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Background: It has been established that there are functional changes in the brain of treatment-resistant depression (TRD) patients, but previous studies of functional connectivity (FC) usually involved selection of regions of interest based on accumulated a priori knowledge of the disorder. In this study, we combine amplitude of low-frequency fluctuation (ALFF) and FC; this approach, based on the abnormal ALFF, may provide some insights into the neural basis of the disease in terms of fMRI signals of low-frequency fluctuations., Methods: A total of 16 TRD patients, who visited the Qingdao Mental Health Center, Shandong Province, China between March 2023 and January 2024, along with 16 normal subjects, were enrolled into this study for functional imaging. In this study, we first explored the ALFF changes of TRD patients at a baseline resting state. Second, we selected the regions that were significantly changed in the ALFF as seeds and calculated the regional activity and functional connectivity (FC) of these regions using a seed-based approach. We also calculated correlations between the percent change in the PDQ-5D scores and ALFF values in brain regions with differing activity for TRD patients., Results: During the baseline resting state, by using the ALFF, we found a significantly decreased or increased ALFF in the TRD patients relative to the controls. These regions were located in the left/right postcentral gyrus (PoCG.L/PoCG.R), right cuneus(CUN.R). We found that the ALFF values of the right hippocampus (HIP.R) in the TRD group were negatively correlated with the PDQ-5D score. Then, we selected these brain regions as seeds to investigate the FC changes in brains of TRD patients. We found abnormal functional connectivity in left/right middle frontal gyrus(MFG.L/MFG.R), the right Inferior frontal gyrus, opercular part (IFGoperc.R), the left/right Anterior cingulate and paracingulate gyri (ACC.L/ACC.R), the right supramarginal gyrus (SMG.R), and the right Calcarine fissure and surrounding cortex (CAL.R)., Conclusion: We found a larger range of altered brain regions in TRD patients compared to healthy controls, especially in the central executive network (CEN), salience network (SN) and default mode network (DMN)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Late-life depression (LLD) is associated with cognitive impairment, but substantial heterogeneity exists among patients. Data on the extent of cognitive impairments are inconclusive, particularly in patients with treatment-resistant depression (TRD). We investigated the cognitive profiles of patients with treatment-resistant versus nonresistant LLD and aimed to identify distinct cognitive subgroups. We also examined whether cognitive subgroups responded differentially to treatment with bilateral repetitive transcranial magnetic stimulation (rTMS)., Methods: A total of 165 patients with LLD were divided into treatment-resistant and nonresistant groups and compared with healthy control participants on measures of executive function, information processing speed, verbal learning, and memory. Cluster analysis identified subgroups based on cognitive scores. Demographic and clinical variables, as well as outcomes with bilateral rTMS, were compared between cognitive subgroups., Results: Patients with LLD, particularly TRD, exhibited significantly worse cognitive performance than healthy controls. A 3-cluster solution was found, including cognitively intact (n = 89), cognitively diminished (n = 29), and impaired memory (n = 47) subgroups. Both the cognitively diminished and impaired memory subgroups had more anxiety symptoms and a higher proportion of patients with TRD than the cognitively intact group, although the latter difference did not survive multiple comparison correction. No significant differences were observed in outcomes to rTMS treatment., Conclusions: Patients with LLD exhibited impairments across cognitive domains, which were more pronounced in TRD. Three cognitive subgroups responded similarly to rTMS treatment, indicating its effectiveness across cognitive profiles, especially when medications are not tolerated. Future research should examine the relationships among cognitive subgroups, cognitive decline, and neurodegeneration., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation (rTMS) that can be administered in a fraction of the time of standard rTMS. Applying multiple daily iTBS sessions (ie, accelerated iTBS) may enable patients to achieve remission more rapidly. However, questions remain regarding the optimal time interval between treatment sessions., Objective: The overall aim of this study was to compare the efficacy and tolerability of two accelerated bilateral iTBS protocols (ie, 30-min or 60-min intervals) and a once-daily bilateral iTBS protocol (ie, 0-min interval) while the number of pulses was held constant, in patients with treatment-resistant depression (TRD)., Methods: 182 patients with TRD were randomised to receive two sessions per day of bilateral iTBS of the dorsomedial prefrontal cortex (DMPFC) at 60-min, 30-min or 0-min intervals. Sham treatments were delivered using a shielded 'sham coil' which produced the auditory and tactile sensations of stimulation. The primary outcome measure was a change in depression scores on the 17-item Hamilton Rating Scale for Depression (HRSD-17) after 20 days of treatment., Results: HRSD-17 scores improved across all groups; however, these improvements did not significantly differ between the three groups after 20 days of treatment. Similarly, response and remission rates did not differ between the treatment groups., Conclusions: These results suggest that contrary to our original hypothesis, implementing a 30-min or 60-min interval between two treatment sessions of DMPFC-iTBS does not lead to a more rapid improvement in symptoms, than once-daily iTBS administration., Trial Registration Number: NCT02778035., Competing Interests: Competing interests: FM reports grants from Mitacs, outside the submitted work. LS reports grants from Ontario Mental Health Foundation, outside the submitted work. TSK has received research support from CIHR and the AFP Innovation Fund. JD has received research and equipment in-kind support for an investigator-initiated study through Brainsway and Magventure. He is also on the scientific advisory board for Brainsway. His work has been supported by the National Institutes of Mental Health (NIMH), the Canadian Institutes of Health Research (CIHR), Brain Canada and the Temerty Family and Grant Family Foundations. JD has received research support from NIH, CIHR, Brain Canada, Ontario Brain Institute, the Klarman Family Foundation, the Krembil Foundation, Arrell Family Foundation and the Buchan Family Foundation, in-kind equipment support for investigator-initiated trials from MagVenture, is an advisor for BrainCheck, Arc Health Partners and Salience Neuro Health, and is a co-founder of Ampa Health. DMB receives research support from CIHR, NIMH (R01MH112815;R21MH128815; R01MH1192850), Brain Canada and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway. He was the site principal investigator for three sponsor-initiated studies for Brainsway. He also received in-kind equipment support from Magventure for two investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He is a scientific advisor for Sooma Medical. He is the Co-Chair of the Clinical Standards Committee of the Clinical TMS Society (unpaid). APT, GK and MG declares no conflicts of interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. Published by BMJ.)

