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Background: Ablative surgery using bilateral anterior capsulotomy (BAC) is an option for treatment resistant depression (TRD) and obsessive-compulsive disorder (TROCD). The location and extent of the lesion within anterior limb of the internal capsule (ALIC) remains uncertain. Accumulating evidence has suggested that the lesion should be located ventrally while limiting the dorsal extent. Our center is now targeting specific fiber tracts within the lower half of the ALIC., Method: Presurgical diffusion tensor Magnetic Resonance Imaging (MRI) was used to identify individual fibre tracts within the ventral aspect of the ALIC in the last two patients who underwent BAC at our center. One patient had TRD and the other had both TROCD and TRD. Radiofrequency-induced thermal lesions were created in the identified targets with lesion volumes between 20 and 229 mm 3 (average 95 mm 3 )., Findings: Both patients were responders with neither experiencing significant side effects including compromised executive functions., Limitations: The generalizability of our findings is limited because the outcome is based on two subjects., Conclusion: This work suggests that BAC can be individually tailored and more limited to the ventral aspect of the ALIC and is effective and safe for TRD and TROCD. Accumulating data also suggests that to be clinically effective the length of the capsulotomy should be about 10mm. BAC's use may increase with the growing utilization and mastery of magnetic resonance guided focused ultrasound., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Evidence has shown a rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression (TRD) and prominent suicidal ideation (SI). The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in the TRD pathomechanisms., Objective: Whether the structural and functional changes of the DLPFC, particularly Brodmann area 46, are associated with the antidepressant and antisuicidal effects of ketamine infusion among such patients is unknown., Methods: We randomized 48 patients with TRD and SI into groups receiving a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The Hamilton Depression Rating Scale and the Montgomery-Asberg Depression Rating Scale were used to assess symptoms. Positron emission tomography (PET)-magnetic resonance imaging was conducted prior to infusion and on Day 3 postinfusion. We performed longitudinal voxel-based morphometry (VBM) analysis to evaluate the gray matter (GM) volume changes of the DLPFC. The standardized uptake value ratio (SUVr) of 18 F-fluorodeoxyglucose PET images was calculated using the SUV of the cerebellum as a reference region., Results: The VBM analysis revealed a small but significant volumetric reduction in the right DLPFC in the ketamine group compared with that in the midazolam group. A greater reduction in depressive symptoms was associated with a smaller decrease in right DLPFC volumes (p = 0.025). However, we found no SUVr changes of the DLPFC between baseline and post-Day 3 ketamine infusion., Discussion: The optimal modulation of the right DLPFC GM volumes may play an essential role in the antidepressant neuromechanisms of low-dose ketamine., Competing Interests: Declaration of competing interest None of the authors in this study had any conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

It is possible to consider the stimulation of the cingulate gyrus in its portion below the corpus callosum (SCC, or subcallosal cingulate cortex) as an effective, promising, and safe alternative intervention for treatment-resistant depression. In studies with deep brain stimulation - DBS, when follow-on with functional magnetic resonance imaging and/or PET-CT (Positron emission tomography-computed tomography) is performed, it is observed an increase in the blood supply and glucose metabolism in this region, which is the anterior part of the limbic system. This same location has good experimental results also for the treatment of anorexia nervosa. The hypotheses suggest a greater activation of the reward system, a greater sense of well-being, and a consequent reduction in depressive symptoms, the objective of the treatment. Over the last 20 years, multicenter studies have shown symptomatic improvement in 50-60% of patients, and about a third even reach criteria for remission of the depressive disorder.

Background: A significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of treatment-resistant depression (TRD) is anhedonia, or the inability to feel pleasure, which has been attributed to disrupted habenula function - a component of the reward network. This study aimed to map detailed neural circuitry architecture related to the habenula to identify neural mechanisms of TRD., Methods: 35 TRD patients, 35 patients with treatment-sensitive depression (TSD), and 38 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Functional connectivity analyses were performed using the left and right habenula as seed regions of interest, and the three groups were compared using whole-brain voxel-wise comparisons., Results: The TRD group demonstrated hyperconnectivity of the left habenula to the left precuneus cortex and the right precentral gyrus, compared to the TSD group, and to the right precuneus cortex, compared to the TSD and HC groups. In contrast, TSD demonstrated hypoconnectivity than HC for both connectivity measures. These connectivity values were significantly higher in patients with a history of suicidal ideation., Conclusions: This study provides evidence that, unlike TSD, TRD is characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard to treat depression., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Esketamine (ESK) has been approved as a rapid-acting intranasal treatment for treatment-resistant depression (TRD). Although existing studies have investigated the efficacy of ESK in the 4-week induction phase, our knowledge about long-term ESK efficacy remains poor. The aim of this systematic review was to summarize the available data on long-term ESK efficacy for TRD. A systematic search was performed including articles in English, up to 31 March 2021. The search found 7 relevant studies, involving 1024 adult TRD patients. Continuing treatment with ESK after the 4-week induction phase may be associated with stable efficacy in relapse prevention among TRD patients. Conversely, the long-term antidepressant effectiveness upon discontinuation of ESK might be limited, although data from three studies had a moderate to high risk of bias. Overall, the results on the effectiveness of this compound in the long term are mixed. According to our findings, ESK treatment should be continued following the induction phase to reach a stable efficacy in relapse prevention, while the long-term antidepressant and anti-suicidal effects of ESK after discontinuation are inconsistent. Currently, the level of proof of ESK efficacy in long-term TRD treatment remains low and more RCTs with larger sample sizes and active comparators are needed.

Whether microRNAs (miRNAs) from plasma exosomes might be dysregulated in patients with depression, especially treatment-resistant depression (TRD), remains unclear, based on study of which novel biomarkers and therapeutic targets could be discovered. To this end, a small sample study was performed by isolation of plasma exosomes from patients with TRD diagnosed by Hamilton scale. In this study, 4 peripheral plasma samples from patients with TRD and 4 healthy controls were collected for extraction of plasma exosomes. Exosomal miRNAs were analyzed by miRNA sequencing, followed by image collection, expression difference analysis, target gene GO enrichment analysis, and KEGG pathway enrichment analysis. Compared with the healthy controls, 2 miRNAs in the plasma exosomes of patients with TRD showed significant differences in expression, among which has-miR-335-5p were significantly upregulated and has-miR-1292-3p were significantly downregulated. Go and KEGG analysis showed that dysregulated miRNAs affect postsynaptic density and axonogenesis as well as the signaling pathway of axon formation and cell growths. The identification of these miRNAs and their target genes may provide novel biomarkers for improving diagnosis accuracy and treatment effectiveness of TRD., (© 2021. The Author(s).)

