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.
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Bobo, W. V., Vande Voort, J. L., Croarkin, P. E. et al. · Depression and Anxiety (2016)
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.
Depression remains highly prevalent and often refractory to treatment, with many patients classified as treatment-resistant after failing adequate courses of antidepressants from at least two pharmacological classes and psychotherapeutic interventions. Electroconvulsive therapy (ECT) and other neuromodulation approaches provide options for treatment-resistant depression (TRD), but a substantial subset of patients do not respond to ECT administered under propofol anaesthesia; the investigators label these individuals as having ECT-resistant depression (ECT-RD). Prior studies have reported short-lived antidepressant effects of ketamine and ketamine-related alterations in brain structure and function, but the utility of combining ketamine with ECT (or as an anaesthetic during ECT) remains uncertain and may carry safety concerns including cardiovascular and addiction risks. Zhang and colleagues conducted a pilot study to test whether alternating intravenous low-dose ketamine and propofol-anaesthetised bilateral ECT over two weeks improves clinical outcomes and induces measurable changes in brain functional connectivity in patients with propofol-ECT-resistant depression. The study aimed to characterise both the time course of clinical response, assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17), and treatment-associated changes in global functional connectivity density (gFCD) and functional connectivity strength (FCS) within the default mode network (DMN) using repeated resting-state fMRI assessments.
This was a single-arm, within-subject pilot study approved by the Tianjin Anding Hospital ethics committee. Patients admitted between December 2014 and December 2018 who had failed to respond to at least 12 sessions of propofol-ECT in the prior two months and met TRD criteria were recruited. The extraction reports that 36 propofol-ECT non-responders (6 males, 30 females) consented; eight were excluded (three for poor image quality and five for failing to complete the second MRI), yielding a final sample of 28 patients. All participants were right-handed and underwent structured clinical interviews (SCID) and baseline HAMD-17 assessment. Exclusion criteria included other psychotic or affective disorders (for example bipolar disorder), substance use disorders, organic brain lesions, major medical or neurological disease, MRI contraindications, and history of prolonged unconsciousness. Intervention: participants received alternating treatments over two weeks (six ketamine sessions and six propofol-ECT sessions). Ketamine was administered intravenously at 0.5 mg/kg over 40–50 minutes at 22:00 the night before each ECT session; vital signs were monitored after infusion. Bilateral ECT was delivered the following morning between 08:30 and 09:30 using a MECTA device with propofol (1–2 mg/kg) for anaesthesia and succinylcholine as muscle relaxant; atropine (0.25–1 mg) was used as needed. Treatments were given three times per week for two weeks. Imaging and assessments: resting-state fMRI and structural MRI were acquired on a 3T GE scanner. Six MRI scans were scheduled at baseline and at days 1, 3, 7, 10 and 14 after the first ketamine plus ECT treatment. HAMD-17 ratings were obtained at baseline, day 7 and day 14. Functional metrics calculated were global functional connectivity density (gFCD), computed voxel-wise with a Pearson correlation threshold R>0.6 limited to grey matter and normalised by the brain mean, and functional connectivity strength (FCS) within the DMN, derived from group-independent component analysis seeds (top 100 voxels per DMN region) and pairwise region mean time-course correlations. Preprocessing and statistics: resting-state data were processed with SPM8, discarding the first 10 volumes, correcting slice timing and motion (head motion <2 mm and <2°), regressing covariates including Friston 24-parameter head motion, white matter and CSF signals, censoring volumes with frame-wise displacement >0.5, band-pass filtering (0.01–0.08 Hz), normalising to MNI space and resampling to 3 mm voxels. gFCD maps were smoothed with a 6 mm Gaussian kernel. Paired t-tests compared pre- and post-treatment HAMD scores and imaging metrics; family-wise error (FWE) correction was applied to gFCD and DMN FCS comparisons, with significance set at p<0.05. In one analysis a double threshold (cluster size ≥30 and FWE-corrected p<0.001) is reported for gFCD changes.