Background: This study investigates the effects of accelerated high-frequency repetitive transcranial magnetic stimulation (aHF-rTMS), applied to the left dorsolateral prefrontal cortex (DLPFC), on locus coeruleus (LC) functional connectivity in the treatment of refractory medication-resistant major depression (MRD)., Methods: We studied 12 antidepressant-free refractory MRD patients, focusing on how aHF-rTMS affects the LC, a central component of the brain's noradrenergic system and key to mood regulation and stress response., Results: A stronger decrease in LC functional connectivity following aHF-rTMS treatment resulted in better clinical improvement. We observed such LC functional connectivity decreases with several brain regions, including the superior frontal gyrus, precentral gyrus, middle occipital gyrus, and cerebellum. Moreover, our exploratory analyses hint at a possible role for E-field modeling in forecasting clinical outcomes. Additional analyses suggest potential genetic and dopaminergic factors influencing changes in LC functional connectivity in relation to clinical response., Conclusions: The findings of this study underscore the pivotal role of the LC in orchestrating higher cognitive functions through its extensive connections with the prefrontal cortices, facilitating decision-making, influencing attention, and addressing depressive rumination. Additionally, the observed enhancement in LC-(posterior) cerebellar connectivity not only highlights the cerebellum's role in moderating clinical outcomes through noradrenergic system modulation but also suggests its potential as a predictive marker for aHF-rTMS efficacy. These results reveal new insights into the neural mechanisms of refractory depression and suggest therapeutic targets for enhancing noradrenergic activity, thereby addressing both cognitive and psychomotor symptoms associated with the disorder.

Thalamocortical connectivity is associated with cognitive and affective processing. The role of thalamocortical connectivity in the pathomechanism of treatment-resistant depression (TRD) remains unclear. This study included 48 patients with TRD and 48 healthy individuals. We investigated thalamocortical connectivity by performing resting-state functional MRI with the bilateral thalamus as the seed. In addition, patients with TRD were evaluated using the Montgomery-Åsberg Depression Rating Scale (MADRS). Compared with the healthy individuals, the patients with TRD exhibited increased functional connectivity (FC) of the thalamus with the insula and superior temporal cortex and reduced the FC of the thalamus with the anterior paracingulate cortex and cerebellum crus II. Our study may support the crucial role of thalamocortical dysconnectivity in the TRD pathomechanism. However, the small sample size may limit the statistical power. A future study with a large sample size of patients with TRD would be required to validate our findings., (© 2024 The Author(s). Journal of Neuroscience Research published by Wiley Periodicals LLC.)

This cohort study investigated whether allostatic load (AL) is associated with treatment response to repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD). Pre-treatment blood samples measured AL across multiple systems. Pre- and post-treatment mood changes were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Associations between AL and treatment outcomes were explored. Higher pre-treatment AL was significantly associated with poorer post-treatment response status but was not significantly associated with smaller reduction in MADRS score after 4 weeks of treatment. Identifying biomarker profiles informed by the AL model could enhance treatment decisions in TRD, reducing risks associated with prolonged, ineffective rTMS trials and emphasizing the need for reliable predictive biomarkers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Ketamine has recently attracted considerable attention for its rapid effects on patients with major depressive disorder, including treatment-resistant depression (TRD). Despite ketamine's promising results in treating depression, a significant number of patients do not respond to the treatment, and predicting who will benefit remains a challenge. Although its antidepressant effects are known to be linked to its action as an antagonist of the N-methyl-D-aspartate (NMDA) receptor, the precise mechanisms that determine why some patients respond and others do not are still unclear., Objective: This study aims to understand the computational mechanisms underlying changes in the auditory mismatch negativity (MMN) response following treatment with intravenous ketamine. Moreover, we aim to link the computational mechanisms to their underlying neural causes and use the parameters of the neurocomputational model to make individual treatment predictions., Methods: This is a prospective study of 30 patients with TRD who are undergoing intravenous ketamine therapy. Prior to 3 out of 4 ketamine infusions, EEG will be recorded while patients complete the auditory MMN task. Depression, suicidality, and anxiety will be assessed throughout the study and a week after the last ketamine infusion. To translate the effects of ketamine on the MMN to computational mechanisms, we will model changes in the auditory MMN using the hierarchical Gaussian filter, a hierarchical Bayesian model. Furthermore, we will employ a conductance-based neural mass model of the electrophysiological data to link these computational mechanisms to their neural causes., Conclusion: The findings of this study may improve understanding of the mechanisms underlying response and resistance to ketamine treatment in patients with TRD. The parameters obtained from fitting computational models to EEG recordings may facilitate single-patient treatment predictions, which could provide clinically useful prognostic information., Trial Registration: Clinicaltrials.gov NCT05464264. Registered June 24, 2022., Competing Interests: VB is supported by an Academic Scholar Award from the University of Toronto Department of Psychiatry and has received research support from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ontario Ministry of Health Innovation Funds, Royal College of Physicians and Surgeons of Canada, Department of National Defence (Government of Canada), Associated Medical Services Inc. Healthcare, American Foundation for Suicide Prevention, Roche Canada, Novartis, and Eisai. KSL is supported in part by Merit Awards from the Department of Anesthesiology and Pain Medicine at the University of Toronto. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Martin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The present pilot study assessed the effects of multi-session intermittent theta-burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 17 treatment resistant depressed inpatients (TRDs) showing cortisol non-suppression to the overnight dexamethasone suppression test (DST) at baseline (i.e., maximum post-DST cortisol [COR max ] level > 130 nmol/L). After 20 iTBS sessions, the DST was repeated in all TRDs. At baseline, post-DST COR max levels were higher in TRDs compared to healthy control subjects (HCs; n = 17) (p < 0.0001). After 20 iTBS sessions, post-DST COR max levels decreased from baseline (p < 0.03) and were comparable to HCs. Decreases in post-DST COR max levels were related to decreases in 17-item Hamilton Depression Rating Scale (HAMD-17) scores (ρ = 0.53; p < 0.03). At endpoint, 10 TRDs showed DST normalization (among them 7 were responders [i.e., HAMD-17 total score > 50% decrease from baseline]), and 7 did not normalize their DST (among them 6 were non-responders) (p < 0.05). Our results suggest that successful iTBS treatment may restore normal glucocorticoid receptor feedback inhibition at the pituitary level., Competing Interests: Declaration of Competing Interest No conflict of interest is declared, (Copyright © 2024. Published by Elsevier Ltd.)