Objectives: Antidepressants are first-line treatments for major depressive disorder (MDD), but 40-60% of patients will not respond, hence, predicting response would be a major clinical advance. Machine learning algorithms hold promise to predict treatment outcomes based on clinical symptoms and episode features. We sought to independently replicate recent machine learning methodology predicting antidepressant outcomes using the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) dataset, and then externally validate these methods to train models using data from the Canadian Biomarker Integration Network in Depression (CAN-BIND-1) dataset., Methods: We replicated methodology from Nie et al (2018) using common algorithms based on linear regressions and decision trees to predict treatment-resistant depression (TRD, defined as failing to respond to 2 or more antidepressants) in the STAR*D dataset. We then trained and externally validated models using the clinical features found in both datasets to predict response (≥50% reduction on the Quick Inventory for Depressive Symptomatology, Self-Rated [QIDS-SR]) and remission (endpoint QIDS-SR score ≤5) in the CAN-BIND-1 dataset. We evaluated additional models to investigate how different outcomes and features may affect prediction performance., Results: Our replicated models predicted TRD in the STAR*D dataset with slightly better balanced accuracy than Nie et al (70%-73% versus 64%-71%, respectively). Prediction performance on our external methodology validation on the CAN-BIND-1 dataset varied depending on outcome; performance was worse for response (best balanced accuracy 65%) compared to remission (77%). Using the smaller set of features found in both datasets generally improved prediction performance when evaluated on the STAR*D dataset., Conclusion: We successfully replicated prior work predicting antidepressant treatment outcomes using machine learning methods and clinical data. We found similar prediction performance using these methods on an external database, although prediction of remission was better than prediction of response. Future work is needed to improve prediction performance to be clinically useful., Competing Interests: JJN, TN, YZ, RTN, JC, and RU have no disclosures. BNF has a research grant from Pfizer. RM has received consulting and speaking honoraria from AbbVie, Allergan, Janssen, KYE, Lundbeck, Otsuka, and Sunovion, and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI and OMHF. SHK has received honoraria or research funds from Abbott, Alkermes, Allergan, BMS, Brain Canada, CIHR, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, Xian-Janssen, and holds stock in Field Trip Health. RWL has received ad hoc speaking/consulting fees or research grants from: Allergan, Asia-Pacific Economic Cooperation, BC Leading Edge Foundation, Canadian Institutes of Health Research (CIHR), Canadian Network for Mood and Anxiety Treatments (CANMAT), Canadian Psychiatric Association, Healthy Minds Canada, Janssen, Lundbeck, Lundbeck Institute, MITACS, Myriad Neuroscience, Ontario Brain Institute, Otsuka, Pfizer, University Health Network Foundation, and VGH-UBCH Foundation. CAN-BIND is sponsored by non-for-profit and government funding agencies and by commercial sponsors including Lundbeck, Bristol-Myers Squibb, Pfizer, and Servier. None of the sponsors were involved in study design, conduct of the study, data analysis, data sharing (except for the government funded Ontario Brain Institute, as stated in the Data Availability Statement), interpretation of results, drafting of the manuscript, or final approval and publication of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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.

Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression., Competing Interests: Eli Lilly & Co, a commercial source, provided partial funding for this work. The contents herein do not express the views of the Department of Veterans Affairs or the US government. Parties interested in data sharing should contact the Minneapolis Veterans Health Care System IRB (One Veterans Drive, Minneapolis, MN 55417) to establish a data use agreement. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI., Methods: We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a >50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques., Results: Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity., Limitations: Normalization by intracranial volume nullified some between-group differences in volumetric measures., Conclusion: There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials., Competing Interests: M. Chakravarty is a member of the JPN editorial board; he was not involved in the decision-making on this manuscript. P. Giacobbe and S. Kennedy have received honoraria from St. Jude Medical, Inc. H. Mayberg has received consulting and intellectual property fees from St. Jude Medical, Inc. C. Hamani is a consultant for St. Jude Medical, Inc. A. Lozano is a consultant to Medtronic, Inc., St. Jude Medical, Inc., and Boston Scientific, Inc.; serves on the scientific advisory board of Ceregene, Codman, Neurophage, Aleva and Alcyone Life Sciences; is co-founder of Functional Neuromodulation Inc.; and holds intellectual property in the field of deep brain stimulation. T. Sankar, N. Jawa, S. Li and S. Rizvi report no biomedical financial interests or other conflicts of interest., (© 2020 Joule Inc. or its licensors)

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: Increasing evidence suggests that infusion of a subanesthetic dose of ketamine exerts antidepressant and antisuicidal effects in patients with treatment-resistant depression (TRD)., Aims: In this investigation, we used the resting functional connectivity magnetic resonance imaging (fcMRI) to determine the effects of ketamine on the functional connectivity (FC) of prefrontal cortex (PFC)-related circuits in patients with TRD., Methods: Forty-eight patients with TRD were recruited and randomly divided into three groups on the basis of ketamine infusion dose: 0.5 mg/kg (standard dose), 0.2 mg/kg (low dose), or normal saline (a placebo infusion). Resting functional MRI data and clinical data were recorded at the baseline and on the third day after ketamine infusion treatment., Results: The standard-dose group showed a reduction in the FC of the left dorsal anterior cingulate cortex (dACC) and right dorsolateral (dl)PFC with the other frontal regions. The low-dose group demonstrated a more pervasive reduction of FC in the bilateral dACC with other frontal and parietal regions. A negative correlation was observed between the reduction in suicidal ideation and the reduction in the FC between the left dACC and right ACC regions in the standard-dose group, whereas a positive correlation was observed between the reduction in suicidal ideation and the increase in the FC between the right dlPFC and left superior parietal region in the low-dose group., Conclusions: Our results support the hypothesis that PFC-related circuit modulation is crucial to the antidepressant and antisuicidal effects of the ketamine infusion treatment., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: 20-30% of depressed patients experience Treatment Resistant Depression (TRD). Electroconvulsive Therapy (ECT) remains the treatment of choice for TRD. However, the exact mechanism of ECT remains unclear. We aim to assess grey matter changes in patients with TRD undergoing bilateral ECT treatment at different points during and after treatment., Methods: Patients are recruited at the University Hospital of Toulouse. Eligibility criteria include a diagnosis of TRD and an age between 50 and 70 years old. Patients received clinical assessments (Hamilton Depression Rating Scale) and structural scans (MRI) at three points: baseline (within 48 h before the first ECT); V2 (after the first ECT considered effective); and V3 (within 1 week of completing ECT)., Results: At baseline, controls had significantly higher cortical thickness than patients in the fusiform gyrus, the inferior, middle and superior temporal gyrus, the parahippocampal gyrus and the transverse temporal gyrus (respectively: t(35)=2.7, p = 0.02; t(35)=2.89, p = 0.017; t(35)=3.1, p = 0.015; t(35)=3.6, p = 0.009; t(35)=2.37, p = 0.031; t(35)=2.46, p = 0.03). This difference was no longer significant after ECT. We showed an increase in cortical thickness in superior temporal gyrus between (i) baseline and V3 (t(62)=-3.43 p = 0.009) and (ii) V2 and V3 (t(62)=-3.42 p = 0.009). We showed an increase in hippocampal volume between (i) baseline and V3 (t(62)=-5.23 p < 0.001) and (ii) V2 and V3 (t(62)=-5.3 p < 0.001)., Conclusion: We highlight that there are grey matter changes during ECT treatment in a population with TRD compared to a healthy control population. These changes seem to occur after several rounds of ECT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

