than adults, or because the initial dosing strategy used ideal body weight rather than actual body weight.

In this study, participants with a higher BMI received higher doses of ketamine, and had better responses than those with a lower BMI. This preliminary finding suggests a possible dose – response relationship for ketamine’s effect on depression symptoms in adolescents with TRD.

Ketamine administration in serials may be more effective than single administrations for treating TRD. However, our results did not support a pattern of progressive improvement over the six infusions.

A history of trauma was not a significant predictor of response to ketamine, but those with a trauma history showed less reduction in depression than those without a history of trauma.

We found a low rate of adverse events with ketamine infusions. The safety of short-term use of ketamine for anesthesia, analgesia, and sedation in clinical settings is well established, however, little is known about the long-term efficacy or safety of continued ketamine treatment.

In this study, we observed a very low rate of attrition, especially for those adolescents that showed no clinical improvement throughout the study. This could be due to strong commitment to the study from patients and parents, or hopes and expectations for what ketamine treatment could deliver.

When considering ketamine as a treatment for adolescent depression, safety concerns take center stage. Little information is available to address the question of inducing a substance use disorder, and adolescents with a current diagnosis of substance abuse disorder were excluded from the study.

Ketamine exposure can worsen substance abuse, and can cause neurotoxicity. Adolescents are at particular risk, so treatment and progression of illness must be carefully assessed.

This study has limitations, but the results may be attenuated in participants with a history of severe and persistent depression, and a dose – response relationship may ameliorate concerns regarding expectation or regression to the mean. This study was not designed to identify optimal dose, and the small sample size limited the external validity of the study. Additionally, strategies to sustain response and remission are needed in clinical practice.

Conclusion

Ketamine’s biological effects may serve to enhance neuroplasticity, making the adolescent period particularly amenable to ketamine treatment. However, large-scale, double-blind, randomized control designs are needed to determine if ketamine is a safe and effective treatment for adolescent TRD.

Clinical Significance

This study examined the effects of intravenous ketamine on depression in 13 adolescents who had failed multiple prior treatments. The findings suggest that ketamine may be effective for some but not all adolescents with TRD.

Acknowledgments

The authors would like to thank the adolescents and families who volunteered to participate in this study.