The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine's effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine's temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine's antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Electroencephalographic (EEG) deficits in slow wave activity or Delta power (0.5-4 Hz) indicate disturbed sleep homeostasis and are hallmarks of depression. Sleep homeostasis is linked to restorative sleep and potential antidepressant response via non-rapid eye movement (NREM) slow wave sleep (SWS) during which neurons undergo essential repair and rejuvenation. Decreased Low Delta power (0.5-2 Hz) was previously reported in individuals with depression. This study investigated power levels in the Low Delta (0.5-<2 Hz), High Delta (2-4 Hz), and Total Delta (0.5-4 Hz) bands and their association with age, sex, and disrupted sleep in treatment-resistant depression (TRD). Mann-Whitney U tests were used to compare the nightly progressions of Total Delta, Low Delta, and High Delta in 100 individuals with TRD and 24 healthy volunteers (HVs). Polysomnographic parameters were also examined, including Total Sleep Time (TST), Sleep Efficiency (SE), and Wake after Sleep Onset (WASO). Individuals with TRD had lower Delta power during the first NREM episode (NREM1) than HVs. The deficiency was observed in the Low Delta band versus High Delta. Females with TRD had higher Delta power than males during the first NREM1 episode, with the most noticeable sex difference observed in Low Delta. In individuals with TRD, Low Delta power correlated with WASO and SE, and High Delta correlated with WASO. Low Delta power deficits in NREM1 were observed in older males with TRD, but not females. These results provide compelling evidence for a link between age, sex, Low Delta power, sleep homeostasis, and non-restorative sleep in TRD., Competing Interests: Declaration of competing interest Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise., (Published by Elsevier Ltd.)

In this chapter, we explore the historical evolution, current applications, and future directions of Deep Brain Stimulation (DBS) for Treatment-Resistant Depression (TRD). We begin by highlighting the early efforts of neurologists and neurosurgeons who laid the foundations for today's DBS techniques, moving from controversial lobotomies to the precision of stereotactic surgery. We focus on the advent of DBS, emphasizing its emergence as a significant breakthrough for movement disorders and its extension to psychiatric conditions, including TRD. We provide an overview of the neural networks implicated in depression, detailing the rationale for the choice of common DBS targets. We also cover the technical aspects of DBS, from electrode placement to programming and parameter selection. We then critically review the evidence from clinical trials and open-label studies, acknowledging the mixed outcomes and the challenges posed by placebo effects and trial design. Safety and ethical considerations are also discussed. Finally, we explore innovative directions for DBS research, including the potential of closed-loop systems, dual stimulation strategies, and noninvasive alternatives like ultrasound neuromodulation. In the last section, we outline recommendations for future DBS studies, including the use of alternative designs for placebo control, the collection of neural and behavioral recordings, and the application of machine-learning approaches., (© 2024. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

Electroconvulsive therapy is one of the useful treatment methods for symptom improvement and remission in patients with treatment-resistant depression. Considering the various clinical characteristics of patients experiencing depression, key indicators are extracted from structural brain magnetic resonance imaging, functional brain magnetic resonance imaging, and electroencephalography (EEG) data taken before treatment, and applied as explanatory variables in machine learning and network analysis. Studies that attempt to make reliable predictions about the degree of response to electroconvulsive treatment and the possibility of remission in patients with treatment-resistant depression are continuously being published. In addition, studies are being conducted to identify the correlation with clinical improvement by taking structural-functional brain magnetic resonance imaging after electroconvulsive therapy in depressed patients. By reviewing and integrating the results of the latest studies on the above matters, we aim to present the usefulness of electroconvulsive therapy for improving the personalized prognosis of patients with treatment-resistant depression., (© 2024. The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.)

Understanding why some patients with depression remain resistant to antidepressant medication could be elucidated by investigating their associated neural features. Although research has consistently demonstrated abnormalities in the anterior cingulate cortex (ACC) - a region that is part of the default mode network (DMN) - in treatment-resistant depression (TRD), a considerable research gap exists in discerning how these neural networks distinguish TRD from treatment-sensitive depression (TSD). We aimed to evaluate the resting-state functional connectivity (rsFC) of the ACC with other regions of the DMN to better understand the role of this structure in the pathophysiology of TRD. 35 TRD patients, 35 TSD patients, and 38 healthy controls (HC) underwent a resting-state functional MRI protocol. Seed-based functional connectivity analyses were performed, comparing the three groups for the connectivity between two subregions of the ACC (the subgenual ACC (sgACC) and the rostral ACC (rACC)) and the DMN (p < 0.05 FWE corrected). Furthermore, inter-network connectivity of the DMN with other neural networks was explored by independent component (ICA) analyses (p < 0.01, FDR corrected). The results demonstrated hyperconnectivity between the rACC and the posterior cingulate cortex in TRD relative to TSD and HC (F(2,105) = 5.335, p < 0.05). ICA found DMN connectivity to regions of the visual network (TRDTSD), differentiating the two clinical groups. These results provide confirmatory evidence of DMN hyperconnectivity and preliminary evidence for its interactions with other neural networks as key neural mechanisms underlying treatment non-responsiveness., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Anthony Harris received funding from Takeda Pharmaceutical Company for this project. There are no other financial disclosures related to the work. Mayuresh Korgaonkar received funding from Takeda Pharmaceutical Company for this project. There are no other financial disclosures related to the work. And all other authors have declared that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient, with an average response rate of ∼50%. The engagement of specific fiber tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here we provide a computational framework that can explore each individual's brain response characteristics elicited by selective stimulation of fiber tracts. We use a novel personalized in-silico approach, the Virtual Big Brain, which makes use of high-resolution virtual brain models at a mm-scale and explicitly reconstructs more than 100,000 fiber tracts for each individual. Each fiber tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient, even though validation against empirical patient data reveals some limitations (i.e., the need for individual parameter adjustment, and differential accuracy across stimulation locations). This study provides evidence for the capacity of personalized high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalized optimization of brain stimulation., Competing Interests: Declaration of Competing Interest The authors declare no competing interest., (Copyright © 2021. Published by Elsevier Inc.)

Cortical processing depends on finely tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here we test the effect of reduced somatostatin interneuron-mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrate human cellular, circuit, and gene expression data to generate detailed models of human cortical microcircuits in health and depression. We simulate microcircuit baseline and response activity and find a reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. We thus apply models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To characterize the functional connectivity (FC) of target brain regions for deep brain stimulation (DBS) in patients with treatment-resistant depression (TRD), and to evaluate its gender and brain lateralization dependence., Methods: Thirty-one TRD patients and twenty-nine healthy control (HC) subjects participated. FC of subcallosal cingulate gyrus (SCG), ventral caudate (VCa), nucleus accumbens (NAc), lateral habenula (LHb), and inferior thalamic peduncle (ITP) were evaluated using resting-state fMRI. FC was characterized by calculating the nodal 'degree', a major feature of the graph theory., Results: The degree measures of the left and right VCa, the left LHb, and the left ITP were significantly greater in the TRD than in the HC group. The degree was greater in females with TRD in all these regions except the right LHb. Finally, the left hemisphere was generally more affected by depression and presented significant degrees in LHb and ITP regions of the patients., Conclusion: Our findings demonstrate the ability of degree to characterize brain FC and identify the regions with abnormal activities in TRD patients. This implies that the degree may have the potential to be used as an important graph-theoretical feature to further investigate the mechanisms underlying TRD, and consequently along with other diagnostic markers, to assist in the determination of the appropriate target region for DBS treatment in TRD patients., (Copyright © 2021. Published by Elsevier Inc.)

