Susceptibility to Treatment-Resistant Depression Within Families.

Importance: Antidepressant responses and the phenotype of treatment-resistant depression (TRD) are believed to have a genetic basis. Genetic susceptibility between the TRD phenotype and other psychiatric disorders has also been established in previous genetic studies, but population-based cohort studies have not yet provided evidence to support these outcomes. Objective: To estimate the TRD susceptibility and the susceptibility between TRD and other psychiatric disorders within families in a nationwide insurance cohort with extremely high coverage and comprehensive health care data. Design, Setting, and Participants: This cohort study assessed data from the Taiwan national health insurance database across entire population (N = 26 554 001) between January 2003 and December 2017. Data analysis was performed from August 2021 to April 2023. TRD was defined as having experienced at least 3 distinct antidepressant treatments in the current episode, each with adequate dose and duration, based on the prescribing records. Then, we identified the first-degree relatives of individuals with TRD (n = 34 467). A 1:4 comparison group (n = 137 868) of first-degree relatives of individuals without TRD was arranged for the comparison group, matched by birth year, sex, and kinship. Main Outcomes and Measures: Modified Poisson regression analyses were performed and adjusted relative risks (aRRs) and 95% CIs were calculated for the risk of TRD, the risk of other major psychiatric disorders, and different causes of mortality. Results: This study included 172 335 participants (88 330 male and 84 005 female; mean [SD] age at beginning of follow-up, 22.9 [18.1] years). First-degree relatives of individuals with TRD had lower incomes, more physical comorbidities, higher suicide mortality, and increased risk of developing TRD (aRR, 9.16; 95% CI, 7.21-11.63) and higher risk of other psychiatric disorders than matched control individuals, including schizophrenia (aRR, 2.36; 95% CI, 2.10-2.65), bipolar disorder (aRR, 3.74; 95% CI, 3.39-4.13), major depressive disorder (aRR, 3.65; 95% CI, 3.44-3.87), attention-deficit/hyperactivity disorders (aRR, 2.38; 95% CI, 2.20-2.58), autism spectrum disorder (aRR, 2.26; 95% CI, 1.86-2.74), anxiety disorder (aRR, 2.71; 95% CI, 2.59-2.84), and obsessive-compulsive disorder (aRR, 3.14; 95% CI, 2.70-3.66). Sensitivity and subgroup analyses validated the robustness of the findings. Conclusions and Relevance: To our knowledge, this study is the largest and perhaps first nationwide cohort study to demonstrate TRD phenotype transmission across families and coaggregation with other major psychiatric disorders. Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance; therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy.

Efficacy and acceptability of noninvasive brain stimulation for treating posttraumatic stress disorder symptoms: A network meta-analysis of randomized controlled trials.

INTRODUCTION: Despite its high lifetime prevalence rate and the elevated disability caused by posttraumatic stress disorder (PTSD), treatments exhibit modest efficacy. In consideration of the abnormal connectivity between the dorsolateral prefrontal cortex (DLPFC) and amygdala in PTSD, several randomized controlled trials (RCTs) addressing the efficacy of different noninvasive brain stimulation (NIBS) modalities for PTSD management have been undertaken. However, previous RCTs have reported inconsistent results. The current network meta-analysis (NMA) aimed to compare the efficacy and acceptability of various NIBS protocols in PTSD management. METHODS: We systematically searched ClinicalKey, Cochrane Central Register of Controlled Trials, Embase, ProQuest, PubMed, ScienceDirect, Web of Science, and ClinicalTrials.gov to identify relevant RCTs. The targeted RCTs was those comparing the efficacy of NIBS interventions, such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and transcutaneous cervical vagal nerve stimulation, in patients with PTSD. The NMA was conducted using a frequentist model. The primary outcomes were changes in the overall severity of PTSD and acceptability (to be specific, rates of dropouts for any reason). RESULTS: We identified 14 RCTs that enrolled 686 participants. The NMA demonstrated that among the investigated NIBS types, high-frequency rTMS over bilateral DLPFCs was associated with the greatest reduction in overall PTSD severity. Further, in comparison with the sham controls, excitatory stimulation over the right DLPFC with/without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms, including depression and anxiety symptoms, and overall PTSD severity. CONCLUSIONS: This NMA demonstrated that excitatory stimulation over the right DLPFC with or without excitatory stimulation over left DLPFC were associated with significant reductions in PTSD-related symptoms. TRIAL REGISTRATION: PROSPERO CRD42023391562.

