•A single dose of ketamine infusion reduces TNF-α levels at 40 min and 240 min postinfusion.•There is a positive correlation between changes in cytokine levels after ketamine infusion and ...improvements in depressive symptoms.•The rapid suppression of proinflammatory cytokines may contribute to the rapid antidepressant effect of the ketamine infusion.
Increasing evidence supports the rapid antidepressant effect of a low-dose ketamine infusion in treatment-resistant depression (TRD). Proinflammatory cytokines play a crucial role in the pathophysiology of TRD. However, it is unknown whether the rapid antidepressant effect of ketamine is related to the rapid suppression of proinflammatory cytokines. Seventy-one patients with TRD were randomized into three groups according to the treatment received: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and normal saline infusion. Proinflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α were examined at baseline and at 40 min, 240 min, Day 3, and Day 7 postinfusion. Montgomery–Åsberg Depression Rating Scale (MADRS) was assessed for depressive symptoms across time. Log-transformed IL-6 and TNF-α levels differed significantly over time. The decrease in TNF-α between baseline and 40 min postinfusion was positively correlated with a decrease in MADRS scores across time in the 0.5 mg/kg ketamine group. This is the first clinical study to support a positive correlation between changes in cytokine levels after ketamine infusion and improvements in depressive symptoms with TRD. The rapid suppression of proinflammatory cytokines may contribute to the rapid antidepressant effect of the ketamine infusion.
Theta-burst transcranial magnetic stimulation could modulate cortical excitability and has the potential to treat refractory depression. However, there has been a lack of large randomized studies of ...the antidepressant efficacy of different forms of theta-burst stimulation, such as intermittent and continuous theta-burst stimulation. A randomized sham-controlled study was conducted to investigate antidepressant efficacy of theta-burst stimulation and to compare efficacy among left-prefrontal intermittent theta-burst stimulation, right-prefrontal continuous theta-burst stimulation and a combination of them in patients showing different levels of antidepressant refractoriness. A group of 60 treatment-refractory patients with recurrent major depressive disorder were recruited and randomized to four groups (Group A: continuous theta-burst stimulation; Group B: intermittent theta-burst stimulation; Group C: a combination of continuous and intermittent theta-burst stimulation; and Group D: sham theta-burst stimulation; 15 patients were included in each group). After 2 weeks of theta-burst stimulation treatment, depression improved in all groups. Groups B and C had better antidepressant responses (as reflected by % decreases in depression score) than Groups A and D (P = 0.001, post hoc analysis: B > A, B > D, C > A, and C > D), even after controlling for age and refractoriness scores. The mean antidepressant effect was highest in Group C and followed by that in Group B. Additionally, a significant placebo effect was found in patients with low refractoriness; this disappeared in patients with moderate-to-high refractoriness. A significant correlation existed between refractoriness scores and treatment responses. Treatment refractoriness was a significant factor negatively predicting efficacy of theta-burst stimulation (P = 0.039). This randomized sham-controlled study demonstrated that active theta-burst stimulation is a well-tolerated form of repetitive transcranial magnetic stimulation and has good antidepressant efficacy, particularly in depressed subjects within a certain range of treatment refractoriness.
Prolonged intermittent theta burst stimulation (piTBS) with triple doses of the standard protocol is an updated form of repetitive transcranial magnetic stimulation, and it is an effective add-on ...intervention for major depressive disorder. In the present study, our objective was to investigate the antidepressant efficacy of piTBS monotherapy. Efficacy between the standard 5-cm method and magnetic resonance imaging (MRI)–guided coil positioning to the left dorsolateral prefrontal cortex method was also compared.
In the present double-blind, randomized, sham-controlled trial, 105 patients with recurrent depression who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode were assigned randomly to one of three groups: piTBS monotherapy (n = 35), repetitive transcranial magnetic stimulation monotherapy (n = 35), or sham stimulation (n = 35). The acute treatment period was 2 weeks. Half of the patients were randomized to MRI navigation in each group.
No serious adverse events were observed. The piTBS group exhibited significantly greater decreases in depression scores than the sham group at week 2 (−40.0% vs. −13.9%; p < .001 after correcting for multiple comparisons by Bonferroni effect size (Cohen’s d) = 1.12), and the odds ratio for responses was high. The MRI navigation method (−32.4%) did not yield better antidepressant effects than the standard method (−40.6%). Brain stimulation and 17-item Hamilton Depression Rating Scale changes in the first week were the most important variables for predicting antidepressant responses.
