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.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
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.
Depression often begins in adolescence and can cause substantial disability and suicide risk. Standard pharmacological and psychotherapeutic interventions frequently fail: about 40% of adolescents do not respond to a first treatment and only half of those nonresponders improve with a second trial. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist used in anaesthesia, has shown rapid antidepressant effects in adults with treatment-resistant depression (TRD), including after single low-dose (0.5 mg/kg) intravenous infusions and in studies of repeated administrations. However, little is known about ketamine's efficacy or tolerability in adolescents, a developmental period with heightened neuroplasticity that might influence both response and duration of benefit. Cullen and colleagues set out to evaluate six serial open-label intravenous ketamine infusions (0.5 mg/kg over 40 minutes) administered across 2 weeks in adolescents with TRD. The study had three aims: to measure the extent and short-term duration of clinical response and remission (primary outcome: percent change on the Children's Depression Rating Scale–Revised, CDRS-R, with response defined as ≥50% reduction and remission as CDRS-R ≤28), to assess tolerability including dissociative and haemodynamic effects, and to explore clinical and demographic predictors of response. The investigators also prespecified a naturalistic follow-up of responders with weekly visits for 6 weeks and a 6-month visit to capture relapse timing and persistence of benefit.
This was a single-arm, open-label clinical trial conducted at a single centre and approved by the local Institutional Review Board. Adolescents aged 12–18 years with a current diagnosis of Major Depressive Disorder and treatment resistance (failure to respond to at least two adequate antidepressant trials, as rated on the Antidepressant Treatment History Form) were eligible. Required baseline severity was a CDRS-R raw score >40. Current psychotropic medications had to be stable for 2 months; pre-study washout periods were specified (2 weeks for mood stabilisers/antipsychotics, 4 weeks for antidepressants, 1 week for stimulants). Exclusion criteria included current substance use disorder, primary psychotic disorder, bipolar disorder, autism spectrum disorder, intellectual disability, nonpsychiatric neurological disorder, or significant medical illness. After informed consent/assent and diagnostic assessment using the K-SADS-PL (adolescents and parents interviewed separately), baseline symptom measures included the CDRS-R (primary outcome), MADRS, BDI-II, Snaith–Hamilton Pleasure Scale (SHAPS), and Temporal Experience of Pleasure Scale (TEPS). Intelligence was estimated with the Wechsler Abbreviated Scale of Intelligence. Participants who met inclusion criteria received six open-label intravenous ketamine infusions administered on alternate weekdays over 2 weeks, each infusion given at 0.5 mg/kg over 40 minutes followed by 2 hours of monitoring. For the first five participants, dose was calculated using ideal body weight; after observing no responders in that subgroup, dosing was switched to actual body weight for subsequent participants. Safety monitoring during and after each infusion included vital signs (heart rate, blood pressure, respiratory rate, oxygen saturation) measured at baseline and every 15 minutes, and dissociation assessments with the Clinician-Administered Dissociative States Scale (CADSS) immediately postinfusion and at 1 and 2 hours. Depression and clinical global measures (MADRS, CGI) and self-report measures (BDI-II, SHAPS, TEPS) were collected before each infusion and at 2 hours postinfusion. The primary endpoint was percent change in CDRS-R from baseline to the day following the final infusion; response was defined as ≥50% reduction and remission as CDRS-R ≤28. Responders were invited for six weekly follow-up visits and a 6-month visit during which clinical care was naturalistic. Statistical analysis comprised descriptive statistics, paired t-tests for pre/post changes on primary and secondary measures, and linear regression analyses using CDRS-R percent change as the continuous outcome to explore potential predictors (age, sex, age at depression onset, illness duration, baseline severity measures, number of past medication trials, trauma history, BMI and dosing strategy). The investigators documented adverse events. The extracted text does not state use of an intention-to-treat framework; sample size was small (13 completers) and no formal power calculation is reported in the extracted material.