Decoding and reconstructing disease relations between dry eye and depression: a multimodal investigation comprising meta-analysis, genetic pathways and Mendelian randomization.

INTRODUCTION: The clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined. OBJECTIVES: To this end, we set up a three-segment study that employed multimodality results (meta-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP. METHODS: A meta-analysis comprising 26 case-control studies was first conducted to confirm the DED-DEP association. Next, we performed a linkage disequilibrium (LD)-adjusted GWAS and targeted phenotype association study (PheWAS) in East Asian TW Biobank (TWB) and European UK Biobank (UKB) populations. Single-nucleotide polymorphisms (SNPs) were further screened for molecular interactions and common pathways at the functional gene level. To further elucidate the activated pathways in DED and DEP, a systemic transcriptome review was conducted on RNA sequencing samples from the Gene Expression Omnibus. Finally, 48 MR experiments were implemented to examine the bidirectional causation between DED and DEP. RESULTS: Our meta-analysis showed that DED patients are associated with an increased DEP prevalence (OR = 1.83), while DEP patients have a concurrent higher risk of DED (OR = 2.34). Notably, cross-disease GWAS analysis revealed that similar genetic architecture (rG = 0.19) and pleiotropic functional genes contributed to phenotypes in both diseases. Through protein-protein interaction and ontology convergence, we summarized the pleiotropic functional genes under the ontology of immune activation, which was further validated by a transcriptome systemic review. Importantly, the inverse variance-weighted (IVW)-MR experiments in both TWB and UKB populations (p value <0.001) supported the bidirectional exposure-outcome causation for DED-to-DEP and DEP-to-DED. Despite stringent LD-corrected instrumental variable re-selection, the bidirectional causation between DED and DEP remained. CONCLUSION: With the multi-modal evidence combined, we consolidated the association and causation between DED and DEP.

Current suicide risk, but not lifetime history of attempted suicide, predicts treatment response to low-dose ketamine infusion: Post Hoc analysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression.

Whether current suicide risk or a history of attempted suicide is related to the antidepressant effect of a low-dose ketamine infusion remains unclear. In total, 47 patients with treatment-resistant depression (TRD), including 32 with low current suicide risk and 15 with moderate or high current suicide risk, were randomized to groups receiving a low-dose ketamine infusion of either 0.2 or 0.5 mg/kg. Among the patients, 21 had a lifetime history of attempted suicide. Suicide risk was assessed based on the Suicidal scale of the Mini-International Neuropsychiatric Interview. The 17-item Hamilton Depression Rating Scale (HDRS) was used to measure depressive symptoms at baseline, at 40 and 240 min after infusion, and sequentially on Days 2-7 and 14 after ketamine infusion. Generalized estimating equation models indicated that the time effects of both 0.5 and 0.2 mg/kg ketamine infusions were significant during the study period. The models also indicated that current suicide risk (p = .037) but not lifetime history of attempted suicide (p = .184) was related to the trajectory of total HDRS scores. Patients with moderate-to-high current suicide risk benefited more from the low-dose ketamine infusion compared with those with the low current suicide risk. Patients with TRD having moderate or high current suicide risk may be prioritized to receive a low-dose ketamine infusion, which may aid suicide prevention. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Comparing different non-invasive brain stimulation interventions for bipolar depression treatment: A network meta-analysis of randomized controlled trials.