Left prefrontal piTBS monotherapy is effective for the treatment of recurrent depression, and the MRI-guided method of coil targeting is not better than the standard method.
The periaqueductal gray (PAG) is known to play a crucial role in pain modulation and has shown a strong interaction with anterior cingulate cortex in previous functional imaging studies. We ...investigated the intrinsic functional connectivity of PAG using resting fMRI data from 100 subjects. The results showed that PAG is functionally connected to ACC (rostral and pregenual ACC) and also rostral ventromedial medulla (RVM), forming a core ACC–PAG–RVM network for pain modulation even no pain stimulus is applied. The comparison between genders showed that for the contrast of female minus male, significant difference was observed at mid-cingulate cortex; for the contrast of male minus female, significant differences were observed at left medial orbital prefrontal cortex, and uncus; right insula/operculum and prefrontal cortex.
We believe eluciation of this intrinsic PAG network duing the resting state will enhance our physiological and pathological understandings of the development and maintenance of chronic pain states.
Kinship, friendship alliances, and perceptions of others' beliefs guide social interactions and are central to cohesive group behavior. Under certain conditions, brain systems that involve regions ...along the frontal midline increase activity when inferences are drawn about others who share a similar view to one's own (similarity). A prominent hypothesis is that these regions contribute to social cognition by simulating the other person's perspective based on one's own experience. An alternative is that certain regions process the social relevance of the person (closeness) to oneself and contribute to the assessment akin to signals that govern behavioral approach responses. These alternatives were explored across four functional magnetic resonance imaging experiments (n = 98). Experiment 1 localized the target midline regions in the rostral anterior cingulate cortex and anterior medial prefrontal cortex by having participants make personal judgments. The two dimensions (similarity, closeness) were crossed in experiment 2 using actual friends of the participant and unknown others. Making judgments about oneself and friends resulted in increased midline response relative to unknown others regardless of whether the friends shared similar views as the participant. Experiment 3 revealed that similarity was not a factor even when close others were not included. Experiment 4 directly contrasted two extremes: participants made inferences about similar, unknown others and dissimilar friends. Judgments about the close others again increased blood oxygenation level-dependent response along the frontal midline. These results encourage further exploration of the idea that frontal systems linked with limbic circuits facilitate assessment of the relevance or personal significance in social contexts.
Objective
Research evidence has shown that bipolar disorder (BD) and unipolar depression (UD) are both related to inflammatory dysregulation, but few studies have compared the levels of cytokines ...between these two disorders.
Methods
Study subjects were age‐ and gender‐matched outpatients with BD or UD and normal controls (NC). Severities of depression and mania symptoms were assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Young Mania Rating Scale (YMRS). Pro‐inflammatory cytokines, including soluble interleukin‐6 receptor (sIL‐6R), soluble interleukin‐2 receptor (sIL‐2R), C‐reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF‐R1), soluble p‐selectin receptor (sP‐selectin), and monocyte chemotactic protein‐1 (MCP‐1), were assessed in all subjects by enzyme‐linked immunosorbent assays.
Results
In all, 130 patients with BD, 149 patients with UD, and 130 NC were enrolled in the study; 67.6% were female and the average age was mean ± standard deviation (SD) 43.5 ± 11.8 years. The BD group had a significantly higher smoking rate, more medical comorbidity, higher body mass index (BMI), and higher levels of sIL‐2R, sIL‐6R, CRP, sTNF‐R1, and MCP‐1 (all p < 0.01) than the UD and NC groups. When the remitted patients with BD (YMRS scores ≤ 12) were compared with the patients with UD, controlling for age, MADRS score, smoking, medical comorbidity, and BMI in the regression model, the results showed that the BD group had significantly higher levels of sIL‐6R (p < 0.001), CRP (p = 0.045), sTNF‐R1 (p = 0.036), and MCP‐1 (p = 0.001) than the UD group.
Conclusions
Higher levels of sIL‐6R, CRP, sTNF‐R1, and MCP‐1 were noted in BD than in UD. These results may suggest a more severe inflammatory dysregulation in BD. Further studies are required to investigate whether these cytokines could be biomarkers for affective disorders.