There is considerable diversity in how treatment-resistant depression (TRD) is defined. However, every definition incorporates the concept that patients with TRD have not benefited sufficiently from one or more adequate trials of antidepressant treatment. This review examines the issues fundamental to the systematic evaluation of antidepressant treatment adequacy and resistance. These issues include the domains of interventions deemed effective in treatment of major depressive episodes (e.g., pharmacotherapy, brain stimulation, and psychotherapy), the subgroups of patients for whom distinct adequacy criteria are needed (e.g., bipolar vs. unipolar depression, psychotic vs. nonpsychotic depression), whether trials should be rated dichotomously as adequate or inadequate or on a potency continuum, whether combination and augmentation strategies require specific consideration, and the criteria used to evaluate the adequacy of treatment delivery (e.g., dose, duration), trial adherence, and clinical outcome. This review also presents the Antidepressant Treatment History Form: Short-Form (ATHF-SF), a completely revised version of an earlier instrument, and details how these fundamental issues were addressed in the ATHF-SF., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Studies of patients with major depressive disorder (MDD) have consistently reported reduced hippocampal volumes; however, the exact pattern of these volume changes in specific anatomical subfields and their functional significance is unclear. We sought to clarify the relationship between hippocampal tail volumes and (i) a diagnosis of MDD, and (ii) clinical remission to anti-depressant medications (ADMs). Outpatients with nonpsychotic MDD (n=202) based on DSM-IV criteria and a 17-item Hamilton Rating Scale for Depression (HRSD 17 ) score ⩾16 underwent pretreatment magnetic resonance imaging as part of the international Study to Predict Optimized Treatment for Depression (iSPOT-D). Gender-matched healthy controls (n=68) also underwent MRI scanning. An automated pipeline was used to objectively measure hippocampal subfield and whole brain volumes. Remission was defined as an HRSD 17 of ⩽7 following 8 weeks of randomized open-label treatment ADMs: escitalopram, sertraline or venlafaxine-extended release. After controlling for age and total brain volume, hippocampal tail volume was larger in the MDD cohort compared to control subjects. Larger hippocampal tail volume was positively related to clinical remission, independent of total hippocampal volume, total brain volume and age. These data provide convergent evidence of the importance of the hippocampus in the development or treatment of MDD. Hippocampal tail volume is proposed as a potentially useful biomarker of sensitivity to ADM treatment.

Introduction: Pharmacotherapy for the treatment of depressive disorders in Alzheimer's Disease (AD) represents a clinical challenge. pharmacological options are often attempted after a period of watchful waiting (8-12 weeks). monoaminergic antidepressant drugs have shown only modest or null clinical benefits, maybe because the etiology of depressive symptoms in ad patients is fundamentally different from that of nondemented subjects., Areas Covered: The following article looks at the selective serotonin reuptake inhibitor sertraline, which is one of the most frequently studied antidepressant medications in randomized controlled trials (RCTs). It also discusses many other pharmacological approaches that have proven to be inadequate (antipsychotics, acetylcholinesterase inhibitors, anticonvulsants, hormone replacement therapy) and new drug classes (mainly affecting glutamate transmission) that are being studied for treating depression in AD. It also gives discussion to the phase II RCT on the alternative drug S47445 and the potential effect on cognition of the multimodal antidepressant vortioxetine in older depressed patients. Finally, it discusses the N-methyl-D-aspartate antagonist ketamine., Expert Opinion: The present RCT methodologies are too disparate to draw firm conclusions. Future studies are required to identify effective and multimodal pharmacological treatments that efficiently treat depression in AD. Genotyping may boost antidepressant treatment success.

Background: A single low-dose ketamine infusion exhibited a rapid antidepressant effect within 1h. Despite its short biological half-life (approximately 3h), the antidepressant effect of ketamine has been demonstrated to persist for several days. However, changes in brain function responsible for the persistent antidepressant effect of a single low-dose ketamine infusion remain unclear METHODS: Twenty-four patients with treatment-resistant depression (TRD) were randomized into three groups according to the treatment received: 0.5mg/kg ketamine, 0.2mg/kg ketamine, and normal saline infusion. Standardized uptake values (SUVs) of glucose metabolism measured through 18 F-FDG positron-emission-tomography before infusion and 1day after a 40-min ketamine or normal saline infusion were used for subsequent whole-brain voxel-wise analysis and were correlated with depressive symptoms, as defined using the Hamilton Depression Rating Scale-17 (HDRS-17) score RESULTS: The voxel-wise analysis revealed that patients with TRD receiving the 0.5mg/kg ketamine infusion had significantly higher SUVs (corrected for family-wise errors, P = 0.014) in the supplementary motor area (SMA) and dorsal anterior cingulate cortex (dACC) than did those receiving the 0.2mg/kg ketamine infusion. The increase in the SUV in the dACC was negatively correlated with depressive symptoms at 1day after ketamine infusion DISCUSSION: The persistent antidepressant effect of a 0.5mg/kg ketamine infusion may be mediated by increased activation in the SMA and dACC. The higher increase in dACC activation was related to the reduction in depressive symptoms after ketamine infusion. A 0.5mg/kg ketamine infusion facilitated the glutamatergic neurotransmission in the SMA and dACC, which may be responsible for the persistent antidepressant effect of ketamine much beyond its half-life., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype., Methods: Unmedicated subjects with treatment-resistant MDD ( n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion)., Results: Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects ( n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers ( n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine., Conclusion: Baseline subcortical volumes implicated in MDD did not correlate with ketamine's antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker.