Non-invasive brain stimulation (NIBS) is a promising treatment for bipolar depression. We systematically searched for randomized controlled trials on NIBS for treating bipolar depression (INPLASY No: 202340019). Eighteen articles (N = 617) were eligible for network meta-analysis. Effect sizes were reported as standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs). Anodal transcranial direct current stimulation over F3 plus cathodal transcranial direct current stimulation over F4 (a-tDCS-F3 +c-tDCS-F4; SMD = -1.18, 95%CIs = -1.66 to -0.69, N = 77), high-definition tDCS over F3 (HD-tDCS-F3; -1.17, -2.00 to -0.35, 25), high frequency deep transcranial magnetic stimulation (HF-dTMS; -0.81, -1.62 to -0.001, 25), and high frequency repetitive TMS over F3 plus low frequency repetitive TMS over F4 (HF-rTMS-F3 +LF-rTMS-F4; -0.77, -1.43 to -0.11, 38) significantly improved depressive symptoms compared to sham controls. Only a-tDCS-F3 +c-tDCS-F4 (OR = 4.53, 95%CIs = 1.51-13.65) and HF-rTMS-F3 +LF-rTMS-F4 (4.69, 1.02-21.56) showed higher response rates. No active NIBS interventions exhibited significant differences in dropout or side effect rates, compared with sham controls.

Effects of melancholic features on positive and negative suicidal ideation in patients with treatment-resistant depression and strong suicidal ideation receiving low-dose ketamine infusion.

The role of melancholic features on the antisuicidal effect of 0.5 mg/kg ketamine infusion has remained unclear in patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI). Whether ketamine diminishes suicidal ideation in patients with TRD-SI was also unknown. We enrolled 84 patients with TRD-SI, including 27 with melancholic features and 57 without, and then randomly administered a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) item 10, Columbia Suicide Severity Rating Scale-Ideation Severity Subscale (CSSRS-ISS), and self-reported Positive and Negative Suicide Ideation Inventory (PANSI) were used to assess suicidal symptoms from baseline to day 7. Generalized estimating equation models showed that only patients without melancholic features (MADRS item 10: infusion group effect, p = 0.017; CSSRS-ISS: infusion group × time effect, p = 0.008; PANSI-negative suicidal ideation: infusion group effect, p = 0.028) benefited from the antisuicidal effect of low-dose ketamine. The PANSI-positive ideation scores were higher in the ketamine group than in the midazolam group (p = 0.038) for patients with melancholic features. Additional studies are necessary to clarify the neuromechanisms underlying the ketamine-related positive effect against SI and antisuicidal effects among patients with TRD-SI. Additional studies are necessary to clarify the neuromechanisms underlying the ketamine-related positive effect against SI and antisuicidal effects among patients with TRD-SI.

Effects of transcranial pulse stimulation on autism spectrum disorder: a double-blind, randomized, sham-controlled trial.

Transcranial pulse stimulation has been proven effective to improve cognition, memory and depressive symptoms of Alzheimer's disease, but supporting evidence on other neurological diseases or neuropsychiatric disorders remains limited. This study aimed to investigate the effects of transcranial pulse stimulation on the right temporoparietal junction, which is a key node for social cognition for autism spectrum disorder, and to examine the association between transcranial pulse stimulation and executive and social functions. This double-blinded, randomized, sham-controlled trial included 32 participants (27 males), aged 12-17 years with autism spectrum disorder. All eligible participants were randomized into either the verum or sham transcranial pulse stimulation group, on a 1:1 ratio, based on the Childhood Autism Rating Scale screening score. Sixteen participants received six verum transcranial pulse stimulation sessions (energy level: 0.2-0.25 mJ/mm2; pulse frequency: 2.5-4.0 Hz, 800 pulse/session) in 2 weeks on alternate days. The remaining 16 participants received sham transcranial pulse stimulation. The primary outcome measure included Childhood Autism Rating Scale score changes, evaluated by parents, from baseline to 3-month follow-ups. Secondary outcomes included a self-reported questionnaire responded to by parents and cognitive tests responded to by participants. A licensed mental health professional evaluated clinical global impression severity, improvement, efficacy and total score. Results revealed significant interactions in Childhood Autism Rating Scale and other secondary outcomes. Significant group and time effects were found in most secondary outcomes. Additionally, significant differences were found between the transcranial pulse stimulation and sham transcranial pulse stimulation groups in Childhood Autism Rating Scale and clinical global impression improvement and total score immediately after 2 weeks of transcranial pulse stimulation intervention (all P < 0.05), and effects were sustainable at 1- and 3-month follow-up, compared with baseline. The effect size of Childhood Autism Rating Scale (d = 0.83-0.95) and clinical global impression improvement (d = 4.12-4.37) were large to medium immediately after intervention and sustained at 1-month post-stimulation; however, the effects were reduced to small at 3-month post-stimulation (d = 2.31). These findings indicated that transcranial pulse stimulation over right temporoparietal junction was effective to reduce the core symptoms of autism spectrum disorder, as evidenced by a 24% reduction in the total Childhood Autism Rating Scale score in the verum transcranial pulse stimulation group. Additionally, the clinical global impression total score was reduced by 53.7% in the verum transcranial pulse stimulation group at a 3-month follow-up, compared with the baseline. Participants in the verum transcranial pulse stimulation group had shown substantial improvement at 1- and 3-month follow-ups, compared with baseline, although some of the neuropsychological test results were deemed statistically insignificant. Future replication of this study should include a larger sample derived from multi-nations to determine transcranial pulse stimulation as an alternative top-on treatment option in neuropsychiatry.

