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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.

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. 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. We enrolled 5 patients in our trial. A Friedman repeated-measures analysis of variance revealed a significant effect of treatment (χ21 = 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. The small sample size limited the statistical power and external validity. 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. NCT01268137 (ClinicalTrials.gov).

Overgeneralised self-blame and worthlessness are key symptoms of major depressive disorder (MDD) and have previously been associated with self-blame-selective changes in connectivity between right superior anterior temporal lobe (rSATL) and subgenual frontal cortices. Another study showed that remitted MDD patients were able to modulate this neural signature using functional magnetic resonance imaging (fMRI) neurofeedback training, thereby increasing their self-esteem. The feasibility and potential of using this approach in symptomatic MDD were unknown. This single-blind pre-registered randomised controlled pilot trial probed a novel self-guided psychological intervention with and without additional rSATL-posterior subgenual cortex (BA25) fMRI neurofeedback, targeting self-blaming emotions in people with insufficiently recovered MDD and early treatment-resistance ( = 43, = 35 completers). Participants completed three weekly self-guided sessions to rebalance self-blaming biases. As predicted, neurofeedback led to a training-induced reduction in rSATL-BA25 connectivity for self-blame other-blame. Both interventions were safe and resulted in a 46% reduction on the Beck Depression Inventory-II, our primary outcome, with no group differences. Secondary analyses, however, revealed that patients without DSM-5-defined anxious distress showed a superior response to neurofeedback compared with the psychological intervention, and the opposite pattern in anxious MDD. As predicted, symptom remission was associated with increases in self-esteem and this correlated with the frequency with which participants employed the psychological strategies in daily life. These findings suggest that self-blame-rebalance neurofeedback may be superior over a solely psychological intervention in non-anxious MDD, although further confirmatory studies are needed. Simple self-guided strategies tackling self-blame were beneficial, but need to be compared against treatment-as-usual in further trials. https://doi.org/10.1186/ISRCTN10526888.

Amygdala hemodynamic responses to positive stimuli are attenuated in major depressive disorder (MDD), and normalize with remission. Real-time functional MRI neurofeedback (rtfMRI-nf) offers a non-invasive method to modulate this regional activity. We examined whether depressed participants can use rtfMRI-nf to enhance amygdala responses to positive autobiographical memories, and whether this ability alters symptom severity. Unmedicated MDD subjects were assigned to receive rtfMRI-nf from either left amygdala (LA; experimental group, n = 14) or the horizontal segment of the intraparietal sulcus (HIPS; control group, n = 7) and instructed to contemplate happy autobiographical memories (AMs) to raise the level of a bar representing the hemodynamic signal from the target region to a target level. This 40s Happy condition alternated with 40s blocks of rest and counting backwards. A final Transfer run without neurofeedback information was included. Participants in the experimental group upregulated their amygdala responses during positive AM recall. Significant pre-post scan decreases in anxiety ratings and increases in happiness ratings were evident in the experimental versus control group. A whole brain analysis showed that during the transfer run, participants in the experimental group had increased activity compared to the control group in left superior temporal gyrus and temporal polar cortex, and right thalamus. Using rtfMRI-nf from the left amygdala during recall of positive AMs, depressed subjects were able to self-regulate their amygdala response, resulting in improved mood. Results from this proof-of-concept study suggest that rtfMRI-nf training with positive AM recall holds potential as a novel therapeutic approach in the treatment of depression.

Recurrent episodes in major depressive disorder (MDD) are common but the neuroimaging features predictive of recurrence are not established. Participants in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study who achieved remission after 12 weeks of treatment withcognitive behavior therapy, duloxetine, or escitalopram were prospectively monitored for up to 21 months for recurrence. Neuroimaging markers predictive of recurrence were identified from week 12 functional magnetic resonance imaging scans by analyzing whole-brain resting state functional connectivity (RSFC) using seeds for four brain networks that are altered in MDD. Neuroimaging correlates of established clinical predictors of recurrence, including the magnitude of depressive (Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale) symptom severity at time of remission, and a comorbid anxiety disorder were examined for their similarity to the neuroimaging predictors of recurrence. Of the 344 patients randomized in PReDICT, 61 achieved remission and had usable scans for analysis, 9 of whom experienced recurrence during follow-up. Recurrence was predicted by: 1) increased RSFC between subcallosal cingulate cortex (SCC) and right anterior insula, 2) decreased RSFC between SCC and bilateral primary visual cortex, and 3) decreased RSFC between insula and bilateral caudate. Week 12 depression and anxiety scores were negatively correlated with RSFC strength between executive control and default mode networks, but they were not correlated with the three RSFC patterns predicting recurrence. We conclude that altered RSFC in SCC and anterior insula networks are prospective risk factors associated with MDD recurrence, reflecting additional sources of risk beyond clinical measures.