Background: Successful treatment of major depressive disorder (MDD) can be challenging, and failures ("treatment-resistant depression" [TRD]) are frequent. Steps to address TRD include increasing antidepressant dose, combining antidepressants, adding adjunctive agents, or using nonpharmacological treatments. Their relative efficacy and tolerability remain inadequately tested. In particular, the value and safety of increasingly employed second-generation antipsychotics (SGAs) and new esketamine, compared to lithium as antidepressant adjuncts remain unclear., Methods: We reviewed randomized, placebo-controlled trials and used random-effects meta-analysis to compare odds ratio (OR) versus placebo, as well as numbers-needed-to-treat (NNT) and to-harm (NNH), for adding SGAs, esketamine, or lithium to antidepressants for major depressive episodes., Results: Analyses involved 49 drug-placebo pairs. By NNT, SGAs were more effective than placebo (NNT = 11 [CI: 9-15]); esketamine (7 [5-10]) and lithium (5 [4-10]) were even more effective. Individually, aripiprazole, olanzapine+fluoxetine, risperidone, and ziprasidone all were more effective (all NNT < 10) than quetiapine (NNT = 13), brexpiprazole (16), or cariprazine (16), with overlapping NNT CIs. Risk of adverse effects, as NNH for most-frequently reported effects, among SGAs versus placebo was 5 [4-6] overall, and highest with quetiapine (NNH = 3), lowest with brexpiprazole (19), 5 (4-6) for esketamine, and 9 (5-106) with lithium. The risk/benefit ratio (NNH/NNT) was 1.80 (1.25-10.60) for lithium and much less favorable for esketamine (0.71 [0.60-0.80]) or SGAs (0.45 [0.17-0.77])., Conclusions: Several modern antipsychotics and esketamine appeared to be useful adjuncts to antidepressants for acute major depressive episodes, but lithium was somewhat more effective and better tolerated., Limitations: Most trials of adding lithium involved older, mainly tricyclic, antidepressants, and the dosing of adjunctive treatments were not optimized.

Background: Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states., Methods: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined., Results: A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results., Conclusions: These preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Objective: Postictal generalized electroencephalographic suppression (PGES) has been defined as electroencephalographic (EEG) activity of less than 10 microvolts following a generalized seizure. PGES is associated with an increased risk of sudden unexplained death in epilepsy, as well as treatment efficacy of electroconvulsive therapy (ECT). We investigated the impact of anesthetic on PGES expression and temporal characteristics., Methods: We recorded postictal EEG in 50 ECT sessions in 11 patients with treatment resistant depression (ClinicalTrials.gov NCT02761330). For each participant, repeated sessions included either ketamine or etomidate general anesthesia during ECT. An automated algorithm was employed to detect PGES within 5 minutes after seizure termination., Results: PGES was detected in 31/50 recordings, with intermittent epochs recurring up to five minutes after seizure termination. PGES total duration was greater following ketamine than etomidate anesthesia (p = 0.04). PGES expression declined loglinearly as a function of time (r = -0.89, p < 10 -4 ). EEG amplitude during PGES did not vary linearly with time., Conclusions: PGES can occur intermittently for several minutes following seizure termination. Anesthetic effects should be considered when correlating PGES duration to clinical outcomes., Significance: Prolonged EEG monitoring several minutes following seizure termination may be necessary to fully evaluate the presence and total duration of PGES., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is amongst the most prevalent of psychiatric disorders. Unfortunately, a third of patients will not respond to conventional treatments and suffer from treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) has been proven effective in treating TRD. The research suggests that rTMS acts via neuroplastic effects on the brain, which can be measured by changes in hippocampal and amygdala volume as well as cortical thickness. This sham-controlled study investigates longitudinal effects of rTMS on the volumes of the hippocampus and amygdala and cortical thickness in patients with chronic TRD. 31 patients received 20 sessions of high-frequency rTMS (N = 15) or sham treatment (N = 16) over the left dorsolateral prefrontal cortex during 4 consecutive weeks. Using structural magnetic resonance imaging, we investigated longitudinal treatment effects on hippocampus and amygdala volume as well as thickness of the paralimbic cortex. We found no clinical differences between the active and sham rTMS group. Longitudinal changes in hippocampal and amygdala volume did not differ significantly, although males showed a significant decrease in left amygdala volume, irrespective of treatment group. Changes in cortical thickness of the paralimbic cortex differed significantly between the active and sham groups. Most notably, the increase in cortical thickness of the isthmus of the left cingulate gyrus was greater in the active as compared to the sham rTMS group. Our data suggest that rTMS can induce neuroplastic changes, particularly in cortical thickness, independent of treatment response. We also found longitudinal changes in amygdala volume in males. For clinical effects to follow these neuroplastic effects, more intensive rTMS treatment might be needed in chronically depressed patients.Trial registration number: ISRCTN 15535800, registered on 29-06-2017.

Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Frontostriatal disconnectivity plays a crucial role in the pathophysiology of major depressive disorder. However, whether the baseline functional connectivity of the frontostriatal network could predict the treatment outcome of low-dose ketamine infusion remains unknown., Methods: In total, 48 patients with treatment-resistant depression were randomly divided into 3 treatment groups (a single-dose 40-minute i.v. infusion) as follows: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and saline placebo infusion. Patients were subsequently followed-up for 2 weeks. Resting-state functional magnetic resonance imaging was performed for each patient before infusion administration. In addition, the baseline frontostriatal functional connectivity of patients with treatment-resistant depression was also compared with that of healthy controls., Results: Compared with the healthy controls, patients with treatment-resistant depression had a decreased functional connectivity in the frontostriatal circuits, especially between the right superior frontal cortex and executive region of the striatum and between the right paracingulate cortex and rostral-motor region of the striatum. The baseline hypoconnectivity of the bilateral superior frontal cortex to the executive region of the striatum was associated with a greater reduction of depression symptoms after a single 0.2-mg/kg ketamine infusion., Conclusion: Reduced connectivity of the superior frontal cortex to the striatum predicted the response to ketamine infusion among patients with treatment-resistant depression., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Background: The present multicenter study aimed at defining the clinical profile of patients with major depressive disorder (MDD) and comorbid migraine., Methods: Demographic and clinical information for 1410 MDD patients with vs without concurrent migraine were compared by descriptive statistics, analyses of covariance, and binary logistic regression analyses., Results: The point prevalence rate for comorbid migraine was 13.5% for female and 6.2% for male patients. MDD + migraine patients were significantly younger, heavier, more likely female, of non-Caucasian origin, outpatient, and suffering from asthma. The presence of MDD + migraine resulted in a significantly higher functional disability. First-line antidepressant treatment strategy revealed a trend towards agomelatine. Second-generation antipsychotics were significantly less often administered for augmentation treatment in migraineurs. Overall, MDD + migraine patients tended to respond worse to their pharmacotherapy., Conclusion: Treatment guidelines for comorbid depression and migraine are warranted to ensure optimal efficacy and avoid possible pitfalls in psychopharmacotherapy, including serotonin syndrome., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