Risk of All-Cause and Suicide Death in Patients With Schizophrenia: An Entire-Population Longitudinal Study in Taiwan.

Background: Schizophrenia increases mortality from all causes and specific causes. Comprehensive research on modifiable risk factors for early mortality from multiple sources is needed.Methods: Taiwan's National Health Insurance Research Database, which contains claims data from a lifetime insurance program for the whole population, provided extensive medical inpatient and outpatient data categorized by ICD-9-CM and ICD-10 for this nationwide retrospective longitudinal cohort study. The National Mortality Registry provided data on all-cause, natural, suicide, and accidental deaths. 191,553 patients with schizophrenia and 26,362,448 individuals without schizophrenia were monitored from January 1, 2003, to December 31, 2017. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for mortality risk were calculated using Cox regression models. We compared different mortality risks associated with schizophrenia across age, sex, and Charlson Comorbidity Index (CCI) subgroups.Results: We found that schizophrenia results in a relatively higher increase in suicidal mortality in those aged ≤ 20 years (aHR = 15.55; 95% CI, 13.95-17.34), and that effect decreased with age. The effect of schizophrenia in female individuals (suicide death: female, aHR = 11.82, 95% CI, 11.21-12.46; male, aHR = 8.11, 95% CI, 7.77-8.47; difference, P < .001) and individuals without comorbidity (natural cause of death, CCI = 0 aHR = 5.94, 95% CI, 5.68-6.22; CCI = 1-2 aHR = 3.62, 95% CI, 3.52-3.73; CCI > 2 aHR = 1.61, 95% CI, 1.58-1.64) led to comparatively higher mortality risks. The effect of schizophrenia in individuals with AIDS (suicide death, aHR = 2.73, 95% CI, 1.70-4.39) resulted in a relatively smaller increase in suicide mortality compared to individuals with other comorbidities; however, in patients with connective tissue diseases, a diagnosis of schizophrenia still leads to an alarming increase in natural and unnatural mortality.Conclusions: Schizophrenia in combination with younger age, female sex, comorbid connective tissue disease, or major organ problems necessitates more tailored countermeasures to lessen the higher mortality risk in these patients compared with patients who have these characteristics and conditions but do not have schizophrenia.

Efficacy and safety of esketamine nasal spray in addition to standard of care in patients with major depressive disorder who have active suicidal ideation with intent: A subgroup analysis of the Asian cohort of ASPIRE I (a randomized, double-blind, placebo-controlled study).

This post-hoc analysis evaluated the efficacy and safety of intranasal esketamine in the Asian subgroup from ASPIRE I. Patients with major depressive disorder and suicidal ideation with intent received intranasal esketamine (n = 26) or placebo (n = 27), plus standard of care for 25 days. The primary endpoint was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to Day 2. The MADRS score improved in favor of esketamine (least squares mean difference: -3.8). No unexpected safety concerns were noted. The Asian subgroup showed a similar efficacy and safety profile as the total ASPIRE I cohort.

Role of klotho on antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression and suicidal ideation.

