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High-frequency (HF) transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is widely used in Major Depressive Episode (MDE). Optimization of its efficacy with a neuro-navigation system has been proposed based on a small randomized controlled trial (RCT) supporting a large effect. This evaluator- and patient-blind, multicenter RCT assessed the superiority in terms of efficacy of 10 HF rTMS sessions of the left DLPFC targeted with MRI based neuro-navigation versus similar sessions targeted by the standard 5 cm technique. The study was conducted between January 2013 and April 2017, at 4 hospitals centers in France where both in- and out- patients with MDE were included. Randomization was computer-generated (1:1), with allocation concealment implemented within the e-CRF. The main outcome measure was the percentage of responders 44 days (D44) after the rTMS session. Secondary outcomes were percentage of remitters, Beck Depression Inventory and psychomotor retardation assessed with Salpêtrière retardation rating scale (SRRS) for depression at D14 and D44. The results are presented along with their 95% confidence intervals. 105 patients were randomized and 92 were evaluable with respectively 45 patients in the neuronavigation group and 47 in the standard group. A treatment response was observed for 14 (31.8%) of 44 patients analyzed in the intervention group, and for 16 (35.6%) of 45 patients analyzed in the control group with no statistical difference (relative risk 0.89; 95% confidence interval, [0.50;1.61]). No difference was evidenced for secondary outcomes at D44 whether it concerns remission at D44 (relative risk, 0.82; 95% CI, 0.36 to 1.88), or BDI results (difference in means, 0,01; 95% CI, -3.06 to 3.26), or SRRS results (difference in means, 0.11; 95% CI, -2.42 to 5.02). Similar results were observed at D14. Rates of adverse events were similar in both groups with 23 (47.9%) and 1 (2.1%) of adverse events and serious adverse events in the neuro-navigation group versus 20 (40.8%) and 0 (0%) in the standard group. This study failed to reproduce previous findings supporting the use of neuro-navigation system to optimize rTMS efficacy. Limitations of this study includes a small sample size and a number of rTMS sessions that may appear substandard in 2025. NCT01677078.

Although major depressive disorder (MDD) is associated with altered functional coupling between disparate neural networks, the degree to which such measures are ameliorated by antidepressant treatment is unclear. It is also unclear whether functional connectivity can be used as a predictive biomarker of treatment response. Here, we used whole-brain functional connectivity analysis to identify neural signatures of remission following antidepressant treatment, and to identify connectomic predictors of treatment response. 163 MDD and 62 healthy individuals underwent functional MRI during pre-treatment baseline and 8-week follow-up sessions. Patients were randomized to escitalopram, sertraline or venlafaxine-XR antidepressants and assessed at follow-up for remission. Baseline measures of intrinsic functional connectivity between each pair of 333 regions were analyzed to identify pre-treatment connectomic features that distinguish remitters from non-remitters. We then interrogated these connectomic differences to determine if they changed post-treatment, distinguished patients from controls, and were modulated by medication type. Irrespective of medication type, remitters were distinguished from non-remitters by greater connectivity within the default mode network (DMN); specifically, between the DMN, fronto-parietal and somatomotor networks, the DMN and visual, limbic, auditory and ventral attention networks, and between the fronto-parietal and somatomotor networks with cingulo-opercular and dorsal attention networks. This baseline hypo-connectivity for non-remitters also distinguished them from controls and increased following treatment. In contrast, connectivity for remitters was higher than controls at baseline and also following remission, suggesting a trait-like connectomic characteristic. Increased functional connectivity within and between large-scale intrinsic brain networks may characterize acute recovery with antidepressants in depression.

Psilocybin therapy shows antidepressant potential, but its therapeutic actions are not well understood. We assessed the subacute impact of psilocybin on brain function in two clinical trials of depression. The first was an open-label trial of orally administered psilocybin (10 mg and 25 mg, 7 d apart) in patients with treatment-resistant depression. Functional magnetic resonance imaging (fMRI) was recorded at baseline and 1 d after the 25-mg dose. Beck’s depression inventory was the primary outcome measure ( MR/J00460X/1 ). The second trial was a double-blind phase II randomized controlled trial comparing psilocybin therapy with escitalopram. Patients with major depressive disorder received either 2 × 25 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily placebo (‘psilocybin arm’) or 2 × 1 mg oral psilocybin, 3 weeks apart, plus 6 weeks of daily escitalopram (10–20 mg) (‘escitalopram arm’). fMRI was recorded at baseline and 3 weeks after the second psilocybin dose ( NCT03429075 ). In both trials, the antidepressant response to psilocybin was rapid, sustained and correlated with decreases in fMRI brain network modularity, implying that psilocybin’s antidepressant action may depend on a global increase in brain network integration. Network cartography analyses indicated that 5-HT2A receptor-rich higher-order functional networks became more functionally interconnected and flexible after psilocybin treatment. The antidepressant response to escitalopram was milder and no changes in brain network organization were observed. Consistent efficacy-related brain changes, correlating with robust antidepressant effects across two studies, suggest an antidepressant mechanism for psilocybin therapy: global increases in brain network integration. The antidepressant response to psilocybin in individuals with treatment-resistant depression is distinct from escitalopram and depends on a global increase in brain network integration.

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 (HRSD17) 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 HRSD17 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.