Increasing evidence supports a rapid antidepressant and antisuicidal effect of a single subanesthetic dose of ketamine infusion for treatment-resistant depression (TRD). Maintaining the initial ...clinical response after ketamine infusion in TRD is a crucial next-step challenge. D-cycloserine (DCS), a partial agonist of the glycine co-agonist of the N-methyl-D-aspartate (NMDA) glutamate receptor, is potentially effective as a depression augmentation treatment. However, whether DCS maintains the antidepressant and antisuicidal effects of ketamine infusion remains unknown. In all, 32 patients with TRD (17 with major depression and 15 with bipolar depression) who responded to ketamine infusion with an average 17-item Hamilton Depression Rating Scale (HAMD) score of 9.47 ± 4.11 at baseline were randomly divided to 6-week DCS treatment (250 mg for 2 days, 500 mg for 2 days, 750 mg for 3 days, and 1000 mg for 5 weeks) and placebo groups. Depression symptoms were rated at timepoints of dose titration and weekly. During the 6-week treatment, the total scores of HAMD did not differ between the DCS and placebo groups. The results remained consistent when stratified by disorder. A mixed model analysis indicated that the DCS group exhibited lower scores of HAMD item 3 (suicide) compared with the placebo group throughout the follow-up period (p = 0.01). A superior maintenance of the antisuicidal effect of ketamine was observed in the DCS group than in the placebo group. DCS may be therapeutically beneficial for patients with TRD who responded to ketamine infusion but have a residual suicidal risk.
The antidepressant effects of ketamine are thought to depend on brain-derived neurotrophic factor (BDNF) genotype and dose. The purpose of this study was to characterize the dose-related ...antidepressant effects of ketamine in patients with treatment-resistant depression drawn from a Chinese population predominately possessing lower activity BDNF genotypes (Val/Met, Met/Met). We conducted a double-blind, randomized, parallel-group, placebo-controlled trial of a single ketamine infusion (saline, 0.2 mg/kg, 0.5 mg/kg). Patients (N=71; BDNF genotype: Val/Val (N=12, 17%), Val/Met (N=40, 56.3%), and Met/Met (N=19, 26.8%)) received mood ratings before infusion, after infusion, and for the subsequent 14 days. Plasma ketamine levels and BDNF genotypes were assessed. This study found a significant dose-related ketamine effect on scores on the Hamilton Depression Rating Scale (HAMD). The responder analysis (>50% reduction from baseline HAMD on at least 2 days between days 2 and 5) also revealed a significant dose-related effect (saline: 12.5%, 0.2 mg/kg: 39.1%; 0.5 mg/kg: 45.8%). This is the first report to our knowledge to demonstrate the dose-related efficacy of R/S-ketamine for treatment-resistant depression and the first to characterize ketamine effects in a genotyped Chinese population in which most (83%) patients possessed at least one copy of the lower functioning Met allele of the BDNF gene.
Evidence suggested the crucial roles of brain-derived neurotrophic factor (BDNF) and glutamate system functioning in the antidepressant mechanisms of low-dose ketamine infusion in treatment-resistant ...depression (TRD).
65 patients with TRD were genotyped for 684,616 single nucleotide polymorphisms (SNPs). Twelve ketamine-related genes were selected for the gene-based genome-wide association study on the antidepressant effect of ketamine infusion and the resulting serum ketamine and norketamine levels.
Specific SNPs and whole genes involved in BDNF–TrkB signaling (i.e., rs2049048 in BDNF and rs10217777 in NTRK2) and the glutamatergic and GABAergic systems (i.e., rs16966731 in GRIN2A) were associated with the rapid (within 240 min) and persistent (up to 2 weeks) antidepressant effect of low-dose ketamine infusion and with serum ketamine and norketamine levels.
Our findings confirmed the predictive roles of BDNF–TrkB signaling and glutamatergic and GABAergic systems in the underlying mechanisms of low-dose ketamine infusion for TRD treatment.
•The specific genes involving BDNF–TrkB signaling and glutamatergic system may predict the rapid antidepressant effect of ketamine.•Several SNPs in NTRK2, GRIN2A, and GRIN2B are related to the resulting serum levels of ketamine and norketamine after infusion.•Those genes may be involved in NMDAR blockade, GABA and glutamate nerve terminals, and postsynaptic dendritic spines.
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