OBJECTIVE: Previous studies have found an association between klotho, an anti-aging hormone, and major depressive disorder. However, whether low-dose ketamine infusion alters klotho levels among patients with treatment-resistant depression (TRD) remains unknown. METHODS: In total, 48 patients with TRD and strong suicidal ideation were randomly assigned to a single 0.5 mg/kg ketamine or 0.045 mg/kg midazolam regimen and were subjected to a 2-week follow-up. Depressive and suicidal symptoms were assessed before the infusion and during the follow-up. The serum levels of klotho were assessed at baseline and 3 days postinfusion. RESULTS: A generalized linear model with adjustment of baseline klotho levels showed that, despite the fact that ketamine did not significantly increase levels of klotho, patients in the ketamine group had higher levels of klotho at Day 3 postinfusion than patients in the midazolam group (p = 0.043). However, we found no association between changes in klotho levels and changes in depressive and suicidal symptoms (all p > 0.05). Higher klotho levels at baseline were associated with poorer antidepressant effect of low-dose ketamine during postinfusion follow-up. DISCUSSION: Klotho may play a role in the antidepressant effect of low-dose ketamine. Additional molecular studies are necessary to elucidate the neuromechanisms of TRD, ketamine, and klotho.

Prediction of antidepressant responses to non-invasive brain stimulation using frontal electroencephalogram signals: Cross-dataset comparisons and validation.

BACKGROUND: 10-Hz repetitive transcranial magnetic stimulation(rTMS) and intermittent theta-burst stimulation(iTBS) over left prefrontal cortex are FDA-approved, effective options for treatment-resistant depression (TRD). Optimal prediction models for iTBS and rTMS remain elusive. Therefore, our primary objective was to compare prediction accuracy between classification by frontal theta activity alone and machine learning(ML) models by linear and non-linear frontal signals. The second objective was to study an optimal ML model for predicting responses to rTMS and iTBS. METHODS: Two rTMS and iTBS datasets (n = 163) were used: one randomized controlled trial dataset (RCTD; n = 96) and one outpatient dataset (OPD; n = 67). Frontal theta and non-linear EEG features that reflect trend, stability, and complexity were extracted. Pretreatment frontal EEG and ML algorithms, including classical support vector machine(SVM), random forest(RF), XGBoost, and CatBoost, were analyzed. Responses were defined as ≥50 % depression improvement after treatment. Response rates between those with and without pretreatment prediction in another independent outpatient cohort (n = 208) were compared. RESULTS: Prediction accuracy using combined EEG features by SVM was better than frontal theta by logistic regression. The accuracy for OPD patients significantly dropped using the RCTD-trained SVM model. Modern ML models, especially RF (rTMS = 83.3 %, iTBS = 88.9 %, p-value(ACC > NIR) < 0.05 for iTBS), performed significantly above chance and had higher accuracy than SVM using both selected features (p < 0.05, FDR corrected for multiple comparisons) or all EEG features. Response rates among those receiving prediction before treatment were significantly higher than those without prediction (p = 0.035). CONCLUSION: The first study combining linear and non-linear EEG features could accurately predict responses to left PFC iTBS. The bootstraps-based ML model (i.e., RF) had the best predictive accuracy for rTMS and iTBS.

Trajectory of changes in depressive symptoms after acute repetitive transcranial magnetic stimulation: A meta-analysis of follow-up effects.

BACKGROUND: The follow-up effect after acute repetitive transcranial magnetic stimulation (rTMS) for major depressive episodes remains unclear. Furthermore, the benefits of maintenance rTMS are poorly understood. AIM: To investigate the trajectory of changes in depressive symptoms after acute rTMS and effects of maintenance rTMS during this period. METHOD: This meta-analysis (PROSPERO: CRD42022374077) searched major databases up to October 1, 2022. Treatment outcome was depressive scores collected at least 3 months after the end of an acute rTMS course for depression. We extracted data at different time points after acute rTMS and categorized by whether maintenance rTMS was performed. A single-stage random-effects dose-response meta-analysis was undertaken to model the nonlinear relationships. Effect sizes were calculated as standardized mean differences (SMDs) with 95% confidence intervals (CIs). RESULTS: 24 eligible studies comprising 911 total patients-225 of whom received maintenance rTMS-were included. Maintenance rTMS contributed to relative stability in patients' mood symptoms during the first 5 months (SMD [95% CI]: 3rd month, -0.10 [-0.30 to 0.10]; 5th month, 0.00 [-0.55 to 0.55]), with heterogeneity characterized as low to moderate. Further analysis revealed that maintenance rTMS performed monthly or more frequently provided sustained benefits for up to 6-12 months. Conversely, patients without maintenance rTMS had moderate to high heterogeneity, although the change in mean mood symptom scores during the 12-month follow-up was also minor (6th month, 0.03 [-0.51 to 0.56]; 12th month, 0.10 [-0.59 to 0.79]). CONCLUSION: Maintenance rTMS might keep patients' mood relatively stable for up to 5 months after acute rTMS. Monthly or more frequent maintenance rTMS offers greater benefits.