Background: Studies have reported that ketamine potentially increases subjective happiness in healthy volunteers. However, whether ketamine-induced happiness can predict the treatment response of ketamine infusion among patients with treatment-resistant depression (TRD) remains unknown., Methods: Between 2012 and 2015, 71 adult patients with TRD (based on DSM-IV-TR criteria) were enrolled and randomly assigned to receive a 40-minute ketamine (0.5 mg/kg or 0.2 mg/kg) or normal saline placebo infusion. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale. Measurements were conducted prior to infusion, at 40 and 240 minutes postinfusion, and, sequentially, on days 2 to 7 and 14 postinfusion. The visual analog scale for happiness (VASH) was used to assess happiness during infusion. The positive symptoms subscale of the Brief Psychiatric Rating Scale (BPRS-P) was used to measure the potential psychotomimetic effects of ketamine., Results: For both the 2-factor (ketamine vs placebo) and 3-factor (ketamine 0.5 mg/kg vs 0.2 mg/kg vs placebo) models, a generalized estimating equation model indicated that infusion response type (happiness vs nonhappiness) significantly (P = .008 vs P = .002) predicted the trajectory of depressive symptoms after infusion. Changes in VASH and BPRS-P measures were not associated with each other., Conclusions: Subjective happiness during ketamine infusion predicted the antidepressant effect of both 0.5 mg/kg and 0.2 mg/kg ketamine infusion over time. Happiness during ketamine infusion, which was not related to the psychotomimetic effect of ketamine, may be associated with the reduction of depressive symptoms during the follow-up., Trial Registration: UMIN Clinical Trials Registry registration number: UMIN000016985., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Background: Electroconvulsive therapy (ECT) is a powerful and fast-acting anti-depressant strategy, often used in treatment-resistant patients. In turn, patients with treatment-resistant depression often present an increased inflammatory response. The impact of ECT on several pathophysiological mechanisms of depression has been investigated, with a focus which has largely been on cellular and synaptic plasticity. Although changes in the immune system are known to influence neurogenesis, these processes have principally been explored independently from each other in the context of ECT., Objective: The aim of this review was to compare the time-dependent consequences of acute and chronic ECT on concomitant innate immune system and neurogenesis-related outcomes measured in the central nervous system in pre-clinical studies., Results: During the few hours following acute electroconvulsive shock (ECS), the expression of the astrocytic reactivity marker glial fibrillary acidic protein (GFAP) and inflammatory genes, such as cyclooxygenase-2 (COX2), were significantly increased together with the neurogenic brain-derived neurotrophic factor (BDNF) and cell proliferation. Similarly, chronic ECS caused an initial upregulation of the same astrocytic marker, immune genes, and neurogenic factors. Interestingly, over time, inflammation appeared to be dampened, while glial activation and neurogenesis were maintained, after either acute or chronic ECS., Conclusion: Regardless of treatment duration ECS would seemingly trigger a rapid increase in inflammatory molecules, dampened over time, as well as a long-lasting activation of astrocytes and production of growth and neurotrophic factors, leading to cell proliferation. This suggests that both innate immune system response and neurogenesis might contribute to the efficacy of ECT.

Background: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients ( n = 28) and healthy controls ( n = 45)., Aims: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale., Results: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed ( rho = -0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation ( rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed., Conclusions: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.

Purpose: To review the efficacy, safety, and place in therapy of intranasal esketamine, a treatment modality for treatment-resistant depression., Summary: An electronic literature search of PubMed, MEDLINE, and the ClinicalTrials.gov and Food and Drug Administration (FDA) websites covering the period April 2015 through June 2020 was performed using the following search terms: esketamine, intranasal esketamine, depression, and treatment-resistant depression. Other resources included review articles and the manufacturer's product labeling. All relevant English-language articles and reports on clinical trials conducted in humans were included. Esketamine (Spravato, Janssen Pharmaceuticals) is an intranasal antidepressant approved by FDA for management of treatment-resistant depression (TRD) in patients with inadequate response to traditional antidepressant therapy. Esketamine is self-administered under the supervision of a healthcare provider and is used as an adjunct to oral antidepressant therapy. Patients are supervised for 2 hours after self-administering the medication to monitor for sedation, dizziness, dissociation reactions, and increased blood pressure. Esketamine has a favorable risk-to-benefit profile, with demonstrated efficacy in reducing depressive symptoms more rapidly than monotherapy with traditional oral antidepressants. Reported adverse effects include sedation, dizziness, dissociation reactions, and blood pressure elevations, but these effects are primarily confined to the 2-hour postdose monitoring window., Conclusion: Patients with moderate to severe depression who are not sufficiently responsive to traditional strategies for managing TRD may benefit from adjunctive esketamine therapy., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression., Methods: Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT., Results: One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects., Conclusions: SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

Background: This study aimed to identify clinical and cognitive factors associated with increased risk for difficult-to-treat depression (DTD) or treatment-resistant depression (TRD)., Methods: A total of 229 adult outpatients with major depression were recruited from the mental health unit at a public hospital. Participants were subdivided into resistant and nonresistant groups according to their Maudsley Staging Model score. Sociodemographic, clinical, and cognitive (objective and subjective measures) variables were compared between groups, and a logistic regression model was used to identify the factors most associated with TRD risk., Results: TRD group patients present higher verbal memory impairment than the nonresistant group irrespective of pharmacological treatment or depressive symptom severity. Logistic regression analysis showed that low verbal memory scores (odds ratio [OR]: 2.02; 95% confidence interval [CI]: 1.38-2.95) together with high depressive symptom severity (OR: 1.29; CI95%: 1.01-1.65) were associated with TRD risk., Conclusions: Our findings align with neuroprogression models of depression, in which more severe patients, defined by greater verbal memory impairment and depressive symptoms, develop a more resistant profile as a result of increasingly detrimental neuronal changes. Moreover, our results support a more comprehensive approach in the evaluation and treatment of DTD in order to improve illness course. Longitudinal studies are warranted to confirm the predictive value of verbal memory and depression severity in the development of TRD.

