Purpose
The purpose of Phillips et al.’s randomized controlled trial was to test the efficacy of ketamine infusions for treating major depressive disorder using different infusion configurations. The study aimed to determine whether ketamine infusion is more effective than placebo, examine the efficacy of a serial administration algorithm, and investigate symptom dynamics when the infusion frequency is reduced (Phillips et al., 2019). The study’s aim is promising and addresses the knowledge gaps previously identified by the authors. Investigating the clinical effects of ketamine as an antidepressant agent from multiple angles reinforces the nature of this study.
Study Population
Forty-one participants with a history of treatment-resistant depression were recruited for the study. The age distribution of the participants ranged from 18 to 65, and each had a MADRS depression score of at least 25. Exclusion criteria used included drug dependence, high body mass index (≥35), and threshold urine, blood, and cardiovascular function tests (not reported). Given the initial number of pre-collected participants, the final sample size was 65%, which can be considered a good result given the reasons for excluding previously approved candidates.
Length of the Trial
The study, which ran from 2013 to 2017 (nearly five years), was divided into three phases. The first phase (a randomized, double-masked, crossover study) lasted at least 14 days, and participants received two infusions of either placebo or ketamine seven days apart. The second phase also lasted 14 days. A third phase with a reduced infusion frequency compared to the second phase lasted another four weeks. In total, the active part of the study lasted two months, a characteristic of time-consuming RCTs (Nimavat et al., 2020).
Data Collection Methods
The type of data collected was similar between phases. During phase 1, baseline data were collected using valid MADRS and QIDS-SR scales. During Phases 2 and 3, the MADRS scale was used to assess participants’ symptom trends and compare them to the intensity of ketamine infusions. The MADRS and QIDS-SR scales are scientifically valid and widely used in therapeutic practice (Liu et al., 2021). Referring to them in this study is appropriate and academically supported.
Outcome Measures
Measures collected included characteristics of the severity of ongoing depression given different time intervals after the first infusion was administered. In addition, outcomes included the number of individuals who showed marked improvement (as measured by the MADRS) in their illness across infusion regimens. The information collected was multifaceted and systematically structured, which has positive implications for a robust study.
Results and Conclusions
The results showed the success of ketamine compared to placebo in reducing symptoms of depression, improved treatment efficacy at a high frequency of drug use, and reasonable maintenance of the antidepressant effect of ketamine at a low frequency of use. The findings suggest that ketamine therapy has promising potential for treating depression even at low infusion frequencies.
This study has several ethical limitations. Although informed consent was obtained, it is not specified to what extent participants were informed of all the risks associated with RCT (Goldstein et al., 2018). The question also arises regarding the care of patients who took a placebo and continued to suffer from depressive syndrome. It is not reported whether the study is sponsored or whether the authors have a conflict of interest. In addition, the efficacy of ketamine for the treatment of depression creates unanswered questions about the availability of such treatment.
Thus, the use of RCT allowed for the complete anonymization of the methodological part of the study, enabling a critical evaluation of the efficacy of ketamine. Randomization was used to randomly assign participants to the ketamine or placebo groups, thereby creating an entirely masked study with no bias. The three-phase method allowed complex issues to be addressed and the effects of ketamine therapy to be critically and multilaterally evaluated.
Reference
Goldstein, C. E., Weijer, C., Brehaut, J. C., Fergusson, D. A., Grimshaw, J. M., Horn, A. R., & Taljaard, M. (2018). Ethical issues in pragmatic randomized controlled trials: A review of the recent literature identifies gaps in ethical argumentation. BMC Medical Ethics, 19(1), 1-10.
Liu, R., Wang, F., Liu, S., Zhang, Q., Feng, Y., Sim, K., & Xiang, Y. T. (2021). Reliability and validity of the quick inventory of depressive symptomatology — self-report scale in older adults with depressive symptoms. Frontiers in Psychiatry, 12, 1-6.
Nimavat, B. D., Zirpe, K. G., & Gurav, S. K. (2020). Critical analysis of a randomized controlled trial. Indian Journal of Critical Care Medicine: Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine, 24(Suppl 4), 215-222.
Phillips, J. L., Norris, S., Talbot, J., Birmingham, M., Hatchard, T., Ortiz, A., & Blier, P. (2019). Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: A randomized controlled trial. American Journal of Psychiatry, 176(5), 401-409.