Adolescents with TRD were recruited through community postings and clinical referrals. Inclusion criteria included age 12-18 years, current diagnosis of Major Depressive Disorder, Children's Depression Rating Scale-Revised (CDRS-R)raw score >40, and treatment resistance defined as a failure to exhibit a satisfactory response to at least two antidepressant medications. Rigor of antidepressant trials was assessed using the Antidepressant Treatment History Form; past trials were considered sufficient if they scored at least a ''3'' (on a scale of 1 to 4; as an example, a rating of ''3'' for fluoxetine is 4 weeks or more and dosage 20-39 mg/day, a rating of ''4'' is 4 weeks or more and dosage ‡40 mg/day), or if the trial was truncated due to intolerance (as opposed to an early decision regarding inefficacy). Current psychotropic medications had to be dose stable for 2 months. If participants opted to discontinue any psychotropic medications before the study, we required a washout period of 2 weeks for mood stabilizers and antipsychotic medications, 4 weeks for antidepressants, and 1 week for stimulants. Exclusion criteria were the presence of a current substance use disorder, a primary psychotic disorder, bipolar disorder, autism spectrum disorder, a history of intellectual disability, a nonpsychiatric neurological disorder, or a significant medical illness.
The primary outcome measure was percent change in depression symptoms as measured by the CDRS-R. Percent change was calculated using the formula: (baseline raw CDRS-Rposttreatment raw CDRS-R)/(baseline raw CDRS-R -17); treatment response was defined as at least a 50% reduction in depression symptoms. Remission was defined as CDRS-R score £28. Relapse was defined as a CDRS score ‡50% of the pretreatment baseline (in other words, surpassing the threshold required to define response). Secondary outcome measures included MADRS, BDI-II, SHAPS, TEPS, and CGI severity scores at posttreatment, and CADSS and vital sign measurements during infusions.
Ketamine research has generated considerable excitement because of its rapid-acting antidepressant effects in adults with TRD). To our knowledge, this represents the first report on the use of ketamine as a treatment for adolescent TRD. Since adolescence is a time period notable both for onset of depression and ongoing neurodevelopment) it represents a critical window to intervene and restore healthy developmental trajectories. In this study, six serial infusions of open-label ketamine were associated with a significant decrease in depressive symptoms. Five adolescents (38%) met criteria for clinical response and remission, with three of these responders showing sustained remission at The rate of response to ketamine in this adolescent study was lower than what has been observed in adult TRD studies. One reason for this could be developmental; earlier onset of depression tends to be associated with a more severe course; when TRD emerges early in life, it may reflect a distinct pathophysiology requiring more extensive treatment to remedy underlying neuropathologies. A second consideration is that in this study, the first five patients (all nonresponders, four overweight) received smaller doses because our initial dosing strategy used ideal body weight. In that subsample, mean dose was 29.3 mg; mean dose divided by actual weight was 0.35 mg/kg. After the switch to dosing based on actual body weight, five of eight participants were responders. Thus, while ideal body weight dosing may be sufficient for adults), this strategy may not be optimal for adolescents. The current findings add to past research showing that rates of response in children and adolescents to other antidepressants do not always match what is observed with adult depression. In this study we observed that participants who received higher doses (due to having a higher BMI) had the best responses. This preliminary finding suggests a possible dose-response relationship for ketamine's effect on depression symptoms in adolescents with TRD, adding to previous reports from adults that 0.5 mg/kg was superior to lower doses (0.1-0.4 mg/kg)) and that dose escalation from 0.5 to 0.75 mg/kg was effective in some patients. It is important to note that to achieve FIG.. Consort diagram summarizing subject flow through the study. We completed initial screening with parents of 36 adolescents. Four participants were screened out due to presence of exclusionary diagnoses, insufficient antidepressant history, or recent medication changes. Parents of 18 adolescents chose not to participate for a variety of reasons, including travel costs, time burden, and safety concerns. Fourteen adolescents completed the consent process and diagnostic interview; one dropped out before receiving infusions. Thirteen adolescents completed all six infusions and posttreatment assessment. Responders were invited back for follow-up visits to measure time to relapse. All five responders completed the week 6 follow-up visit; four of five responders completed the 6-month