This open-label study (n=77) examines the sustained effects of six consecutive ketamine infusions (0.5mg/kg over 40 min) in Chinese patients with major depressive disorder (MDD). Six ketamine infusions increased rates of response and remission when compared to a single-dose ketamine infusion in patients with MDD.
Abstract
“Objective: Single-dose intravenous ketamine has rapid but time-limited antidepressant effects. We aimed to examine the sustained effects of six consecutive ketamine infusions in Chinese patients with major depressive disorder.
Methods: Seventy-seven patients with major depressive disorder were eligible to receive augmentation with six ketamine infusions (0.5 mg/kg over 40 min) administered over the course of 12 days (Monday–Wednesday–Friday). The coprimary outcome measures were the rates of response and remission as measured on the 10-item Montgomery-Asberg Depression Rating Scale. Psychotomimetic and dissociative symptoms were measured with the Brief Psychiatric Rating Scale-positive symptoms and the Clinician Administered Dissociative States Scale, respectively.
Results: After the first ketamine infusion, only 10 (13.0%) and 6 (7.8%) patients responded and remitted, respectively; after six ketamine infusions, 52 (67.5%) patients responded and 37 (48.1%) remitted. There was a significant mean decrease in Montgomery-Asberg Depression Rating Scale score at four hours after the first ketamine infusion (7.0±7.5, p<0.001), and this decrease was maintained for the duration of the infusion period. The response to ketamine treatment was positively associated with no history of psychiatric hospitalization (odds ratio=3.56, p=0.009). Suicidal ideation rapidly decreased across the entire study sample, even among the nonresponder group. No significant differences were found regarding Brief Psychiatric Rating Scale and Clinician Administered Dissociative States Scale scores from the first infusion at baseline to four hours post-infusion.
Conclusion: Six ketamine infusions increased rates of response and remission when compared to a single-dose ketamine infusion in patients with major depressive disorder. Future controlled studies are warranted to confirm and expand these findings.“
Authors: Wei Zheng, Yan-Ling Zhou, Wei-Jian Liu, Cheng-Yu Wang, Yan-Ni Zhan, Han-Qiu Li, Li-Jian Chen, Ming D. Li & Yu-Ping Ning
Summary
Introduction
Major depressive disorder (MDD) is a chronic, severe, and debilitating psychiatric disorder that causes disability worldwide. Current treatment approaches are ineffective, and novel approaches are warranted for improving treatment outcomes in MDD.
Ketamine, a high-affinity noncompetitive NMDA receptor antagonist, exerts a rapid but transient antidepressant effect in MDD. Ketamine has been shown to have effect onset within 40 min post-infusion, up to peak effect sizes at 24 h, and sustained effects ranging from 5 – 8 days.
Ketamine has rapid but time-limited antidepressant effects.
Six consecutive ketamine infusions increased rates of response and remission in Chinese patients with major depressive disorder when compared to a single-dose ketamine infusion. Suicidal ideation rapidly decreased across the entire study sample, even among the nonresponder group.
Ketamine has rapid antidepressant effects, but a gradual loss of the therapeutic benefit is followed by repeated-dose IV infusions of ketamine. A recent study showed that 66.7% of patients who received repeated-dose IV infusion of ketamine achieved remission and 91.6% responded.
Currently available literature on ketamine use in treating patients with MDD has several limitations, including small sample size, focus on patients with TRD or mood disorders, and washed out from previous psychotropic medications. This study aimed to examine the efficacy and safety of repeated-dose IV ketamine in Chinese patients with MDD.
Methods
Study design
In this study, patients with mood disorders received six IV infusions of 0.5 mg/kg ketamine over 40 min administered over the course of 12 days. The infusions were administered by an intravenous pump infusion, and vital signs were recorded every 10 min for one hour.
Ketamine may be used with other psychotropic medications, but nonpharmacological interventions such as psychotherapy and repeated transcranial magnetic stimulation are not permitted.
Study subjects
The study was performed at the Affiliated Brain Hospital of Guangzhou Medical University on male and female adults aged 18 – 65 years, who had been diagnosed with MDD, suicidal ideations, or TRD. We focused on patients with TRD or apparent suicidal ideations and no other psychiatric diagnoses, a negative result on urotoxicological screening, and no other major medical condition or central nervous system disease.
Clinical assessments
The severity of depressive symptoms was evaluated using the Montgomery-Asberg Depression Rating Scale, the SSI-part 1 and the Hamilton Anxiety Scale, and the Clinician Administered Dissociative States Scale and the four-item positive symptom subscale of the Brief Psychiatric Rating Scale.
Patients were assessed with the above rating scales at baseline, four hours and 24 hours after each infusion and at a two-week follow-up after the completion of the last infusion. Five raters independently provided outcome ratings.
Statistical analysis
Statistical analysis was conducted for the intent-to-treat sample to examine the relationships between sociodemographic and clinical characteristics and the response status at t+24h after the completion of six ketamine infusions. A linear mixed model was applied to examine changes over time between responder and nonresponder groups with regard to continuous variables.
Baseline characteristics
Patients with a response to treatment were more likely to be employed, have a higher personal income and education levels, and have no history of psychiatric hospitalization.
Treatment response and remission
The response and remission rate for patients with MDD were 67.5% and 48.1%, respectively, after six ketamine infusions, and the response rate was positively associated with no history of psychiatric hospitalization.
The response and remission rate for patients with relapsed TRD were 13.0% and 8.3%, respectively, at t+24h after the first infusion.
Symptom ratings
At four hours after the first infusion, the mean MADRS score, SSI-part 1 score and HAMA score decreased significantly. These decreases were sustained throughout the course of the subsequent infusions among the entire sample, but not among the nonresponder subgroup.
Adverse events
During the first infusion, no significant difference was found regarding psychotomimetic and dissociative symptoms measured by the BPRS-four items and CADSS, respectively.
Discussion
In the first study of six IV infusions of ketamine at subanesthetic doses for Chinese patients with MDD, the antidepressant response to six ketamine infusions was positively related to no history of psychiatric hospitalization.
Ketamine infusion resulted in a large antidepressant effect, but traditional antidepressants have a delayed onset and have undesirable neurocognitive effects, making electroconvulsive therapy the last choice in the treatment of MDD.
In this study, 67.5% of patients with MDD achieved a response criterion and 48.1% remitted after six ketamine infusions, compared to 50% after a single infusion. The relapse rate was 28.8% at a 14-day follow-up, compared to 92% within the 14-day post-ketamine follow-up in previous studies.
Ketamine may act by blocking NMDA receptors, activating the AMPA receptor, and activating neuroplasticity-related signaling pathways, leading to restoration of prefrontal synaptic connectivity and increased number and function of new spine synapses in the prefrontal cortex.
Ketamine resulted in a rapid reduction in suicidal ideation across the entire study sample, even among subjects in the nonresponder group, and a history of psychiatric hospitalization was the sole predictor for clinical improvement in MDD from ketamine after controlling for other potential confounders.
Ketamine has an independent antisuicidal effect, and in a recent RCT focusing on MDD patients with clinically significant suicidal ideation, ketamine showed a significantly greater reduction in suicidal ideations than midazolam.
The current study had some limitations, such as a lack of placebo arm, an open-label design, and a short follow-up period. However, numerous meta-analyses of RCTs have consistently reported that a single-dose ketamine infusion at subanesthetic doses had a significantly more rapid and robust antidepressant effect when compared with placebo.