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study.

BACKGROUND: Prolonged intermittent theta-burst stimulation (iTBS) is effective for major depressive disorder (MDD). However, whether longer piTBS treatment in a single session could have antidepressant efficacy remains elusive. Therefore, this double-blind, randomized, sham-controlled study aimed to investigate the antidepressant efficacy of 2 daily piTBS sessions for treating MDD patients with a history of poor responses to at least 1 adequate antidepressant trial in the current episode. METHODS: All patients received 2 uninterrupted sessions per day for 10 weekdays (i.e., 2 weeks; a total of 20 sessions). Seventy-two patients were recruited and 1:1:1 randomly assigned to one of three groups: piTBS (piTBSx2), 10-Hz rTMS (rTMSx2), or sham treatment (shamx2, randomly assigned to piTBS or rTMS). 10-Hz rTMS group was included as an active comparison group to enhance assay sensitivity. RESULTS: piTBSx2 group had significantly more responders at week 2 than shamx2 group, but it did not yield better antidepressant effects regarding the %depression changes. The changes of antidepressant scores were not different among the three groups at week 1 (-26.2% vs. -23.3% vs. -22.%) or at week 2 (-34.1% vs. -37.1% vs. -30.1%). Longer treatment duration did not result in stronger placebo effects [sham(piTBS)x2: - 31.7% vs. sham(rTMS)x2: - 26.7%]. CONCLUSION: The present sham-controlled study confirmed that piTBS is an effective antidepressant option, but found no evidence to support that longer piTBS treatment duration resulted in more rapid or better antidepressant effects. A high placebo effect was observed, but longer treatment duration of brain stimulation was not linearly associated with stronger placebo effects.

Association of Neurofilament Light Chain With the Antidepressant Effects of Low-Dose Ketamine Infusion Among Patients With Treatment-Resistant Depression.

BACKGROUND: The role of neurofilament light chain (NFL) in treatment-resistant depression (TRD) is unclear. Whether baseline NFL concentrations are associated with the antidepressant effects of low-dose ketamine infusion has not been determined. METHODS: The NFL concentrations of 71 patients with TRD and 17 healthy controls were assessed. Patients with TRD were randomly administered a single infusion of 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline. Depressive symptoms were assessed before infusion and sequentially at postinfusion timepoints (after 240 minutes and after 2-7 and 14 days) using the Hamilton Depression Rating Scale (HDRS). RESULTS: After adjustment for age, sex, and body mass index, patients with TRD were more likely to have higher concentrations of NFL than healthy controls (P < .001). A generalized estimating equation model with adjustments for infusion group, age, sex, body mass index, and baseline HDRS scores showed that baseline NFL concentrations were positively associated with subsequent HDRS scores following low-dose ketamine infusion (P = .038). DISCUSSION: Higher concentrations of NFL were observed among patients with TRD compared with healthy controls. Baseline NFL concentrations may predict the antidepressant effects of low-dose ketamine infusion.

Effects of low-dose ketamine infusion on vascular endothelial growth factor and matrix metalloproteinase-9 among patients with treatment-resistant depression and suicidal ideation.

