This open-label study (n=28) investigated whether ketamine (35mg/70kg) treatment prior to propofol-assisted electroconvulsive therapy (ECT) can improve clinical symptoms of depression. The addition of ketamine improved treatment, and this was accompanied by increased global functional connectivity density in the left temporal and subgenual anterior cingulated cortex and decreased functional connectivity strength within the default mode network for a period of 10 days. However, the remission of depressive symptoms only lasted 7 days.
Abstract
“Introduction: New methods for using ketamine in patients with propofol-electroconvulsive therapy-resistant depression (ECTRD) are needed in the clinic.
Methods: This study aimed to investigate the therapeutic efficacy of ketamine plus ECT in ECT-RD patients, along with the treatment-induced brain alterations. A total of 28 ECT-RD patients were intravenously injected with ketamine six times and treated with propofol-ECT six times alternately within two weeks. The Hamilton Depression Scale was used to assess the treatment effect. Global functional connectivity density (gFCD) and functional connectivity strength (FCS) were used to evaluate functional brain alterations.
Results: As compared with the propofol-ECT treatment group, the addition of ketamine could improve the therapeutic outcomes in patients with ECT-RD. The treatment increased gFCD in the left temporal and subgenual anterior cingulated cortex. Simultaneously, the treatment decreased FCS within the default mode network. Although increased functional connectivity could be sustained for 10 days, the clinical effect was only sustained 7 days, indicating that the clinical effect and functional brain alterations were disjointed.
Discussion: Ketamine plus propofol-ECT can obviously improve the effects of propofol-ECT in ECT-RD patients. However, the effect is limited in 7 days, suggesting the benefit is short-term.
Authors: Jianjing Zhang, Hongjun Tian, Jie Li, Shengzhang Ji, Suling Chen, Jingjing Zhu, Deguo Jiang, Lina Wang, Gongying Li, Min Chen, Wenqiang Wang, Xiaodong Lin & Chuanjun Zhuo
Summary
Ketamine plus ECT improved the therapeutic outcomes in patients with propofol-electroconvulsive therapy-resistant depression, but the effect was short-term. Ketamine increased global functional connectivity density and decreased functional connectivity strength in the left temporal and subgenual anterior cingulated cortex.
- Introduction
Depression has high morbidity, relapse, and disability rates, and many patients still experience treatment failure. A pilot study was conducted to investigate a new treatment method for patients with treatment-resistant depression who did not respond to ECT.
Ketamine has been shown to partially alleviate the depressive symptoms in patients with TRD, and some studies have reported that ketamine can induce certain structural and functional brain alterations. Ketamine was first reported as a safe anaesthetic for clinical use during ECT in 1972, but a clinical trial conducted in 2018 reported that ketamine did not improve the efficacy of ECT. A recent meta-analysis reported that ketamine combined with other anaesthetic agents may increase the risk of side effects.
2.1. Subjects
36 patients with ECT-RD were recruited from Tianjin Anding Hospital, China, and were assessed with the SCID-I/P and HAMD-17. They were diagnosed with ECT-RD if they failed to improve with adequate dose-duration antidepressants from two different categories with different chemical structures or psychotherapeutic treatments. Propofol-ECT resistant patients were defined as those who experienced at least 12 sessions of propofol-ECT in the past two months with no alleviation of depressive symptoms.
2.2. Assessment methods
Functional connectivity strength (FCS) and depressive symptoms (HAMD) were used to assess brain functional activity alterations in ECT-RD patients.
2.3. Study procedure
HAMD was used to assess the severity of depression, followed by MRI. Ketamine was intravenously injected at 10:00 pm the day before the propofol-ECT treatment, and propofol-ECT was also given six times during a period of two weeks (three times per week).
2.4. Intravenous injection of ketamine
Ketamine was injected into the patients six times in 14 days before the propofol-ECT session. The patients’ ECG, blood pressure, and oxygen levels were monitored.