Background: Although treatment-resistant and nontreatment-resistant depressed patients show structural brain anomalies relative to healthy controls, the difference in regional volumetry between these two groups remains undocumented., Methods: A whole-brain voxel-based morphometry (VBM) analysis of regional volumes was performed in 125 participants' magnetic resonance images obtained on a 1.5 Tesla scanner; 41 had treatment-resistant depression (TRD), 40 nontreatment-resistant depression (non-TRD), and 44 were healthy controls. The groups were comparable for age and gender. Bipolar/unipolar features as well as pharmacological treatment classes were taken into account as covariates., Results: TRD patients had higher gray matter (GM) volume in the left and right amygdala than non-TRD patients. No difference was found between the TRD bipolar and the TRD unipolar patients, or between the non-TRD bipolar and non-TRD unipolar patients. An exploratory analysis showed that lithium-treated patients in both groups had higher GM volume in the superior and middle frontal gyri in both hemispheres., Conclusions: Higher GM volume in amygdala detected in TRD patients might be seen in perspective with vulnerability to chronicity, revealed by medication resistance., (© 2017 Wiley Periodicals, Inc.)

Background: Parcellating brain regions into functionally homogeneous subdivisions is critical for understanding normal and abnormal brain functions., New Method: In this study, we developed a new sparse representation-based parcellation method for functional magnetic resonance imaging (fMRI) data, and applied the new method to investigate functional insular subdivisions in treatment-resistant major depressive disorder (MDD). Realistic simulations were implemented to demonstrate the feasibility of the method. Subsequently, the method was used to parcellate the insula in a sample of fifty-six MDD patients and thirty-six healthy volunteers (HVs). The optimal number of clusters was determined by an independent test-retest dataset. Finally, differences of the functional connectivity profiles of each insular subdivision between patients and HVs were inspected., Results: The results from both simulated and test-retest fMRI datasets demonstrated the feasibility of the proposed elastic net-based (EN) method. With the proposed method, the insula was parcellated into four subdivisions (dorsal anterior dAI; ventral anterior vAI; middle, MI and posterior, PI). Whereas patients showed hypo-connectivity between vAI and right medial temporal lobe, there were no functional volumetric differences in insular subdivisions between MDD patients and HVs., Comparison With Existing Method: Results from both simulated and real fMRI datasets showed that the proposed EN method achieved higher accuracy than least absolute shrinkage and selection operator-based (LASSO) method., Conclusions: These findings suggest that EN-based parcellation has the potential to be a useful addition to the parcellation techniques for fMRI data, and provide evidence of decreased functional connectivity without functional volumetric changes of the insula in treatment-resistant MDD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) may involve alterations in brain functional connectivity in multiple neural circuits and present large-scale network dysfunction. Patients with treatment-resistant depression (TRD) and treatment-sensitive depression (TSD) show different responses to antidepressants and aberrant brain functions. This study aims to investigate functional connectivity patterns of TRD and TSD at the whole brain resting state. Seventeen patients with TRD, 17 patients with TSD, and 17 healthy controls matched with age, gender, and years of education were recruited in this study. The brain was divided using an automated anatomical labeling atlas into 90 regions of interest, which were used to construct the entire brain functional networks. An analysis method called network-based statistic was used to explore the dysconnected subnetworks of TRD and TSD at different frequency bands. At resting state, TSD and TRD present characteristic patterns of network dysfunction at special frequency bands. The dysconnected subnetwork of TSD mainly lies in the fronto-parietal top-down control network. Moreover, the abnormal neural circuits of TRD are extensive and complex. These circuits not only depend on the abnormal affective network but also involve other networks, including salience network, auditory network, visual network, and language processing cortex. Our findings reflect that the pathological mechanism of TSD may refer to impairment in cognitive control, whereas TRD mainly triggers the dysfunction of emotion processing and affective cognition. This study reveals that differences in brain functional connectivity at resting state reflect distinct pathophysiological mechanisms in TSD and TRD. These findings may be helpful in differentiating two types of MDD and predicting treatment responses., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Electroconvulsive therapy (ECT) is the most effective treatment for patients suffering from severe or treatment-resistant major depressive disorder (MDD). Unfortunately its underlying neurobiological mechanisms are still unclear. One line of evidence indicates that the seizures produced by ECT induce or stimulate neuroplasticity effects. Although these seizures also affect the cortex, the effect of ECT on cortical thickness is not investigated until now. We acquired structural magnetic resonance imaging data in 19 treatment-resistant MDD patients before and after a bilateral ECT course, and 16 healthy controls at 2 time points, and compared changes in cortical thickness between the groups. Our results reveal that ECT induces significant, bilateral increases in cortical thickness, including the temporal pole, inferior and middle temporal cortex and the insula. The pattern of increased cortical thickness was predominant in regions that are associated with seizure onset in ECT. Post hoc analyses showed that the increase in thickness of the insular cortex was larger in responders than in non-responders, which may point to a specific relationship of this region with treatment effects of ECT.

Converging evidence has linked the anterior mid-cingulate cortex to negative affect, pain and cognitive control. It has previously been proposed that this region uses information about punishment to control aversively motivated actions. Studies on the effects of lesions allow causal inferences about brain function; however, naturally occurring lesions in the anterior mid-cingulate cortex are rare. In two studies we therefore recruited 94 volunteers, comprising 15 patients with treatment-resistant depression who had received bilateral anterior cingulotomy, which consists of lesions made within the anterior mid-cingulate cortex, 20 patients with treatment-resistant depression who had not received surgery and 59 healthy control subjects. Using the Ekman 60 faces paradigm and two Stroop paradigms, we tested the hypothesis that patients who received anterior cingulotomy were impaired in recognizing negative facial affect expressions but not positive or neutral facial expressions, and impaired in Stroop cognitive control, with larger lesions being associated with more impairment. Consistent with this hypothesis, we found that larger volume lesions predicted more impairment in recognizing fear, disgust and anger, and no impairment in recognizing facial expressions of surprise or happiness. However, we found no impairment in recognizing expressions of sadness. Also consistent with the hypothesis, we found that larger volume lesions predicted impaired Stroop cognitive control. Notably, this relationship was only present when anterior mid-cingulate cortex lesion volume was defined as the overlap between cingulotomy lesion volume and Shackman's meta-analysis-derived binary masks for negative affect and cognitive control. Given substantial evidence from healthy subjects that the anterior mid-cingulate cortex is part of a network associated with the experience of negative affect and pain, engaging cognitive control processes for optimizing behaviour in the presence of such stimuli, our findings support the assertion that this region has a causal role in these processes. While the clinical justification for cingulotomy is empirical and not theoretical, it is plausible that lesions within a brain region associated with the subjective experience of negative affect and pain may be therapeutic for patients with otherwise intractable mood, anxiety and pain syndromes., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Major depressive syndrome (so-called depression) is a common but serious mental disease that causes low mood. Most patients are treatable, mainly because of high response rates for medicines such as selective serotonin-reuptake inhibitors (SSRIs). However, there are still a considerable number of patients with refractory or drug-resistant depression. On the other hand, recent findings suggest that angiogenesis, i.e., making new blood vessels, could have an important role in the recovery from depressive disorders, at least in part. It has been reported that the brain capillaries are physiologically capable of undergoing angiogenesis upon stimuli such as exercise and SSRIs seem to accelerate brain angiogenesis. Drugs targeting angiogenesis may possibly be another good concept. In addition, the blood brain barrier (BBB), which is a major obstacle for drug development for the central nervous system, would be circumvented. Here I summarize the reports that relate angiogenesis to a cure for major depression and discuss some of the potential molecular targets.