The hippocampus and amygdala have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Preclinical models suggest that stress-related changes in these regions can be reversed by antidepressants, including ketamine. Clinical studies have identified reduced volumes in MDD that are thought to be potentiated by early life stress and worsened by repeated depressive episodes. This study used 3T and 7T structural magnetic resonance imaging data to examine longitudinal changes in hippocampal and amygdalar subfield volumes associated with ketamine treatment. Data were drawn from a previous double-blind, placebo-controlled, crossover trial of healthy volunteers (HVs) unmedicated individuals with treatment-resistant depression (TRD) (3T: 18 HV, 26 TRD, 7T: 17 HV, 30 TRD) who were scanned at baseline and twice following either a 40 min IV ketamine (0.5 mg/kg) or saline infusion (acute: 1–2 days, interim: 9–10 days post infusion). No baseline differences were noted between the two groups. At 10 days post-infusion, a slight increase was observed between ketamine and placebo scans in whole left amygdalar volume in individuals with TRD. No other differences were found between individuals with TRD and HVs at either field strength. These findings shed light on the timing of ketamine’s effects on cortical structures.

To analyze the symptoms, courses, and severities of depressive disorder, as well as the morphological changes in the spleens and related immune mechanisms, we recruited patients with first-episode or recurrent major depressive disorder (MDD) (patient group) and healthy controls (normal group) matched in age and gender. We measured their plasma MICB (pg/ml), ULBP1 (ng/ml), and splenic volume (cm 3 ) at baseline. The patient group was randomly assigned to receive (S)-ketamine (study group) or saline (control group), and the above indices were collected again on the 4th weekend after administration. At baseline, both MICB and splenic volume were significantly higher in the patient group than in the normal group. A positive correlation was observed between MICB and splenic volume in the patient group. After (S)-ketamine administration, the elevated splenic volume and MICB levels decreased. These results suggest that the pathogenesis of MDD may involve abnormal MICB expression and splenic morphology. (S)-ketamine may ameliorate inflammation and enhance splenic function, thereby relieving MDD symptoms.   Highlights ● Abnormal immune functions are associated with MDD, characterized mainly by abnormal MICB expression and splenic morphology. ● The spleen may be involved in the pathogenesis of depression through regulating MICB-NKG2D. ● (S)-ketamine may relieve inflammation and improve splenic function, thereby promoting short-term recovery in patients.

Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus–pituitary–adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.

Although the cost of poor treatment outcomes of depression is staggering, we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in major depressive disorder (MDD) and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test-retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. A total of 80 MDD outpatients were scanned prior to treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin-norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). A total of 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by ⩾50% symptom improvement on the 17-item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (Cohen's d effect size 0.63 to 0.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward 'normalization' post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR (Cohen's d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyper-reactivity, which progressed to hypo-reactivity rather than normalization post-treatment, and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin-norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments.

Individuals with depression differ substantially in their response to treatment with antidepressants. Specific predictors explain only a small proportion of these differences. To meaningfully predict who will respond to which antidepressant, it may be necessary to combine multiple biomarkers and clinical variables. Using statistical learning on common genetic variants and clinical information in a training sample of 280 individuals randomly allocated to 12-week treatment with antidepressants escitalopram or nortriptyline, we derived models to predict remission with each antidepressant drug. We tested the reproducibility of each prediction in a validation set of 150 participants not used in model derivation. An elastic net logistic model based on eleven genetic and six clinical variables predicted remission with escitalopram in the validation dataset with area under the curve 0.77 (95%CI; 0.66-0.88; p = 0.004), explaining approximately 30% of variance in who achieves remission. A model derived from 20 genetic variables predicted remission with nortriptyline in the validation dataset with an area under the curve 0.77 (95%CI; 0.65-0.90; p < 0.001), explaining approximately 36% of variance in who achieves remission. The predictive models were antidepressant drug-specific. Validated drug-specific predictions suggest that a relatively small number of genetic and clinical variables can help select treatment between escitalopram and nortriptyline.