Background: Major depressive disorder (MDD) is highly heterogeneous and can be classified as treatment-resistant depression (TRD) or antidepressant-responsive depression (non-TRD) based on patients' responses to antidepressant treatment. Methods for distinguishing between TRD and non-TRD are critical clinical concerns. Deficits of cortical inhibition (CI) have been reported to play an influential role in the pathophysiology of MDD. Whether TRD patients' CI is more impaired than that of non-TRD patients remains unclear., Methods: Paired-pulse transcranial magnetic stimulation (ppTMS) was used to measure cortical inhibitory function including GABAA- and GABAB-receptor-related CI and cortical excitatory function including glutamate-receptor-related intracortical facilitation (ICF). We recruited 36 healthy controls (HC) and 36 patients with MDD (non-TRD, n = 16; TRD, n = 20). All participants received evaluations for depression severity and ppTMS examinations. Non-TRD patients received an additional ppTMS examination after 3 months of treatment with the SSRI escitalopram., Results: Patients with TRD exhibited reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI), as shown by abnormally higher estimates, than those with non-TRD or HC (F = 11.030, p < 0.001; F = 10.309, p < 0.001, respectively). After an adequate trial of escitalopram treatment, the LICI of non-TRD reduced significantly (t = - 3.628, p < 0.001), whereas the ICF remained lower than that of HC and showed no difference from pretreatment non-TRD., Conclusions: TRD was characterized by relatively reduced CI, including both GABAA- and GABAB-receptor-mediated neurons while non-TRD preserved partial CI. In non-TRD, SSRIs may mainly modulate GABAB-receptor-related LICI. Our findings revealed distinguishable features of CI in antidepressant-resistant and responsive major depression.

Introduction Depression is one of the most important psychiatric disorders, and the rate of recurrence is high. The heavy cost burden of depression is probably due to treatment-resistant depression. The purpose of this study was to determine the effectiveness of mindfulness-based cognitive therapy (MBCT) in patients with treatment-resistant depression (TRD). Method The present study was a quasi-experimental study conducted with twenty-four patients with treatment-resistant depression. Participants were selected by purposive sampling and randomly assigned to two groups, an experimental group and a control group. The experimental group received MBCT and antidepressants, while the control group received antidepressants only. The Hamilton and Beck Depression Inventory, Self-Compassion Scale, Thought Rumination Scale, and Mindfulness Scale were administered. The treatment program was conducted in eight sessions; with a follow-up period of one month subsequent to treatment termination. Data were analyzed using descriptive statistics (mean and standard deviation) and inferential statistics (analysis of variance for repeated measures and Bonferroni's post-hoc test). Results The results showed that MBCT significantly reduced depression and ruminative thinking in the experimental group and also improved mediators such as mindfulness and self-compassion. Patients maintained gains over the one month follow-up period (p < 0.01). Conclusion The present study provides additional evidence for the effectiveness of MBCT for TRD.

Up to 50% of youth with depression do not respond to conventional first-line treatments. However, little research has been conducted on the pathophysiology of youth depression, hindering the identification of more effective treatments. Our goal was to identify neurophysiological markers that differentiate youth with depression from healthy youth and could serve as targets of novel treatments. We hypothesized that youth with depression would exhibit network-specific cortical reactivity and connectivity abnormalities compared with healthy youth. Transcranial magnetic stimulation combined with electroencephalography and magnetic resonance imaging was employed in combination with clinical and behavioral assessments to study cortical reactivity and connectivity in bilateral dorsolateral prefrontal cortex (DLPFC), motor cortex, and inferior parietal lobule, sites linked to the frontoparietal network, sensorimotor network, and default mode network, respectively. In youth depression, greater cortical reactivity was observed specific to the left and right DLPFC stimulation only, which correlated with anhedonia scores. Additionally, the connectivity of the right DLPFC was significantly higher in youth depression. Source reconstruction attributed the observed connectivity dysregulation to regions belonging to the default mode network. The neurophysiological signatures identified in this study have high potential to inform the development of more effective and targeted interventions for the youth depression population., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To describe the clinical characteristics of adolescents with antidepressant treatment-resistant major depressive disorder (MDD) and to examine the utility of the Antidepressant Treatment Record (ATR) in categorizing treatment resistance in this population. Methods: Adolescents with treatment-resistant MDD enrolled in an interventional study underwent a baseline evaluation with the ATR, Children's Depression Rating Scale-Revised (CDRS-R), and Clinical Global Impressions-Severity (CGI-S) scales. Demographic and clinical characteristics were examined with regard to ATR-defined level of resistance (level 1 to ≥3) using analysis of variance and χ 2 tests. Results: In adolescents with treatment-resistant MDD ( N  = 97), aged 12-21 years, most were female (65%), white (89%), and had recurrent illness (78%). Patients were severely ill (median CGI-S score of 5), had a mean CDRS-R score of 63 ± 10, and 17.5% had been hospitalized for depression-related symptoms. Fifty-two patients were classified as ATR 1, whereas 32 were classified as ATR level 2 and 13 patients as ≥3, respectively. For increasing ATR-defined levels, illness duration increased from 12.0 (range: 1.5-31.9) to 14.8 (range: 1.8-31.7) to 19.5 (range: 2.5-36.2) months and the likelihood of treatment with serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors (DNRIs) similarly increased ( p  = 0.006 for both SNRIs and DNRIs) as did the likelihood of treatment with mixed dopamine serotonin receptor antagonists (χ 2  = 17, p  < 0.001). Conclusions: This study underscores the morbidity and chronicity of treatment-resistant MDD in adolescents. The present characterization of related clinical features describes the use of nonselective serotonin reuptake inhibitors in adolescents with treatment-resistant depression and raises the possibility that those with the greatest medication treatment resistance are less likely to have had recurrent episodes. The study also demonstrates the utility of the ATR in categorizing treatment resistance in adolescents with MDD.

Major depressive disorder (MDD) is a chronic, severe psychiatric illness with an incidence of 3% worldwide. MDD patients have a significantly impaired quality of life and reduced life expectancy compared to unaffected individuals, the latter being largely accounted for by an increased incidence of suicide and cardiovascular disorders. The premature mortality observed in MDD has been considered a signature of accelerated aging, a hypothesis supported by data showing altered functioning and morphology of several brain regions that are typically present in the aging population. Telomere shortening is a hallmark of cellular aging, and as such several studies explored the involvement of disrupted telomere dynamics in MDD, reporting contrasting findings. In the current study, we measured leukocyte telomere length (LTL) in a sample of 54 MDD patients and 47 non-psychiatric controls characterized for response to antidepressant treatment. After correcting for age, sex, and body mass index, we showed significantly reduced LTL in affected individuals compared to controls (beta = -.22, p = .02). There was no difference in LTL between treatment resistant or responsive MDD patients. Moreover, we observed no correlation between lifetime exposure to antidepressants and LTL. Our study showed that MDD patients have shorter telomeres compared to controls, supporting the hypothesis of accelerated aging in this disorder. However, LTL seemed not to be influenced by antidepressant treatment or to correlate with clinical response to these antidepressants. Further investigations in larger samples and possibly with longitudinal design are warranted to elucidate the role of altered telomere dynamics in MDD., (© 2019 Wiley Periodicals, Inc.)