Objective: In major depressive disorder (MDD), single nucleotide polymorphisms (SNPs) in monoaminergic genes may impact disease susceptibility, treatment response, and brain volume. The objective of this study was to examine the effect of such polymorphisms on hippocampal volume in patients with treatment-resistant MDD and healthy controls. Candidate gene risk alleles were hypothesised to be associated with reductions in hippocampal volume., Methods: A total of 26 outpatients with treatment-resistant MDD and 27 matched healthy controls underwent magnetic resonance imaging and genotyping for six SNPs in monoaminergic genes [serotonin transporter (SLC6A4), norepinephrine transporter (SLC6A2), serotonin 1A and 2A receptors (HTR1A and HTR2A), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF)]. Hippocampal volume was estimated using an automated segmentation algorithm (FreeSurfer)., Results: Hippocampal volume did not differ between patients and controls. Within the entire study sample irrespective of diagnosis, C allele-carriers for both the NET-182 T/C [rs2242446] and 5-HT1A-1019C/G [rs6295] polymorphisms had smaller hippocampal volumes relative to other genotypes. For the 5-HTTLPR (rs25531) polymorphism, there was a significant diagnosis by genotype interaction effect on hippocampal volume. Among patients only, homozygosity for the 5-HTTLPR short (S) allele was associated with smaller hippocampal volume. There was no association between the 5-HT2A, COMT, and BDNF SNPs and hippocampal volume., Conclusion: The results indicate that the volume of the hippocampus may be influenced by serotonin- and norepinephrine-related gene polymorphisms. The NET and 5-HT1A polymorphisms appear to have similar effects on hippocampal volume in patients and controls while the 5-HTTLPR polymorphism differentially affects hippocampal volume in the presence of depression.

The habenula (Hb) can play an important role in major depressive disorder (MDD) as it is a key node between fronto-limbic areas and midbrain monoaminergic structures. In vivo neuroimaging studies have shown reductions in Hb volume in a post-mortem sample of patients with affective disorders but findings in unipolar MDD are not consistent. The current study aimed to investigate whether the Hb volume differed between patients with different stages of unipolar MDD and healthy subjects. We also explored differences in grey (GM) and white matter (WM) volumes and potential age and gender effects. High-resolution images were acquired using a 3T-scanner from 95 participants (21 with first-episode MDD; 20 with remitted-recurrent MDD; 20 with treatment-resistant/chronic MDD; and 34 healthy controls).Two researchers blinded to clinical data manually delineated habenular nuclei, with excellent inter-rater agreement. Multivariate analysis of covariance revealed a significant group-by-gender interaction (F9,258=2.22; p=0.02). Univariate effects emerged for Hb-WM volumes (F3,86=3.12; p=0.03) but not for total Hb volumes (F3,86=0.59; p=0.62) or Hb-GM volumes (F3,86=2.01; p=0.12). Women with a first-episode MDD had greater Hb-WM volumes than healthy controls and patients with treatment-resistant/chronic MDD (p<0.01). These findings remained unaltered when controlled for total intracranial volume or medication load. Our results do not support decreased total Hb volumes in unipolar MDD, in patients with first-episode or in patients with long-lasting recurrent or chronic depression. However, the increased Hb-WM volume we observed in women with a first-episode suggests involvement of Hb and its projections in early stages of the recovery process and in the course of MDD., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

The application of machine learning techniques to psychiatric neuroimaging offers the possibility to identify robust, reliable and objective disease biomarkers both within and between contemporary syndromal diagnoses that could guide routine clinical practice. The use of quantitative methods to identify psychiatric biomarkers is consequently important, particularly with a view to making predictions relevant to individual patients, rather than at a group-level. Here, we describe predictions of treatment-refractory depression (TRD) diagnosis using structural T1-weighted brain scans obtained from twenty adult participants with TRD and 21 never depressed controls. We report 85% accuracy of individual subject diagnostic prediction. Using an automated feature selection method, the major brain regions supporting this significant classification were in the caudate, insula, habenula and periventricular grey matter. It was not, however, possible to predict the degree of 'treatment resistance' in individual patients, at least as quantified by the Massachusetts General Hospital (MGH-S) clinical staging method; but the insula was again identified as a region of interest. Structural brain imaging data alone can be used to predict diagnostic status, but not MGH-S staging, with a high degree of accuracy in patients with TRD.

Background: To date, antidepressant drugs show limited efficacy, leaving a large number of patients experiencing severe and persistent symptoms of major depression. Previous open-label clinical trials have reported significant sustained improvements with deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) in patients with severe, chronic treatment-resistant depression (TRD). This study aimed to confirm the efficacy and measure the impact of discontinuation of the electrical stimulation., Methods: We conducted a 6-month double-blind, randomized, sham-controlled crossover study in implanted patients with previous severe TRD who experienced full remission after chronic stimulation. After more than 3 months of stable remission, patients were randomly assigned to 2 treatment arms: the ON-OFF arm, which involved active electrode stimulation for 3 months followed by sham stimulation for 3 months, and the OFF-ON arm, which involved sham stimulation for 3 months followed by active stimulation for 3 months. The primary outcome measure was the difference in the 17-item Hamilton Rating Scale for Depression (HAMD-17) total score between sham and active stimulation., Results: We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ(2)1 = 5.0, p = 0.025) in patients with higher depression scores during sham stimulation. At the end of active stimulation, depression was remitted in 4 of 5 patients and none of them had experienced a relapse, whereas at the end of sham stimulation, 2 patients remained in remission, 2 relapsed and 1 showed a progressive worsening without reaching relapse criteria., Limitations: The small sample size limited the statistical power and external validity., Conclusion: These preliminary findings indicate that DBS of the SCG is an effective and safe treatment for severe forms of TRD and that continuous electrical stimulation is required to maintain therapeutic effects., Trial Registration: NCT01268137 (ClinicalTrials.gov).