Depression has high morbidity, relapse, and disability rates. Although a significant number of antidepressants have been introduced, many patients still experience treatment failure. Patients are considered to have treatment-resistant depression (TRD) if there is no effect or minimal effectiveness after receiving adequate dose-duration use of antidepressants from two different categories (must be different chemical structures) and psychotherapeutic treatments (either in combination or succession) in the current depressive episode. Many therapeutic methods, such as electroconvulsive therapy (ECT), repeat transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS), and deep brain stimulation (DBS), can be used either in combination or in succession to treat TRD patients, yet approximately half of patients with TRD fail to respond to these treatments. According to previous reports, a large number of TRD patients who do not respond to propofol-ECT treatment; UK ECT Review Group. Efficacy and safety of electroconvulsive therapy in depressive disorders: a systematic review and. Based on this background, we have conducted a pilot study to investigate a new treatment method for TRD patients. In this pilot study, the patients with TRD who did notReceived 3 December 2019; Received in revised form 2 March 2020; Accepted 5 March 2020 respond to ECT were defined as having ECT-resistant depression (ECT-RD). Ketamine was 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 in some patients with TRD. These studies have converged to support the hypothesis that the strong antidepressant effect of ketamine might be related to the structural and functional brain alterations induced by ketamine. Ketamine was first reported as a safe anaesthetic for clinical use during ECT in 1972, yet a clinical trial conducted in 2018 reported that ketamine, when used as an anaesthetic during ECT, did not improve the efficacy of ECT. While a recent meta-analysis reported that ketamine combined with other anaesthetic agents might have short-term advantages in reducing depressive symptoms during the early stages of ECT, some published studies have shown that the combination treatment may increase the risk of side effects, specifically adverse cardiovascular effects. Previously, Molero et al. reviewed the antidepressant efficacy and tolerability of ketamine and pointed out that major concern that remains is establishing an effective protocol to maintain the clinical antidepressant effect of ketamine with acute administration while managing long-term safety, specifically regarding the potential for neurocognitive, urologic toxicity, and the induction of substance use disorders. A recent review stated the limitations of ketamine, including non-permanent antidepressant effects, high relapse rates, and the need for repeated treatment. Therefore, there is an urgent need for exploring new methods for using ketamine plus propofol-ECT in patients with ECT-RD.
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Schwartz, J., Murrough, J. W., Iosifescu, D. V. · Evidence-Based Mental Health (2016)
According to the extracted text, 28 patients completed the protocol and were analysed. Clinically, mean HAMD-17 scores fell from 32.49 at baseline to 14.57 at day 7 after the treatment sequence, corresponding to a reduction rate of approximately 56.2% (statistically significant, p<0.05). However, symptom improvement was transient: depressive symptoms began to relapse from day 8 onwards, and by day 14 the mean HAMD-17 score had returned to 26.71 ± 5.7, a level described as severe depression. Item-level improvements on day 7 included reductions in depressed mood, work and activities, and psychomotor retardation. Imaging findings indicated dynamic changes in functional connectivity following the combined ketamine plus propofol-ECT regimen. At day 7, gFCD values decreased in several regions including the medial prefrontal cortex, subgenual anterior cingulate cortex (sgACC), posterior cingulate cortex, thalamus, hippocampus and orbitofrontal cortex when applying a double threshold (cluster size ≥30 and FWE-corrected p<0.001); these decreases were reported to have disappeared by day 10. Intra-network analysis of the DMN showed that FCS within the DMN decreased beginning on day 1, reached its nadir at day 3, and then gradually returned toward baseline. The authors report no significant correlation between the magnitude of HAMD score reduction and the observed changes in gFCD or DMN FCS. An increase in gFCD in the amygdala was observed in uncorrected analyses, but this change did not survive FWE correction. The investigators note this trend because of its potential relevance to addiction risk and to hypotheses about tolerance, although it was not statistically significant after correction. The extracted text does not provide detailed adverse event data beyond routine monitoring during ketamine infusions and ECT sessions.