Background: Investigating approaches for determining a functionally meaningful dorsolateral prefrontal cortex (DLPFC) stimulation site is imperative for optimising repetitive transcranial magnetic stimulation (rTMS) response rates for treatment-resistant depression. One proposed approach is neuro-cardiac-guided rTMS (NCG-TMS) in which high frequency rTMS is applied to the DLPFC to determine the site of greatest heart rate deceleration. This site is thought to index a frontal-vagal autonomic pathway that intersects a key pathway believed to underlie rTMS response., Objective: We aimed to independently replicate previous findings of high-frequency NCG-TMS and extend it to evaluate the use of low-frequency rTMS for NCG-TMS., Methods: Twenty healthy participants (13 female; aged 38.6 ± 13.9) underwent NCG-TMS on frontal, fronto-central (active) and central (control) sites. For high-frequency NCG-TMS, three 5 s trains of 10 Hz were provided at each left hemisphere site. For low-frequency NCG-TMS, 60 s trains of 1 Hz were applied to left and right hemispheres and heart rate and heart rate variability outcome measures were analysed., Results: For high-frequency NCG-TMS, heart rate deceleration was observed at the left frontal compared with the central site. For low-frequency NCG-TMS, accelerated heart rate was found at the right frontal compared with central sites. No other site differences were observed., Conclusion: Opposite patterns of heart rate activity were found for high- and low-frequency NCG-TMS. The high-frequency NCG-TMS data replicate previous findings and support further investigations on the clinical utility of NCG-TMS for optimising rTMS site localisation. Further work assessing the value of low-frequency NCG-TMS for rTMS site localisation is warranted., Competing Interests: Declaration of competing interest PBF has received equipment for research from MagVenture A/S, Medtronic Ltd, Neuronetics and Brainsway Ltd and funding for research from Neuronetics. He is on scientific advisory boards for Bionomics Ltd and LivaNova and is a founder of TMS Clinics Australia. MA reports options from Brain Resource (Sydney, Australia), is unpaid research director of the Brainclinics Foundation, a minority shareholder in neuroCare group (Munich, Germany); TAI and MA are co-inventor on a patent application covering NCG-TMS, but do not own the patent nor receive any royalties related to this patent; Research Institute Brainclinics received research funding from Brain Resource (Sydney, Australia) and neuroCare group (Munich, Germany); equipment support from Deymed, neuroConn and MagVenture, however data analyses and writing of this manuscript were unconstrained. We have no other conflicts of interest to declare., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The greatest difficulty in treating cocaine addiction is the enormous rates of relapse, which occur despite immense negative consequences. Relapse risks are even greater in addicts with comorbid depression, perhaps because they use drugs to alleviate depressive symptoms. Only a few preclinical studies have examined this comorbidity, mostly exploring depressive-like effects following drug exposure. We examined rats from two different depression-like models: (a) chronic-mild-stress (CMS), which respond to antidepressant medications and (b) depressed-rat-line (DRL), a genetic model of selective breeding, which is less responsive to antidepressant medications. We tested addictive behaviors in a cocaine self-administration procedure, including the "conflict model," where drug-seeking and relapse encounter adverse consequences: an electrified grid in front of the drug-delivering lever. Following behavioral testing, we explored a potential association between behavioral outcomes and protein expression of brain-derived neurotrophic factor (BDNF). We found that DRL rats self-administer more cocaine compared with both CMS and controls, while CMS and control groups did not differ significantly. Notably, DRL but not CMS rats, displayed higher rates of relapse than controls, and expressed higher levels of BDNF in the prelimbic cortex (PLC). Potential translation of these results suggest that medication-resistant depressed patients tend to consume more drugs and are more susceptible to relapse. The increase in PLC BDNF levels is consistent with previous rat models of depression, and concomitantly, with its suggested role in promoting cocaine-seeking., (© 2019 Society for the Study of Addiction.)

Although in treatment-resistant depression (TRD) subgenual anterior cingulate cortex (sgACC) functional connectivity (FC) is frequently used to examine deregulated brain networks, neurobiological data from other sources may be required to interpret these FC findings. In 16 melancholic TRD patients with a high level of treatment resistance and 16 closely matched healthy never-depressed individuals we verified whether sgACC FC patterns were related to regional metabolic activity (CMRglc) with 18 FDG PET imaging. Notwithstanding that TRD patients displayed stronger sgACC FC with the right lateral frontotemporal cortex, metabolically they exhibited the opposite pattern. Our results indicate that the sgACC seed and its functionally connected regions not automatically follow a similar metabolic pattern in TRD, possibly reflecting the refractory state of the sample. Multimodal brain imaging may help to increase our insight into the pathophysiology of TRD.

Electroconvulsive therapy (ECT) is a rapid and highly effective treatment option for treatment-resistant major depressive disorder (TRD). The neural mechanisms underlying such beneficial effects are poorly understood. Exploring associations between changes of brain structure and clinical response is crucial for understanding ECT mechanisms of action and relevant for the validation of potential biomarkers that can facilitate the prediction of ECT efficacy. The aim of this explorative study was to identify cortical predictors of clinical response in TRD patients treated with ECT. We longitudinally investigated 12 TRD patients before and after ECT. Twelve matched healthy controls were studied cross sectionally. Demographical, clinical, and structural magnetic resonance imaging data at 3 T and multiple cortical markers derived from surface-based morphometry (SBM) analyses were considered. Multiple regression models were computed to identify predictors of clinical response to ECT, as reflected by Hamilton Depression Rating Scale (HAMD) score changes. Symptom severity differences pre-post-ECT were predicted by models including demographic data, clinical data and SBM of frontal, cingulate, and entorhinal structures. Using all-subsets regression, a model comprising HAMD score at baseline and cortical thickness of the left rostral anterior cingulate gyrus explained most variance in the data (multiple R 2  = 0.82). The data suggest that SBM provides powerful measures for identifying biomarkers for ECT response in TRD. Rostral anterior cingulate thickness and HAMD score at baseline showed the greatest predictive power of clinical response, in contrast to cortical complexity, cortical gyrification, or demographical data.

Objectives: Major depression is a highly prevalent disorder that causes economic burden in office workers. We conducted a randomized, double-blind, sham-controlled trial to evaluate the efficacy and safety of deep transcranial magnetic stimulation (dTMS) in office workers with treatment-resistant depression., Methods: In this study, we randomized office workers taking administrative leave for treatment-resistant major depressive disorder or bipolar disorder with current major depressive episode. dTMS treatment was applied at 120% resting motor threshold with 18 Hz over the left dorsolateral prefrontal cortex. The treatment sessions delivered a total of 1,980 pulses a day, 5 days a week, for 4-6 weeks. The primary outcome was change in the total score on the 21-item Hamilton Depression Rating Scale (HDRS-21) from baseline to the end of study in an intent-to-treat analysis. The secondary outcomes were the response and remission rates. We also assessed changes in cognitive function and adverse events., Results: Forty patients were randomized to active or sham dTMS groups (1:1). The change in the total score on the HDRS-21 was more significantly improved in the active group than in the sham group at 6 weeks (p = 0.045). There were no significant differences in the response and remission rates or cognitive measures between the active and sham groups. No serious adverse events were observed in either group., Conclusions: These results suggest that dTMS might be effective and safe in office workers with treatment-resistant depression. Further well-designed studies are needed., (© 2020 S. Karger AG, Basel.)