2.5. Propofol-ECT treatment of patients
In this study, propofol-ECT was given three times within seven days, for a total of 6 times within 14 days. The stimulation intensity was adjusted based on the patients’ ages.
2.6. MRI data acquisition
MRI examinations were conducted six times to precisely characterize the trajectory of ketamine plus propofol-ECT treatment. Resting-state fMRI data were obtained using a gradient- echo-planar imaging sequence and structural images were obtained using a high-resolution 3D Turbo-Fast Echo T1WI sequence.
2.7. Data preprocessing
The resting-state fMRI scans were processed with SPM8, and the covariates were regressed out from the time series of every voxel. The datasets were filtered with band-pass frequencies ranging from 0.01 to 0.08 Hz, and the functional images were resampled into 3-mm cubic voxels for further analysis.
2.8. Calculation of the global functional connectivity density (gFCD)
Functional connectivity between voxels was calculated using an in-house Linux script and standardized using Pearson’s linear correlation. The gFCD was calculated as the total number of functional connections between a voxel and all other voxels using a growth algorithm.
2.9. Calculation of the FCS within default mode network (DMN)
Liu et al. calculated the functional connectivity within DMN by comparing the mean time-courses between two regions of interest.
2.10. Statistical analysis
The family-wise error (FWE) was used to correct for differences between pre- and post-ketamine plus propofol-ECT.
- Results
Patients with ECT-RD were significantly relieved of depressive symptoms after ketamine plus propofol-ECT treatment on the seventh day, but the symptoms relapsed on the eighth day and reached the level of severe depression on the fourteenth day.
Ketamine injection decreased the gFCD and FCS in the medial prefrontal lobe, subgenual anterior cingulated cortex, posterior cingulate, thalamus, hippocampus, and orbitofrontal lobe, and the HAMD score decreased from 32.49 to 14.57, and then gradually increased to 26.71 at day 14 after ketamine injection.
The amygdala showed increased gFCD after ketamine plus propofol-ECT treatment, but the increased gFCD disappeared after FWE correction, which suggests that we should pay more attention to addiction tendencies in the future.
- Discussion
The present study investigated the ideal method to improve the efficacy of ketamine plus propofol-ECT in patients with ECT-RD, and found that the effects were only sustained for seven days. In the present study, the ketamine plus propofol-ECT-induced brain functional alterations were disjointed with the clinical effects. We postulated that the delay in blood oxygen signal may be demonstrated as brain functional connectivity alterations that are sustained longer than the clinical effect.
We postulated that ECT-RD patients may have rapid desensitization characteristics for neurotransmitters, which would weaken the ketamine synergistic effect. We also postulated that gFCD and FCS within the DMN are not suitable to be used as indices to assess the clinical effects.
Previous studies have reported that ketamine can alleviate depressive symptoms of treatment-resistant depression and reduce suicidal ideation. However, no studies have reported that ketamine plus other anaesthetic drugs can be used as an alternative therapy to propofol-ECT.
Our findings are consistent with previous studies to some extent, and support the idea that ketamine can induce brain functional connectivity alterations. Ketamine can also enhance brain metabolism, which may explain the synergistic effect of ketamine and ECT.
The treatment effect of ketamine plus propofol-ECT treatment lasts for only seven days, which may due to an increase in tolerance. A long-term study is needed to clarify the addiction tendency of low dosage ketamine.
This study has several limitations, such as being a self-comparison study and the observation time being short. A long-term cohort study is needed to clarify the dynamic alterations of ketamine plus propofol-ECT on brain functional connectivity alteration.
- Conclusions
Ketamine plus propofol-ECT produced a one-week antidepressant effect in ECT-RD patients. The brain functional alterations were located in the medial prefrontal lobe, subgenual anterior cingulated cortex, posterior cingulated cortex, thalamus, hippocampus, and orbitofrontal lobe.
Ethical approval
The study was approved by the Ethics Committee of Tianjin Anding Hospital, Tianjin, China, and all participants gave written informed consent.
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https://doi.org/10.1016/j.psychres.2020.112907
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