visit. a dissociative state, pediatric patients require higher doses (1.5-2.0 mg/kg in comparison to 1 mg/kg for adults, with adolescents having similar requirements as children; therefore, appropriate dose for achieving antidepressant response in adolescents may be similarly higher. Future research is needed to identify the optimal dose for adolescents with TRD. The optimal schedule for ketamine administration remains unknown. Recent evidence suggests that serial ketamine administrations may be more effective and lasting than single administrations (aan het. In one adult TRD study, response rates increased over the six infusions to reach a 92% cumulative response rate). While our results did not support a pattern of progressive improvement over the six infusions (Supplementary Fig.), it may be that repeated infusions contributed to the sustained remission observed in three of our subjects. Further research is needed to identify the optimal treatment regimen for acute treatment of adolescent TRD. Identification of significant predictors of treatment response to ketamine is a critical step toward future personalized medicine approaches. Although a history of trauma was not a significant predictor of response, similar to past research showing that a history of trauma is a negative prognostic indicator of treatment response, we found that those with a trauma history showed less reduction in depression than those without a history of trauma. Larger samples will be required to more formally test clinical predictors of ketamine response in adolescents. Similar to past reports, we found a low rate of adverse events. As expected, ketamine infusions were associated with transient dissociative symptoms and hemodynamic changes. The safety of short-term use of ketamine for anesthesia, analgesia, and sedation in clinical settings is well established. Due to its efficacy and positive safety profile, ketamine is the most commonly administered sedative/analgesic for children in North America undergoing painful emergency department procedures. Following anesthetic doses of ketamine, follow-up studies (up to 4 months) have not identified adverse effects on psychological functioning). However, very little is known about the longterm efficacy or safety of ongoing, maintenance ketamine treatments. Currently, the field is limited to a handful of case reports of using maintenance strategies in adults with depression over 1-2 years. As the field continues to explore ketamine as a treatment for depression, The CDRS-R was the primary outcome measure of this study. b Baseline SHAPS and TEPS data were missing for one subject. CDRS-R, Children's Depression Rating Scale-Revised; BDI-II, Beck Depression Inventory-II; MADRS, Montgomery-A ˚sberg Depression Rating Scale; SHAPS, Snaith-Hamilton Pleasure Scale; TEPS, Temporal Experience of Pleasure Scale; CGI, Clinical Global Impression; SD, standard deviation. FIG.. Mean blood pressure and heart rate, averaged over all six infusions. Maximum elevations of systolic blood pressure were at 30 minutes (mean increase from baseline of 6.8 mmHg) and 45 minutes (mean increase 7.3 mmHg) from the beginning of the infusion. Maximum increase in diastolic blood pressure was 5.1 mmHg, 45 minutes from beginning of infusion. There were no elevations in heart rate or blood pressure during the study that required intervention. significant knowledge gaps regarding long-term safety of continued ketamine treatment should be addressed. In this study, we observed a very low rate of attrition (at least during the treatment visits); all of those adolescents who received one infusion went on to complete all six infusions. This is somewhat surprising given the presence of some adverse events as noted above, especially for those adolescents that showed no clinical improvement throughout the study. The low attrition for treatment visits and the first posttreatment clinical assessment could reflect strong commitment to the study from patients and parents based on their intimate knowledge of the importance of research investigating new treatments for adolescent TRD. It could also reflect hopes and expectations on the part of patients and families for what ketamine treatment could deliver, based on the reports around that time in public media avenues on the promise of ketamine for depression. Finally, more than half of our patients that entered our study did not reside locally and had traveled from other locations to participate; the process of setting aside the time and financial investment for travel may have increased the commitment to follow through on the entire study. When considering ketamine as a treatment for adolescent depression, safety concerns take center stage. One question raised by parents inquiring about our study was about the risk for inducing a substance use disorder. Little information is available to address this question. One study that assessed participants 1 week to 6 months following participation in single-dose ketamine studies found no reports of ketamine