Zhang and colleagues interpret their findings as evidence that alternating low-dose ketamine infusions with propofol-anaesthetised bilateral ECT can produce a clinically meaningful reduction in depressive symptoms in ECT- resistant patients, but that this benefit is short-lived, lasting approximately seven days. They emphasise the mismatch between the temporal courses of clinical improvement and imaging changes: brain functional connectivity alterations (gFCD and DMN FCS) were detectable beyond the point at which clinical effects had waned, a dissociation the authors describe as “disjointed.” Several possible explanations are proposed. One hypothesis is that the haemodynamic basis of BOLD-fMRI (blood oxygen signals) may outlast changes in neural electrical activity, producing an apparent persistence of connectivity changes after clinical symptoms return; the authors acknowledge that a one-week lag exceeds typical vascular–neural timing differences and therefore remains speculative. A second possibility is rapid neurochemical desensitisation or tolerance in this ECT-RD sample, which could blunt the clinical response despite persistent connectivity changes; the authors concede that tolerance developing within a week seems rapid and requires further study. A third consideration is that gFCD and FCS metrics may not directly index the microphysiological mechanisms that drive clinical improvement, since they are derived from correlational calculations rather than direct measures of neuronal firing. The authors relate their results to prior literature indicating ketamine can transiently reduce depressive symptoms and alter sgACC and DMN connectivity, and they suggest that combined ketamine plus ECT may modulate brain metabolism and connectivity in a manner partly analogous to ECT alone. They highlight the non-significant trend toward increased amygdala gFCD and raise concerns about addiction risk and tolerance with repeated low-dose ketamine, recommending long-term follow-up. Key limitations acknowledged include the single-group, self-comparison design which limits causal inference about neural mechanisms, the relatively short observation period that may have missed longer-term dynamics, and the need for controlled and longer-term studies to better characterise efficacy, durability and safety, including addiction potential.
In this pilot study, alternating low-dose ketamine infusions with propofol-anaesthetised bilateral ECT produced a measurable antidepressant effect in ECT-resistant patients that persisted for approximately one week. Treatment-related functional connectivity changes were observed in medial prefrontal regions, sgACC, posterior cingulate, thalamus, hippocampus, orbitofrontal cortex and within the DMN, but these imaging alterations did not align temporally with the clinical response. The authors conclude that while the combined approach yields short-term benefit, its limited duration and unresolved safety questions, including tolerance and addiction risk, warrant further controlled and longer-term investigation.
The study was approved by the Ethics Committee of Tianjin Anding Hospital, Tianjin, China. Each participant was informed of the purpose and process of the experiment in detail and provided written informed consent. A total of 36 propofol-ECT treatment non-response patients with ECT-RD (6 males and 30 females) who were admitted to Tianjin Anding Hospital from December 2014 to December 2018 were recruited for this study. Structured clinical interviews for DSM-IV Axis I Disorders-Patient Edition (SCID-I/P) were conducted by two senior psychiatrists with more than 10 years of experience. Simultaneously, a 17-item Hamilton Depression Scale (HAMD-17) was used to assess the severity of the symptoms. The exclusion criteria were as follows: (1) Patients had other psychotic or affective disorders, such as bipolar disorder, mental retardation, substances abuse or addiction, organic brain lesions, or other physical and neurological diseases; (2) patients had contraindications for MRI examination; and (3) history of unconsciousness for more than five min due to any reason. The clinical diagnosis of ECT-RD was made according to the following criteria. The treatment of the patients who failed to improve with adequate doseduration antidepressants from two different categories with different chemical structures or psychotherapeutic treatments (either in combination or succession) in the current episode of depression.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 (HAMD scores reduced < 15%) and simultaneously, according to the TRD criteria mentioned above.All of the patients were righthanded. Eight patients were excluded from the study according to the exclusion criteria, including three patients with poor image quality and five patients who failed to undergo the second MRI examination.
Functional connectivity strength (FCS) was used to assess the brain functional activity alterations in these ECT-RD patients according to previous reports. Depressive symptoms in the patients was used HAMD scale (17 items version) to assess.
HAMD was used to assess the severity of depression, followed by MRI. Subsequently, ketamine (0.5 mg/kg, 40-50 min) was intravenously injected at 10:00 pm the day before the propofol-ECT treatment. Next, the patients underwent propofol-ECT at 8:30-9:30 am the next day. In total, ketamine treatment was given six times and propofol-ECT was also given six times during a period of two weeks (three times per week). In this pilot study six times of MRI Scanning were performed (baseline [before the ketamine treatment], 1st day, 3rd day, 7th day, 10th day, and 14th day after the first ketamine plus propofol-ECT treatment), and three times HAMD assessment were performed (baseline, 7th day, and 14th day). The HAMD scores and the MRI alterations were compared, and the therapeutic effects of ketamine plus propofol-ECT were assessed.