Cognitive dysfunction in depression and bipolar disorder (BD) is insufficiently targeted by available treatments. Erythropoietin (EPO) increases neuroplasticity and may improve cognition in mood disorders, but the neuronal mechanisms of these effects are unknown. This functional magnetic resonance imaging (fMRI) study investigated the effects of EPO on neural circuitry activity during working memory (WM) performance. Patients with treatment-resistant major depression, who were moderately depressed, or with BD in partial remission, were randomized to eight weekly infusions of EPO (40 000 IU) (N = 30) or saline (N = 26) in a double-blind, parallel-group design. Patients underwent fMRI, mood ratings and blood tests at baseline and week 14. During fMRI patients performed an n-back WM task. EPO improved WM accuracy compared with saline (p = 0.045). Whole-brain analyses revealed that EPO increased WM load-related activity in the right superior frontal gyrus (SFG) compared with saline (p = 0.01). There was also enhanced WM load-related deactivation of the left hippocampus in EPO-treated compared to saline-treated patients (p = 0.03). Across the entire sample, baseline to follow-up changes in WM performance correlated positively with changes in WM-related SFG activity and negatively with hippocampal response (r = 0.28-0.30, p < 0.05). The effects of EPO were not associated with changes in mood or red blood cells (p ⩾0.08). The present findings associate changes in WM-load related activity in the right SFG and left hippocampus with improved executive function in EPO-treated patients. clinicaltrials.gov: NCT00916552.

Standard depression treatments, including antidepressant medication and cognitive behavioural therapy (CBT), are ineffective for many patients. Prefrontal transcranial direct current stimulation (tDCS) has been proposed as an alternative treatment, but has shown inconsistent efficacy for depression, and its mechanisms are poorly understood. We recruited unmedicated patients with major depressive disorder (N = 71 approached; N = 39 randomised) for a mechanistic, double-blind, randomized controlled trial consisting of eight weekly sessions of prefrontal tDCS administered to the left prefrontal cortex prior to CBT. We probed (1) whether tDCS improved the efficacy of CBT relative to sham stimulation; and (2) whether neural measures predicted clinical response. We found a modest and non-significant effect of tDCS on clinical outcome over and above CBT (active: 50%; sham: 31.6%; odds ratio: 2.16, 95% CI = 0.59–7.99), but a strong relationship, predicted a priori, between baseline activation during a working memory task in the stimulated prefrontal region and symptom improvement. Repeating our analyses of symptom outcome splitting the sample according to this biomarker revealed that tDCS was significantly superior to sham in individuals with high left prefrontal cortex activation at baseline; we also show 86% accuracy in predicting clinical response using this measure. Exploratory analyses revealed several other regions where activation at baseline was associated with subsequent response to CBT, irrespective of tDCS. This mechanistic trial revealed variable, but predictable, clinical effects of prefrontal tDCS combined with CBT for depression. We have discovered a potential explanation for this variability: individual differences in baseline activation of the region stimulated. Such a biomarker could potentially be used to pre-select patients for trials and, eventually, in the clinic.

The aim of the present study was to use fMRI to examine the neural correlates of engaging in rumination among a sample of remitted depressed adolescents, a population at high risk for future depressive relapse. A rumination induction task was used to assess differences in the patterns of neural activation during rumination versus a distraction condition among 26 adolescents in remission from major depressive disorder (rMDD) and in 15 healthy control adolescents. Self-report depression and rumination, as well as clinician-rated depression, were also assessed among all participants. All of the participants recruited regions in the default mode network (DMN), including the posterior cingulate cortex, medial prefrontal cortex, inferior parietal lobe, and medial temporal gyrus, during rumination. Increased activation in these regions during rumination was correlated with increased self-report rumination and symptoms of depression across all participants. Adolescents with rMDD also exhibited greater activation in regions involved in visual, somatosensory, and emotion processing than did healthy peers. The present findings suggest that during ruminative thought, adolescents with rMDD are characterized by increased recruitment of regions within the DMN and in areas involved in visual, somatosensory, and emotion processing.

Growing evidence points to the pivotal role of vitamin D in the pathophysiology and treatment of major depressive disorder (MDD). However, there is a paucity of longitudinal research investigating the effects of vitamin D supplementation on the brain of MDD patients. We conducted a double-blind randomized controlled trial in 46 MDD patients, who were randomly allocated into either VD (antidepressant medication + vitamin D supplementation) or NVD (antidepressant medication + placebos) groups. Data from diffusion tensor imaging, resting-state functional MRI, serum vitamin D concentration, and clinical symptoms were obtained at baseline and after an average of 7 months of intervention. Both VD and NVD groups showed significant improvement in depression and anxiety symptoms but with no significant differences between the two groups. However, a greater increase in serum vitamin D concentration was found to be associated with greater improvement in depression and anxiety symptoms in VD group. More importantly, neuroimaging data demonstrated disrupted white matter integrity of right inferior fronto-occipital fasciculus along with decreased functional connectivity between right frontoparietal and medial visual networks after intervention in NVD group, but no changes in VD group. These findings suggest that vitamin D supplementation as adjunctive therapy to antidepressants may not only contribute to improvement in clinical symptoms but also help preserve brain structural and functional connectivity in MDD patients.

Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits. Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics. Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58). A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.