cravings, psychological, or medical problems. Patients with a history of substance abuse may have increased vulnerability to drug cravings as a result of underlying neuroadaptations in reward circuits). To limit this risk, our study excluded adolescents with a current (past 6 months) diagnosis of substance abuse disorder. Notably, in the context of drug abuse, ketamine doses ranged from 100 to 2500 mg per use(3 to 65 times greater than the average dose in our study). Future research is needed examining long-term risk of low-dose ke-tamine exposure for inducing or worsening substance abuse. A second safety concern is the possible risk for ketamine-induced neurotoxicity. As reviewed by, evidence from animals and humans suggest that higher ketamine doses (e.g., 5-160 mg/kg), especially with chronic exposure, can lead to neurotoxic effects; early developmental periods (prenatal and neonatal) have particularly high risk. Since adolescence represents a time period of ongoing neurodevelopment and vulnerability, the risks associated both with treatment and with progression of illness due to ineffective treatment must be carefully assessed and considered together. Limitations of this study should be considered. First, the singlearm, open label design precludes conclusion that the results are due to drug effect versus expectation effects of (placebo) or regression to the mean. These concerns may be attenuated in this sample: regression to the mean may be less of a concern in participants with a history of severe and persistent depression, and placebo effect could be less in those with multiple past treatment failures. Furthermore, our study's finding of a dose-response relationship may in part ameliorate concerns regarding expectation or regression to the mean. On the other hand, factors such as the requirement of an intravenous catheter and the excitement from the popular press surrounding ketamine during this time period may have enhanced adolescent and parent expectancies. In any case, randomized, placebo-controlled studies are needed to confirm the preliminary findings reported in this study. Second, this study was not designed to identify optimal dose; further work is needed to formally delineate the dose-response relationship in adolescent TRD, and to guide dose optimization in these patients. Third, the small sample size limited the external validity of the study (i.e., our sample may not be fully representative of adolescent TRD) and limited power to examine important potential predictors of response. Finally, this study only examined acute treatment of adolescent TRD, whereas in clinical practice, strategies to sustain response and remission are needed. Future work is needed to address ongoing questions about the efficacy and safety of ketamine as a maintenance treatment, or of other strategies to maintain ketamine-induced clinical improvement.
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Fond, G., Loundou, A., Macgregor, A. et al. · Psychopharmacology (2014)
Short, B., Fong, J., Galvez, V. et al. · Lancet Psychiatry (2017)
Murrough, J. W., Wan, L., Levitch, C. F. et al. · Journal of Clinical Psychiatry (2015)
Zhu, W., Ding, Z., Zhang, Y. et al. · Neuroscience Bulletin (2016)
Papers in Blossom that reference this study
Zhou, Y., Lan, X-F., Wang, C. et al. · Child and Adolescent Psychiatry (2024)
Lan, X-F., Wang, C-Y., Zhang, F. et al. · Child and Adolescent Psychiatry (2023)
Nichols, D. E., Walter, H. · Pharmacopsychiatry (2020)
Thirteen adolescents completed the six-infusion protocol and the posttreatment assessment; the consort diagram indicated initial contact with parents of 36 adolescents, 14 completed consent and diagnostic interview, and one dropped out before receiving infusions. Participant characteristics reported elsewhere in the extracted text include a mean age of 16.9 years (range 14.5–18.8) and eight biologically male, although the Methods section itself did not re-state the full demographic table. On the primary outcome, mean CDRS-R percent change from baseline to the day after the final infusion was 42.5% (SD = 31%). Five participants (38%) met the predefined response criterion (≥50% reduction); three of these responders were in remission at the posttreatment assessment (CDRS-R ≤28). During follow-up, two responders relapsed within 1–2 weeks, two responders remained in remission at 6 weeks, and a third participant who was just below remission at posttreatment reached remission by week 6. Four of the five responders attended the 6-month visit and two remained both in response and remission at that time. Secondary clinician- and self-rated measures (MADRS, BDI-II, CGI) showed significant pre/post improvements; measures of anhedonia (SHAPS, TEPS) did not change significantly. Adverse events were generally transient. Blood pressure increases were modest and peaked during infusions (mean systolic increases up to 6.8 mmHg at 30 minutes and 7.3 mmHg at 45 minutes; maximum mean diastolic increase 5.1 mmHg at 45 minutes); no elevations required intervention. Heart rate, respiratory