The dose of ketamine was based on a previous studyand considered the potential influence of fluctuations in the levels of noradrenaline (NE). A single dose of 0.5 mg/kg ketamine was intravenously injected into the patients within 40-50 min at 10:00 pm before the propofol-ECT session on the second day. After the intravenous injections, ECG, blood pressure, and oxygen levels were monitored. HAMD scores were recorded each week after the ketamine plus propofol-ECT treatment. In total, ketamine was injected six times in 14 days.
In this study, propofol-ECT was given three times within seven days, for a total of 6 times within 14 days, and the parameters were set according to our previous study. ECT was performed using an integrated instrument (MECTA spECTrum 5000Q, MECTA Corp, USA), and bilateral ECT was applied from 8:30 am to 9:30 am with the static resistance of 300-3000 Ω. Depending on the patient's heart rate, the doses of intravenous atropine ranged from 0.25 mg to 1 mg. The intravenous doses of propofol (anaesthetic) and succinylcholine (muscle relaxant) ranged from 1 to 2 mg/kg. The stimulus intensity of ECT was adjusted accordingly by an energy percentage based on the patients' ages. Electrocardiograms, electroencephalograms, electromyography, oxyhaemoglobin saturation and blood pressure were monitored. ECT was applied 6 times in 14 days.
For precisely characterizing the trajectory of ketamine plus propofol-ECT treatment, according to the previous reports, MRI examinations were conducted six times at baseline, 1st day, 3rd day, 7th day, 10th day, and 14th day after the first ketamine plus propofol-ECT treatment, respectively. The MRI was performed on a 3T GE Discovery MR750 scanner (General Electric, Milwaukee, WI, USA) equipped with an eight-channel phased-array head coil. The participants were instructed to lie down in a supine position and to remain resting without falling asleep during the scan. Whole-brain resting-state fMRI (rs-fMRI) data depicting the blood oxygen level-dependant (BOLD) signal were obtained using a gradient-echo-planar imaging sequence with the following parameters: repetition time (TR) = 2000 msec; echo time (TE) = 45 msec; slices = 32; slice thickness= 4 mm; gap=0.5 mm; field of view (FOV) = 220 × 220; matrix size = 64 × 64; and flip angle (FA) = 90°All scans were acquired by parallel imaging using the sensitivity encoding (SENSE) technique with a SENSE factor of 2. Structural images were obtained with a high-resolution 3D Turbo-Fast Echo T1WI sequence with the following parameters: 170 slices, TR/TE = 8.2/3.2, slice thickness = 1 mm, no gap, FA = 12°, matrix size = 256 × 256, FOV = 256 × 256.
SPM8 was used to process the resting-state fMRI scans (). To allow for imaging unit stabilization and subject familiarization, the first 10 volumes of scans were discarded. The remaining volumes were corrected for slice-timing and motion artefacts. Head translation movement for all participants was less than 2 mm, and rotation was less than 2°The covariates, including head motion, white matter signal and cerebrospinal fluid signal, were regressed out from the time series of every voxel. Here, the Friston 24parameter model was used to regress out head motion effects. Next, the frame-wise displacement (FD) was calculated, and the data were regressed out of the study if the FD of a specific volume was > 0.5. The datasets were filtered with band-pass frequencies ranging from 0.01 to 0.08 Hz. Individual structural images were co-registered to the mean functional image, and the transformed structural images were co-registered to the Montreal Neurological Institute (MNI) space using a linear registration. The motion-corrected functional volumes were spatially normalized to the MNI space using parameters estimated during the linear co-registration. Finally, the functional images were resampled into 3-mm cubic voxels for further analysis.