Accumulating evidence underscores the utility of ketamine in treating severely treatment-resistant depressed patients. We investigated the relationship between the rapid antidepressant effects of ketamine and hippocampal volume, a biomarker of antidepressant treatment outcome. We gave 16 medication-free, major depressive disorder (MDD) patients a single, sub-anesthetic dose infusion of ketamine (0.5 mg/kg, over 40 min). We assessed depression severity pre-treatment, and at 24 h post-treatment, with the Montgomery-Åsberg Depression Rating Scale (MADRS). Prior to treatment, patients underwent magnetic resonance imaging (MRI) to estimate their hippocampal volume: We obtained viable MRI data in 13 patients. Delta MADRS (post- minus pre-treatment) was significantly correlated with the pre-treatment volumes of the left hippocampus (r = 0.66; p = 0.01), but not the right hippocampus (r = 0.49; p = 0.09). The correlation between delta MADRS and the left hippocampus remained high (r > 0.6; p = 0.13), after controlling for several demographic and clinical variables, although the p value increased due to the reduced degree of freedom (df = 5). Ketamine exerts enhanced antidepressant effects in patients with a relatively smaller hippocampus, a patient population that has been repeatedly shown to be refractory to traditional antidepressants., (© The Author(s) 2014.)

Introduction: Despite a wide variety of therapeutic interventions for major depressive disorder (MDD), treatment resistant depression (TRD) remains to be prevalent and troublesome in clinical practice. In recent years, deep brain stimulation (DBS) has emerged as an alternative for individuals suffering from TRD not responding to combining antidepressants, multiple adjunctive strategies and electroconvulsive therapy (ECT). Although the best site for TRD-DBS is still unclear, pilot data suggests that the medial forebrain bundle (MFB) might be a key target to accomplish therapeutic efficacy in TRD patients., Objective: To explore the anatomic, electrophysiologic, neurocognitive and treatment data supporting the MFB as a target for TRD-DBS., Results: The MFB connects multiple targets involved in motivated behavior, mood regulation and antidepressant response. Specific phenomenology associated with TRD can be linked specifically to the superolateral branch (sl) of the MFB (slMFB). TRD patients who received DBS-slMFB reported high response/remission rates with an improvement in functioning and no significant adverse outcomes in their physical health or neurocognitive performance., Discussion: The slMFB is an essential component of a network of structural and functional pathways connecting different areas possibly involved in the pathogenesis of mood disorders. Therefore, the slMFB should be considered as an exciting therapeutic target for DBS therapy to achieve a sustained relief in TRD patients., Conclusion: There is an urgent need for clinical trials exploring DBS-slMFB in TRD. Further efforts should pursue measuring baseline pro-inflammatory cytokines, oxidative stress, and cognition as possible biomarkers of DBS-slMFB response in order to aid clinicians in better patient selection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Magnetic resonance imaging studies have provided evidence of structural modifications in cortical-limbic regions in major depressive disorder. To date, however, few studies have tracked structural changes in patients during treatment. This prospective, longitudinal imaging study investigated associations between brain structure and clinical responsiveness in a sample of patients with treatment-resistant major depressive disorder during an approximate 1-year follow-up period., Methods: FreeSurfer software was used to extract volume or cortical thickness values from 6 regions of interest (hippocampus, rostral middle frontal gyrus, orbitofrontal cortex, rostral and caudal anterior cingulate cortices, and inferior temporal gyrus) in patients (n = 26) and matched healthy controls (n = 28). Regions of interest were selected based on previous evidence of potential associations between morphometric characteristics in these regions and treatment response or remission. Analyses were conducted to compare volume and cortical thickness in patients and controls at baseline imaging, determine whether patients' brain structure at treatment initiation was associated with response over follow-up, and compare longitudinal changes in volume and cortical thickness in patients who achieved sustained 6-month remission (Montgomery-Åsberg Depression Rating Scale Score ≤12) with nonremitters., Results: Patients and controls showed no structural differences at baseline. Among patients, thicker right caudal anterior cingulate cortex at baseline was associated with greater symptom improvement over follow-up. Remitters and nonremitters showed subtle changes in volume and thickness over time in opposing directions, with increased hippocampal volume and cortical thickness in the rostral middle frontal gyrus, orbitofrontal cortex, and inferior temporal gyrus in remitters, and decreased volume or thickness in these regions in nonremitters., Conclusions: The results suggest that longitudinal structural trajectories may differ in major depressive disorder patients according to their clinical response to treatment., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Background: Patients with treatment-resistant depression (TRD) commonly report significant disability together with an increased risk of functional impairment. Neuroimaging techniques have been used to investigate the neuropathology of this complex illness, but it is still quite unknown whether abnormalities in the integrity of white matter (WM) of specific brain areas may be considered as trait markers of TRD., Methods: Electronic databases were searched from 1980 to 2013. Nine studies - comprising a total of 228 subjects and 171 controls - fulfilled our inclusion criteria and were analyzed in the present overview., Results: Several cross-sectional studies showed the association between WM abnormalities and TRD. According to the selected studies, sub-callosal cingulated cortex (SCC) WM abnormalities were largely implicated in the pathogenesis of both major depressive disorder and TRD. However, alterations in cortical-limbic or cortical-subcortical circuits, particularly the left middle frontal gyrus (which is thought to have a major role in emotional regulation) may also be involved in the pathophysiology of TRD., Conclusion: TRD may be related to the presence of specific microstructural WM abnormalities. WM abnormalities of specific brain regions such as SCC may have a major involvement in the pathogenesis of TRD.

Several studies demonstrated improvement of depressive symptoms in treatment resistant depression (TRD) after administering dopamine agonists which suggest abnormal dopaminergic neurotransmission in TRD. However, the role of dopaminergic signaling through measurement of striatal dopamine D(2/3) receptor (D2/3R) binding has not been investigated in TRD subjects. We used [(123)I]IBZM single photon emission computed tomography (SPECT) to investigate striatal D2/3R binding in TRD. We included 6 severe TRD patients, 11 severe TRD patients on antipsychotics (TRD AP group) and 15 matched healthy controls. Results showed no significant difference (p = 0.75) in striatal D2/3R availability was found between TRD patients and healthy controls. In the TRD AP group D2/3R availability was significantly decreased (reflecting occupancy of D2/3Rs by antipsychotics) relative to TRD patients and healthy controls (p<0.001) but there were no differences in clinical symptoms between TRD AP and TRD patients. This preliminary study therefore does not provide evidence for large differences in D2/3 availability in severe TRD patients and suggests this TRD subgroup is not characterized by altered dopaminergic transmission. Atypical antipsychotics appear to have no clinical benefit in severe TRD patients who remain depressed, despite their strong occupancy of D2/3Rs.