rate and oxygen saturation did not show clinically significant changes. CADSS dissociation scores were elevated immediately after infusions, with larger effects during earlier infusions, but returned to baseline by the 1-hour assessment. Two participants experienced dysphoria during an infusion; three reported nausea (one vomited, subsequently treated with ondansetron); one reported post-procedural hand pain from IV placement. No respiratory adverse events were observed. One participant with high baseline suicidal thinking reported subjective worsening but structured assessments did not document a change. Exploratory predictor analyses identified actual ketamine dose (F = 8.84, p = 0.01) and BMI (F = 6.28, p = 0.03) as significant predictors of greater CDRS-R percent change. Dosing strategy (actual versus ideal body weight) showed a trend in the regression (F = 4.43, p = 0.06); in a subgroup comparison those dosed by actual body weight had larger mean percent CDRS-R change (55%, SD 31%) than those dosed by ideal body weight (22%, SD 21%; t = 2.3, p = 0.04). None of the five participants dosed by ideal body weight were responders, whereas five of eight participants dosed by actual body weight were responders (chi-square = 2.79, p = 0.10). Trauma history did not emerge as a significant predictor in the regression (trend-level p = 0.15), but a follow-up t-test reported greater improvement among those without a trauma history (mean percent change 60.2%, SD 26.1%) versus those with trauma history (mean 21.9%, SD 24.2%; t = 2.74, p = 0.02). No significant predictive effects were observed for age, sex, estimated IQ, number of past medication trials, age at depression onset, duration of current episode, or baseline severity scores (CDRS-R, BDI-II, SHAPS, TEPS).
Cullen and colleagues interpret these findings as preliminary evidence that serial low-dose intravenous ketamine can produce rapid reductions in depressive symptoms in some adolescents with TRD. They note this is, to their knowledge, the first report of ketamine treatment in an adolescent TRD sample and that six open-label infusions were associated with significant symptom reductions and a 38% responder rate, with several responders maintaining remission through the 6-week follow-up and two remaining in response/remission at 6 months. The authors contrast the observed responder rate with higher rates reported in adult TRD studies and suggest several possible explanations. Developmental factors and earlier illness onset in adolescents may be associated with a more severe or distinct illness course less amenable to brief interventions. A procedural factor likely contributing to lower response is dosing: the initial use of ideal body weight for the first five (all nonresponding, four overweight) resulted in lower mg/kg exposures (mean ~0.35 mg/kg), after which dosing was changed to actual body weight and responders were more frequent. From this they infer a possible dose–response relationship in adolescents, consistent with adult data showing greater efficacy at higher doses in some studies. Regarding safety, the investigators report a low rate of adverse events limited chiefly to transient dissociative symptoms and modest haemodynamic changes, and no respiratory complications. Nonetheless, they emphasise important unknowns: long-term safety of repeated or maintenance low-dose ketamine is inadequately characterised, particularly in a developing brain where animal and some human data suggest potential neurotoxic risk with higher or chronic exposures. Concerns about potential induction of substance use disorder are acknowledged; the trial excluded participants with recent substance use disorder and the authors note that recreational ketamine doses are far larger than those used here, but they call for research on long-term risk. The authors explicitly acknowledge limitations that constrain inference: the open-label, single-arm design cannot rule out placebo or regression-to-the-mean effects; small sample size limits generalisability and statistical power for predictor analyses; the study was not designed to determine optimal dosing or maintenance strategies; and follow-up was limited, so questions about sustained benefits remain. They conclude that larger, double-blind, placebo-controlled trials are required to confirm efficacy, to establish optimal dosing and administration schedules, to characterise predictors of response, and to evaluate long-term safety and strategies to sustain remission in adolescent TRD.
Ketamine produced rapid antidepressant effects in a subset of adolescents with TRD in this open-label series, and the findings provide preliminary evidence for a dose–response relationship favouring dosing by actual body weight. However, the authors caution that definitive conclusions require large-scale, double-blind, randomised trials to determine safety and efficacy in this population, to optimise dosing and patient selection, and to address strategies for maintaining remission and long-term safety after acute treatment.