The FCD of each voxel was calculated using an in-house Linux script as previously reported.Functional connectivity between the voxels was evaluated using Pearson's linear correlation with a correlation coefficient threshold of R> 0.6. The gFCD calculations were limited to those voxels within the cerebral grey matter masque, and the gFCD at any given voxel(x0) was calculated as the total number of functional connections, denoted as k(x0), between x0 and all other voxels using a growth algorithm, which was repeated for all of the x0 voxels. Next, gFCD was divided by the mean value of the qualified voxels in the brain to increase the normality of the distribution. The FCD maps were spatially smoothed with a 6 × 6 × 6 mm 3 Gaussian kernel to minimize differences in the functional anatomy of the brain between the subjects.
According to the method by Liu et al., we calculated the FCS within DMN, briefly described as follows: seeds were created from the top 100 voxels in each DMN region of the group-independent component analysis component. The time course of each region of interest was extracted from the preprocessed data, and the functional connectivity was calculated between the mean time-courses between any two regions of interest.
The pre-and post-treatment differences in gFCD and FCS within DMN were corrected using the family-wise error (FWE). A paired t-test was used to compare the HAMD changes and differences in the gFCD and FCS within DMN before and after ketamine plus propofol-ECT. Any p-values < 0.05 were considered as statistically significant.
The patients' demographics and clinical data are shown in Table. The HAMD scores before and after ketamine plus propofol-ECT treatment were significantly different in patients with ECT-RD on the seventh day, and they were reduced by 56% or more (p < 0.05; Table). However, from the eighth day on, the depressive symptoms relapsed, and at the fourteenth day, the depressive symptom relapse had reached the level of severe depression (HAMD-17 scores: 26.71 ± 5.7). The comparison of HAMD items between before ketamine and after ketamine on the seventh day and the comparison of HAMD items between the 7th day are shown in Tableand 14th day after ketamine treatment are shown in Tablesand, respectively. The symptoms, including depressed mood, work and activities, and retardation were significantly relieved. At a double threshold of ≥ 30 clump size and corrected FEW of p < 0.001, gFCD values decreased in the medial prefrontal lobe, subgenual anterior cingulated cortex (sgACC), posterior cingulate, thalamus, hippocampus, and orbitofrontal lobe on the seventh day, and they were disappeared on the tenth day (Fig.). The intra-network connectivity alterations in the DMN are shown in Fig.. Red and green lines represent decreased and increased connectivity, respectively. The red lines increased after ketamine plus treatment, indicating that FCS within the DMN decreased from the first day. The mean value of FCS within the DMN dynamically decreased to reach the lowest point on the third day and then gradually recovered (Fig.). The HAMD scores decreased from 32.49 to 14.57 after ketamine injection for 7 days and then gradually increased to 26.71 at day 14 after ketamine injection (Fig.). There is no significant correlation between the HAMD score reduction and the alterations of gFCD and FCS within the DMN. As shown in Fig., the amygdala demonstrated increased gFCD. However the increased gFCD in the amygdala disappeared after FWE correction. Although the increased gFCD in the amygdala cannot be defined as statistically significant by FWE correction, these findings suggest that we should pay more attention to addiction tendencies in the future. As shown above, the treatment effect of ketamine plus propofol-ECT treatment disappears quickly, which may be caused by the development of tolerance. Tolerance is usually related to the hyperactivity of the amygdala, which is an important index of addiction risk.