Background: Although white-matter abnormalities have been reported in middle-aged patients with major depressive disorder (MDD), few data are available on treatment-resistant MDD and the influence of relevant variables related to clinical burden of illness is far from being well established., Method: The present study examined white-matter microstructure in a sample of 52 patients with MDD in different stages (treatment-resistant/chronic MDD, n = 18; remitted-recurrent MDD, n = 15; first-episode MDD, n = 19) and 17 healthy controls, using diffusion tensor imaging with a tract-based spatial statistics approach. Groups were comparable in age and gender distribution, and results were corrected for familywise error (FWE) rate., Results: Widespread significant reductions of fractional anisotropy (FA) - including the cingulum, corpus callosum, superior and inferior longitudinal fascicule - were evident in treatment-resistant/chronic MDD compared with first-episode MDD and controls (p < 0.05, FWE-corrected). Decreased FA was observed within the ventromedial prefrontal region in treatment-resistant/chronic MDD even when compared with the remitted-recurrent MDD group (p < 0.05, FWE-corrected). Longer duration of illness (β = -0.49, p = 0.04) and higher depression severity (at a trend level: β = -0.26, p = 0.06) predicted lower FA in linear multiple regression analysis at the whole-brain level. The number of previous episodes and severity of symptoms were significant predictors when focused on the ventromedial prefrontal area (β = -0.28, p = 0.04; and β = -0.29, p = 0.03, respectively). Medication effects were controlled for in the analyses and results remained unaltered., Conclusions: Our findings support the notion that disruptions of white-matter microstructure, particularly in fronto-limbic networks, are associated with resistance to treatment and higher current and past burden of depression.

Objectives: Treatment-resistant depression is a common clinical occurrence among patients with major depressive disorder (MDD), but its neurobiology is poorly understood. We used data collected as part of routine clinical care to study white matter integrity of the brain's limbic system and its association to treatment response., Methods: Electronic medical records of multiple large New England hospitals were screened for patients with an MDD billing diagnosis, and natural language processing was subsequently applied to find those with concurrent diffusion-weighted images, but without any diagnosed brain pathology. Treatment outcome was determined by review of clinical charts. MDD patients (n = 29 non-remitters, n = 26 partial-remitters, and n = 37 full-remitters), and healthy control subjects (n = 58) were analyzed for fractional anisotropy (FA) of the fornix and cingulum bundle., Results: Failure to achieve remission was associated with lower FA among MDD patients, statistically significant for the medial body of the fornix. Moreover, global and regional-selective age-related FA decline was most pronounced in patients with treatment-refractory, non-remitted depression., Conclusions: These findings suggest that specific brain microstructural white matter abnormalities underlie persistent, treatment-resistant depression. They also demonstrate the feasibility of investigating white matter integrity in psychiatric populations using legacy data.

Electroconvulsive therapy (ECT) is the most potent biological therapy in depression. Animal studies suggest that ECT acts via neuroplasticity effects on limbic structures involved in the pathophysiology of depression but in vivo evidence at the human system level is scarce. Therefore, the aim of the present study was to investigate the effect of ECT on hippocampus and amygdala volume in 15 antidepressant-free patients with treatment refractory depression (seven males, range 42-63 years). ECT treatment was successful as indexed by a significant decrease in depressive symptoms (t14=13.6; p<0.001). Analysis of normalized volumetric data before and after ECT treatment revealed a significant volume increase of both hippocampus and amygdala (minimum p<0.005) with no evidence for a change in global brain volume. Though this change in volume cannot be clearly related to treatment effects, ECT is associated with broader neurotrophic effects other than mere adult neurogenesis in the hippocampus, which has been previously suggested as a core mechanism on the basis of animal data., (© 2013 Published by Elsevier Ireland Ltd.)

Background: A literature review suggested age and cognitive problems to be related to an increased prevalence of small areas of signal variation within the hippocampus observed on MRI, described as hippocampal sulcal cavities (HSCs; (Maller et al., 2011)). The current study aimed to describe the prevalence of HSCs in patients with treatment-resistant depression (TRD) and healthy controls over a large age-range., Methods: 115 TRD patients and 86 controls underwent MRI brain scanning. Right and left HSCs were rated separately for prevalence and length., Results: HSCs were observed in 73.04% of those with TRD, statistically more prevalent (p=0.001) than amongst controls (51.16%). These findings are consistent with our review (66% prevalence in memory disorders and 47% in healthy controls). Furthermore, HSC presence and length was associated with aging., Limitations: The study was cross-sectional so its implications for aging are tentative. A larger sample scanned longitudinally will allow for more sophisticated statistical methods by which to investigate the relationship between HSCs, aging, and TRD., Conclusions: Although their clinical significance remains uncertain, the results of the current study suggest that HSCs are related with age and those with TRD have more aged brains than their peers., (Crown Copyright © 2013 Published by Elsevier B.V. All rights reserved.)

Background: Previous studies have commonly shown that patients with treatment-resistant depression (TRD) and treatment-sensitive depression (TSD) demonstrate a different cerebellar activity. No study has yet explored resting-state cerebellar-cerebral functional connectivity (FC) in these two groups. Here, seed-based FC approach was employed to test the hypothesis that patients with TRD and TSD had a different cerebellar-cerebral FC. The identified FC might be used to differentiate TRD from TSD., Methods: Twenty-three patients with TRD, 22 patients with TSD, and 19 healthy subjects (HS) matched with age, gender, and education level participated in the scans. Seed-based connectivity analyses were performed by using cerebellar seeds., Results: Relative to HS, both patient groups showed significantly decreased cerebellar-cerebral FC with the prefrontal cortex (PFC) (superior, middle, and inferior frontal gyrus) and default mode network (DMN) [superior, middle, and inferior temporal gyrus, precuneus (PCu), and inferior parietal lobule (IPL)], and increased FC with visual recognition network (lingual gyrus, middle occipital gyrus, and fusiform) and parahippocampal gyrus. However, the TRD group exhibited a more decreased FC than the TSD group, mainly in connected regions within DMN [PCu, angular gyrus (AG) and IPL]. Further receiver operating characteristic curves (ROC) analyses showed that cerebellar-DMN couplings could be applied as markers to differentiate the two subtypes with relatively high sensitivity and specificity., Conclusions: Both patient groups demonstrate similar pattern of abnormal cerebellar-cerebral FC. Decreased FC between the cerebellum and regions within DMN might be used to separate the two patient groups., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This report describes a 55-year-old woman who had 1 previous episode of major depression that responded favorably to treatment with tricyclic antidepressants. After the development of Addison disease, she experienced a new episode of major depression that failed to respond to adequate treatment with imipramine and was subsequently successfully treated with electroconvulsive therapy (ECT) with steroid cover. The patient did not experience adrenal crisis or adverse effects. After 9 ECT sessions, she attained full remission. These findings support the suggestion that ECT treatment is safe in patients with Addison disease when using 100 mg intravenous hydrocortisone as prophylaxis.