BACKGROUND: Evidence indicates that vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) influence the pathophysiology of depression. However, whether low-dose ketamine regulates VEGF and MMP-9 levels and whether changes in VEGF and MMP-9 levels are associated with the antidepressant and antisuicidal effects of ketamine remained unclear. METHODS: Forty-eight patients with treatment-resistant depression and strong suicidal ideation (TRD-SI) were randomly assigned to a single infusion of 0.5-mg/kg ketamine or 0.045-mg/kg midazolam. The Montgomery-Åsberg Depression Rating Scale (MADRS) and Columbia-Suicide Severity Rating Scale-Ideation Severity Subscale (CSSRS-ISS) were used at baseline and subsequently at several postinfusion timepoints. VEGF and MMP-9 serum levels were analyzed at baseline and on day 3 postinfusion. RESULTS: After adjustment for baseline levels, no significant differences in VEGF (p = .912) and MMP-9 (p = .758) levels were identified on day 3 postinfusion between the study groups. Baseline VEGF levels but not MMP-9 levels were negatively associated with MADRS and CSSRS-ISS scores following infusion. DISCUSSION: A single infusion of low-dose ketamine did not alter the VEGF and MMP-9 levels of the patients with TRD-SI. Higher baseline VEGF levels were associated with greater antidepressant and antisuicidal effects of single low-dose ketamine infusion.

Overview of treatment-resistant depression.

Patients with major depressive disorder (MDD) often exhibit an inadequate treatment response or failure to achieve remission following treatment with antidepressant drugs. Treatment-resistant depression (TRD) is proposed to identify this clinical scenario. Compared to those without TRD, patients with TRD have significantly lower health-related quality of life in mental and physical dimensions, more functional impairment and productivity loss, and higher healthcare costs. TRD imposes a massive burden on the individual, family, and society. However, a lack of consensus on the TRD definition limits the comparison and interpretation of TRD treatment efficacy across trials. Furthermore, because of the various TRD definitions, there is scarce treatment guideline specifically for TRD, in contrast to the rich treatment guidelines for MDD. In this chapter, common issues related to TRD, such as proper definitions of an adequate antidepressant trial and TRD, were carefully reviewed. Prevalence of and clinical outcomes related to TRD were summarized. We also summarized the staging models ever proposed for the diagnosis of TRD. Furthermore, we highlighted variations in the definition regarding the lack of or an inadequate response in treatment guidelines for depression. Up-to-date treatment options for TRD, including pharmacological strategies, psychotherapeutic interventions, neurostimulation techniques, glutamatergic compounds, and even experimental agents were reviewed.

Baseline cognitive function predicts full remission of suicidal symptoms among patients with treatment-resistant depression and strong suicidal ideation after low-dose ketamine infusion.

BACKGROUND: Whether pretreatment working memory and response inhibition function are associated with the rapid and sustained antisuicidal effect of low-dose ketamine among patients with treatment-resistant depression (TRD) and strong suicidal ideation is unclear. METHODS: We enrolled 65 patients with TRD, comprising 33 who received a single infusion of 0.5 mg/kg ketamine and 32 who received a placebo infusion. The participants performed working memory and go/no-go tasks prior to infusion. We assessed suicidal symptoms at baseline and on postinfusion Days 2, 3, 5, and 7. RESULTS: The full remission of suicidal symptoms persisted for 3 days after a single ketamine infusion and the ketamine-related antisuicidal effect persisted for 1 week. Lower cognitive impairment at baseline (indicated by a higher rate of correct responses on a working memory task) was associated with the rapid and sustained antisuicidal effect of low-dose ketamine in patients with TRD and strong suicidal ideation. DISCUSSION: Patients with TRD and strong suicidal ideation but low cognitive impairment may benefit the most from the antisuicidal effect of low-dose ketamine.

A review of critical brain oscillations in depression and the efficacy of transcranial magnetic stimulation treatment.

Repetitive transcranial magnetic stimulation (rTMS) and intermittent theta burst stimulation (iTBS) have been proven effective non-invasive treatments for patients with drug-resistant major depressive disorder (MDD). However, some depressed patients do not respond to these treatments. Therefore, the investigation of reliable and valid brain oscillations as potential indices for facilitating the precision of diagnosis and treatment protocols has become a critical issue. The current review focuses on brain oscillations that, mostly based on EEG power analysis and connectivity, distinguish between MDD and controls, responders and non-responders, and potential depression severity indices, prognostic indicators, and potential biomarkers for rTMS or iTBS treatment. The possible roles of each biomarker and the potential reasons for heterogeneous results are discussed, and the directions of future studies are proposed.