To the best of our knowledge, to date, the present study is the first to investigate the ideal method to improve the efficacy of ketamine plus propofol-ECT in patients with ECT-RD. In the present study, we found that ketamine plus propofol-ECT can obviously improve the antidepressant effects of propofol-ECT in patients with ECT-RD (HAMD scores reduced rate: 56.2%). However, more notably, these effects are only sustained for seven days. This is not an ideal effect, indicating that this ketamine plus propofol-ECT method is not ideal. We should conduct further studies to explore new methods to treat ECT-RD patients. Another important finding of our present study is that the alterations in brain functional activity, even in brain metabolism, were also disjointed with the clinical effects. These findings provided pivotal information for future studies. We postulated the following reasons for this phenomenon. First, the ketamine plus propofol-ECT-induced brain functional alterations can be sustained for a relatively long time, but the induced neural electric activity is attenuated before the brain functional connectivity attenuation, and eventually, the interactions amongst the neurons in brain are based on action potential, and the findings came from fMRI data, mainly based on the blood oxygen signal. Hence, the delay in blood oxygen signal may be demonstrated as brain functional connectivity alterations that are sustained longer than the clinical effect, but this postulation has a limitation, as a one-week delay exceeded the time differences in electric activity and blood oxygen signal. Further studies will be needed to clarify this possibility. Second, these samples may be one of the reasons for this disjointed phenomenon, and we postulated that these ECT-RD patients may have rapid desensitization characteristics for neurotransmitters; hence, the rapid desensitization caused the ketamine synergistic effect was weakened. This postulation also has a limitation, since desensitization in one week's time is so rapid; thus, further studies will be needed to explore this possibility. More notably, if these samples have rapid desensitization characteristics, we must alter the addiction tendency. Previous studies reported that low-dosage ketamine also carries an addiction risk. Third, we postulated that the gFCD and FCS within the DMN are not suitable to be used as indices to assess the clinical effects, as gFCD and FCS are based on calculation, not microimaging, which cannot provide direct evidence for the neural structural alterations or discharge activities. Further studies are needed to clarify this possibility. Previous studies have reported that ketamine can alleviate the depressive symptoms of treatment-resistant depression and reduce suicidal ideation. Accompanied by the clinical effects, a decrease in the FCS within the DMN was observed. Previous studies have reported that ketamine alone can produce antidepressant effects equivalent to ECT treatment, though it may induce alterations in the sgACC and DMN FCS. However, there are no reports on the use of ketamine plus other anaesthetic drugs as an alternative therapy to propofol-ECT. This type of study could help improve treatment options in the future. The treatment of ECT-TRD patients already requires a combination of multiple drugs with varying safety profiles. Our findings are consistent with those of the previous studies to some extent. When considered in the context of previous findings, our findings also support the idea that ketamine can induce brain functional connectivity alterations not only from FCS but also from functional connection numbers. According to Thompson, gFCD can also be used as an index to reflect the brain metabolism; hence, our findings also support that brain metabolism alterations can alleviate depressive symptoms. More interestingly, previous studies reported that the antidepressant effect of ECT can enhance brain metabolism. Ketamine plus ECT effects may be explained by this postulation. However, the ketamine synergistic effect disappeared after one week, which can be explained by this postulation. Further studies will be needed to clarify this possibility. Our findings demonstrated that increased gFCD was located in the amygdala, which cannot withstand the FWE correction. Although these increased gFCD in the amygdala can be defined as insignificant by FEW correction, we remain should pay more attention to addiction tendency in the future. Our data have demonstrated that the treatment effect of ketamine plus propofol-ECT treatment lasts for only seven days, which may due to an increase in tolerance. Increases in tolerance are commonly associated with hyperactivity of accumbens and amygdala, which is an important index of addiction risk. A long-term study is needed to clarify the addiction tendency of low dosage ketamine. There are several limitations to this study. First, the present study is a self-comparison study, which cannot provide strong evidence to explain the neural mechanism of the effect of ketamine plus propofol-ECT on the brain functional connectivity alteration. Second, the observation time was short and not sufficient for us to characterize the dynamic alterations of ketamine plus propofol-ECT on brain functional alterations using another method, such as ketamine administration once per day for one week, and subsequently using ECT for one week; alternating use may acquire a long-term antidepressant effect. Hence, a long-term cohort study is needed to subsequently clarify and precisely characterize the dynamic trajectory of the brain functional connectivity alterations and the clinical effect induced by ketamine plus propofol-ECT treatment. Finally but maybe more importantly, more attention should be given to the tendency of addiction.
In this study, ketamine plus propofol-ECT produced a one-week antidepressant effect in ECT-RD patients. The brain functional alterations induced by ketamine plus propofol-ECT were mainly located in the medial prefrontal lobe, subgenual anterior cingulated cortex (sgACC), posterior cingulated, thalamus, hippocampus, and orbitofrontal lobe and the DMN. More importantly, we also found disjointed results between the clinical effect and brain functional alterations. Although this phenomenon cannot be fully explained, it provides a pivotal clue for us to further explore new methods for the treatment of ECT-RD patients.
The study was approved by the Ethics Committee of Tianjin Anding Hospital, Tianjin, China. All procedures performed in studies involving human participants were in accordance with the ethics standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethics standards. Written informed consent was obtained from all individual participants included in this study.