Approximately 50% of patients with a major depressive episode fail to achieve remission with first-line antidepressant treatments. Second-line treatment strategies for such patients include lithium augmentation of antidepressants, particularly with tricyclic antidepressants. The neurobiological mechanisms underlying the therapeutic effects of lithium augmentation are not yet fully understood. Unravelling these mechanisms could aid the development of more effective antidepressant drugs. In the present study, we investigated whether chronic treatment with a combination of lithium and the tricyclic antidepressant, desipramine, could produce antidepressant-like behaviour in a mouse strain (BALB/cOLaHsd) that exhibited reduced sensitivity to the behavioural effects of chronic desipramine treatment in the novelty-induced hypophagia test. Since chronic treatment with antidepressant drugs increases the proliferation of newly-born cells in the hippocampus, and hippocampal cell proliferation is required for the behavioural effects of at least some antidepressants in neohypophagia tests, the present study also investigated whether lithium plus desipramine increased cell proliferation in the hippocampus. Chronic treatment with lithium plus desipramine but neither drug alone, induced antidepressant-like behaviour and increased hippocampal cell proliferation, thus suggesting that increased hippocampal cell proliferation may be a mechanism underlying lithium augmentation of antidepressants. Moreover, since BALB/cOLaHsd mice respond to lithium plus desipramine but not to either drug alone, they may become useful in the development of a mouse model of treatment-refractory depression for which there is an unmet need., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Clinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine., Methods: Twenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores., Results: Patients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders., Conclusions: These findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The association between alterations of the white matter (WM) integrity in brain regions and mood dysregulation has been reported in major depressive disorder (MDD). However, there has never been a neuroimaging study in patients who have treatment-resistant depression (TRD) and are in a current treatment-resistant state. In the present study, we used diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) method to investigate the WM integrity of different brain regions in patients who had TRD and were in a current treatment-resistant state., Methods: Twenty-three patients with TRD and Hamilton Rating Scale total score of ≥18 and 19 healthy controls matched with age, gender, and education level to patients were scanned with DTI. Thirty 4 mm thick, no gap, contiguous axial slices were acquired and fractional anisotropy (FA) images were generated for each participant. An automated TBSS approach was used to analyze the data., Results: Voxel-wise statistics revealed that patients with TRD had lower FA values in the right anterior limb of internal capsule, the body of corpus callosum, and bilateral external capsule compared to healthy subjects. Patients with TRD did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain region and patients' demographics and the severity of illness., Conclusions: Our findings suggest the abnormalities of the WM integrity of neuronal tracts connecting cortical and subcortical nuclei and two brain hemispheres may play a key role in the pathogenesis of TRD., (Copyright © 2012 Elsevier Inc. All rights reserved.)

As the prevalence of treatment resistant depression (TRD) continues to rise, it remains a clinically important issue to identify neurobiological-, patient- and treatment-related factors that could potentially predict response to treatment. Medial temporal lobe (MTL) structures, in particular the hippocampus and amygdala have been implicated in inferior treatment response. The role of related structures such as the entorhinal cortex and the impact of MTL abnormalities on neurocognitive function, however, have not been systematically examined. The current study investigated MTL abnormalities and neurocognitive characteristics of eventual treatment responders and non-responders to a course of repetitive transcranial magnetic stimulation (rTMS) in order to identify potential predictors of treatment outcome. Prior to rTMS treatment all patients underwent magnetic resonance imaging (MRI) and neuropsychological assessment. MRI analysis was conducted using FreeSurfer 5.0. There was a 50% response rate following up to a 6-week course of daily rTMS treatments. Treatment response was defined as 50% reduction in Hamilton Depression Rating Scale and BDI-II scores from baseline. There was no difference in pre-treatment neurocognitive profiles and MTL volumes between eventual treatment responders and non-responders. Smaller pre-treatment left hippocampus volume showed a trend towards predicting eventual subjective improvement in depressive symptomatology. Although preliminary, our findings suggest that structural abnormalities may have some potential for predicting outcome to rTMS., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Studies of patients with major depressive disorder (MDD) and schizophrenia (SCH) have revealed reduced hippocampal volumes, but findings have been inconsistent due to sample and measurement differences. The current study sought to measure this structure in a large sample of MDD, SCH, and healthy subjects, using a strict measurement protocol, to elucidate morphological-specific volumetric differences. Patients with treatment-resistant MDD (N = 182) and treatment-resistant SCH with auditory-verbal hallucinations (N = 52), and healthy controls (N = 76) underwent psychiatric assessments and brain MRI. The findings indicate that (1) MDD and SCH patients have reduced total hippocampal volume which was marked in the tails (more so in patients with MDD), (2) region of interest estimation protocols and sample characteristics may help explain volumetric differences between previous SCH studies., (Copyright © 2010 Wiley Periodicals, Inc., Inc.)

We previously reported that adrenocorticotropic hormone (ACTH)-treated rats serve as a valuable animal model for tricyclic antidepressant-resistant depressive conditions. The present study was undertaken to investigate the changes in neurogenesis in the hippocampus of ACTH-treated rats. Chronic treatment of ACTH decreased the number of bromodeoxyuridine-labeled cells in the dentate gyrus, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. Furthermore, chronic ACTH treatment also decreased the expression of brain-derived neurotrophic factor, and the coadministration of imipramine and lithium, and electroconvulsive stimuli recovered these reductions. These results suggest that antidepressant-resistant depression is caused by the suppression of neurogenesis, and the coadministration of imipramine and lithium, and electroconvulsive stimuli exert an antidepressant-like effect by recovering proliferative signals and neurogenesis.

Background: Using a newly developed regional homogeneity (ReHo) approach, we were to explore the features of brain activity in patients with treatment-resistant depression (TRD) in resting state, and further to examine the relationship between abnormal brain activity in TRD patients and specific symptom factors derived from ratings on the Hamilton Rating Scale for Depression (HRSD)., Methods: 24 patients with TRD and 19 gender-, age-, and education-matched healthy subjects participated in the fMRI scans., Results: 1. Compared with healthy controls, decreased ReHo were found in TRD patients in the left insula, superior temporal gyrus, inferior frontal gyrus, lingual gyrus and cerebellumanterior lobe (culmen) (p<0.05, corrected). 2. Compared with healthy controls, increased ReHo were found in the left superior temporal gyrus, cerebellum posterior lobe (tuber), cerebellum anterior lobe (culmen), the right cerebellar tonsil and bilateral fusiform gyrus (p<0.05, corrected). 3. There was no correlation between the ReHo values in any brain region detected in our study and the patients' age, years of education, illness duration, HRSD total score and its symptom factors., Limitation: The influence of antidepressants to the brain activity in TRD patients was not fully eliminated., Conclusions: The pathogenesis of TRD may be attributed to abnormal neural activity in multiple brain regions., (Copyright © 2011 Elsevier Inc. All rights reserved.)