A growing number of recent studies has suggested that the neuroplastic effects of electroconvulsive therapy (ECT) might be prominent enough to be detected through changes of regional gray matter volumes (GMV) during the course of the treatment. Given that ECT patients are difficult to recruit for imaging studies, most publications, however, report only on small samples. Addressing this challenge, we here report results of a structural imaging study on ECT patients that pooled patients from five German sites. Whole-brain voxel-based morphometry (VBM) analysis was performed to detect structural differences in 85 patients with unipolar depression before and after ECT, when compared to 86 healthy controls. Both task-independent and task-dependent physiological whole-brain functional connectivity patterns of these regions were modeled using additional data from healthy subjects. All emerging regions were additionally functionally characterized using the BrainMap database. Our VBM analysis detected a significant increase of GMV in the right hippocampus/amygdala region in patients after ECT compared to healthy controls. In healthy subjects this region was found to be enrolled in a network associated with emotional processing and memory. A region in the left fusiform gyrus was additionally found to have higher GMV in controls when compared with patients at baseline. This region showed minor changes after ECT. Our data points to a GMV increase in patients post ECT in regions that seem to constitute a hub of an emotion processing network. This appears as a plausible antidepressant mechanism and could explain the efficacy of ECT not only in the treatment of unipolar depression, but also of affective symptoms across heterogeneous disorders., Competing Interests: Declaration of Competing Interest The authors state that they have no conflict of interest., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Multiple prior treatment failures are associated with reduced rates of remission to subsequent antidepressant treatment, including rTMS. The degree of treatment resistance that is especially predictive of inferior outcome is uncertain. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS where less is known regarding clinical predictors of remission. The THREE-D study demonstrated that iTBS is non-inferior to 10 Hz rTMS for the treatment of depression., Objective: Determine if the number and type of prior pharmacotherapy trials affect the rate of remission with two types of rTMS., Method: Compare remission rates based on prior pharmacotherapy using data from the THREE-D trial (NCT01887782)., Results: No differences in remission rates were noted between the three levels of treatment resistance, however, participants with 3 compared to <3 treatment failures had lower rates of remission: 17.3% versus 29.4% (χ 2 4.87; df = 1; p = 0.03)., Conclusions: Three or more treatment failures may be associated with lower remission rates with rTMS., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The breakthrough discovery has been made that a single dose of ketamine, an N-methyl-D-aspartate receptor antagonist, achieves rapid and sustained (~7 days) antidepressant activity in patients with major depressive disorder (MDD). This discovery has ushered in an exciting era of research and brought new hope for patients with MDD. However, the mechanisms underlying the specific antidepressant actions of ketamine in humans remain to be elucidated., Objectives: This study protocol was designed to test the main hypothesis that ketamine could rapidly reverse depression- and stress-associated synaptic loss and deficits in resting-state functional connectivity and that this action could be affected by circadian rhythm, in patients with treatment-resistant depression., Methods/study Design: In this clinical study, adults (aged 18-65 years) with treatment-resistant depression will be randomized to intravenous administration of placebo (control group) or ketamine (0.5 mg/kg body weight) at 11 a.m. (daytime group), or 6 p.m. (nighttime group) for 24 weeks. The primary outcome will be the change from baseline to 24 weeks in the total Montgomery-Asberg Depression Rating Scale score. Brain imaging, sleep, and genetic studies, including functional magnetic resonance imaging, positron emission tomography, polysomnography, and genetic analyses, will be performed to examine whether and how ketamine can rapidly reverse deficits in synaptic function and to identify objective markers for the assessment of ketamine infusion therapy for treatment-resistant depression., Conclusions: This clinical study protocol is the first, to our knowledge, to describe the prospective testing of the hypothesis that daytime and nighttime administrations of ketamine would have different antidepressant effects. The brain imaging, sleep, and genetic findings from patients with treatment-resistant depression are expected to shed new light on the mechanisms of ketamine and its interaction with target sites in the brain, which can be used for objective evaluation of the efficacy of ketamine., (© 2019 Tianjin Anding Hospital. Brain and Behavior published by Wiley Periodicals, Inc.)

Background: Treatment-resistant depression is an important contributor to the global burden of depression. Antidepressant augmentation is a recommended treatment strategy for treatment-resistant patients, but outcomes remain poor. Identifying factors that are predictive of response to augmentation treatments may improve outcomes., Aims: This review aimed to synthesise the existing literature examining predictors of response to augmentation treatments in patients who had insufficiently responded to initial treatment., Methods: A systematic search was conducted identifying 2241 unique manuscripts. 24 examining predictors of outcome to pharmacological or psychological augmentation treatment were included in this review., Results: Atypical antipsychotics were the most frequently assessed treatment class (nine studies), closely followed by mood stabilisers (eight studies). Only one eligible psychological augmentation study was identified. Early response to treatment (week 2) was the best-supported predictor of subsequent treatment outcome, reported by six studies. Many predictor variables were only assessed by one report and others such as pre-treatment severity yielded contradictory results, both within and across treatment classes., Conclusions: This review highlights the importance of early response as a predictor of pharmacological augmentation outcome, with implications for both the monitoring and treatment of resistant unipolar patients. Further replication is needed across specific interventions to fully assess the generalisability of this finding. However, the clear lack of consistent evidence for other predictive factors both within and across treatments, and the scarce examination of psychological augmentation, demonstrates the need for much more research of a high quality if response prediction is to improve outcomes for patients with treatment-resistant depression.

The safety and efficacy of neuronavigated intermittent theta burst stimulation (iTBS) in patients with bipolar depression has not yet been investigated. We hypothesized the superiority of active iTBS over sham. Twenty-six patients were randomly allocated to receive either active (n=12) or sham (n=14) iTBS. Response and remission rates according to changes in depression MADRS score were high following active iTBS (72% and 42% for response and remission rates, respectively), but no significant difference was found after sham stimulation (42%and 25%). No adverse events were observed. This study revealed the safety and tolerability of twice daily iTBS in patients with bipolar depression. Larger controlled studies are warranted to prove iTBS superiority in treatment-resistant bipolar depression., (Copyright © 2019. Published by Elsevier Masson SAS.)