Neural responses to facial emotions and subsequent clinical outcomes in difficult-to-treat depression.

BACKGROUND: Amygdala and dorsal anterior cingulate cortex responses to facial emotions have shown promise in predicting treatment response in medication-free major depressive disorder (MDD). Here, we examined their role in the pathophysiology of clinical outcomes in more chronic, difficult-to-treat forms of MDD. METHODS: Forty-five people with current MDD who had not responded to ⩾2 serotonergic antidepressants (n = 42, meeting pre-defined fMRI minimum quality thresholds) were enrolled and followed up over four months of standard primary care. Prior to medication review, subliminal facial emotion fMRI was used to extract blood-oxygen level-dependent effects for sad v. happy faces from two pre-registered a priori defined regions: bilateral amygdala and dorsal/pregenual anterior cingulate cortex. Clinical outcome was the percentage change on the self-reported Quick Inventory of Depressive Symptomatology (16-item). RESULTS: We corroborated our pre-registered hypothesis (NCT04342299) that lower bilateral amygdala activation for sad v. happy faces predicted favorable clinical outcomes (rs[38] = 0.40, p = 0.01). In contrast, there was no effect for dorsal/pregenual anterior cingulate cortex activation (rs[38] = 0.18, p = 0.29), nor when using voxel-based whole-brain analyses (voxel-based Family-Wise Error-corrected p < 0.05). Predictive effects were mainly driven by the right amygdala whose response to happy faces was reduced in patients with higher anxiety levels. CONCLUSIONS: We confirmed the prediction that a lower amygdala response to negative v. positive facial expressions might be an adaptive neural signature, which predicts subsequent symptom improvement also in difficult-to-treat MDD. Anxiety reduced adaptive amygdala responses.

Effects of ebselen addition on emotional processing and brain neurochemistry in depressed patients unresponsive to antidepressant medication.

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.

Effects of whole-body cryotherapy and static stretching are maintained 4 weeks after treatment in most patients with chronic fatigue syndrome.

In the previous study, whole-body cryotherapy (WBC)+static stretching (SS) has been shown to reduce the severity of some symptoms in Chronic Fatigue Syndrome (CFS) noted just after the therapy. Here we consider the effects of treatment and explore the sustainability of symptom improvements at four weeks (one-month) follow-up. Twenty-two CFS patients were assessed one month after WBC + SS programme. Parameters related to fatigue (Chalder Fatigue Questionnaire (CFQ), Fatigue Impact Scale (FIS), Fatigue Severity Scale (FSS)), cognitive function (Trial Making test part A and B (TMT A and TMT B and its difference (TMT B-A)), Coding) hemodynamic, aortic stiffness (aortic systolic blood pressure (sBP aortic)) and autonomic nervous system functioning were measured. TMT A, TMT B, TMT B-A and Coding improved at one month after the WBC + SS programme. WBC + SS had a significant effect on the increase in sympathetic nervous system activity in rest. WBC + SS had a significant, positive chronotropic effect on the cardiac muscle. Peripheral and aortic systolic blood pressure decreased one month after WBC + SS in comparison to before. Effects of WBC + SS on reduction of fatigue, indicators of aortic stiffness and symptoms severity related to autonomic nervous system disturbance and improvement in cognitive function were maintained at one month. However, improvement in all three fatigue scales (CFQ, FIS and FSS) was noted in 17 of 22 patients. In addition, ten patients were treated initially but they were not assessed at 4 weeks, and are thus not included in the 22 patients who were examined on follow-up. The overall effects of WBC + SS noted at one month post-treatment should be interpreted with caution.

Brain Serotonin Release Is Reduced in Patients With Depression: A [11C]Cimbi-36 Positron Emission Tomography Study With a d-Amphetamine Challenge.

BACKGROUND: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. METHODS: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16-30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. RESULTS: Following d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ΔBPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). CONCLUSIONS: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE.

AI-based dimensional neuroimaging system for characterizing heterogeneity in brain structure and function in major depressive disorder: COORDINATE-MDD consortium design and rationale.

BACKGROUND: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. METHODS: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. RESULTS: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. CONCLUSION: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project.

Combination of whole body cryotherapy with static stretching exercises reduces fatigue and improves functioning of the autonomic nervous system in Chronic Fatigue Syndrome.

BACKGROUND: The aim of this study was to explore the tolerability and effect of static stretching (SS) and whole body cryotherapy (WBC) upon fatigue, daytime sleepiness, cognitive functioning and objective and subjective autonomic nervous system functioning in those with Chronic Fatigue Syndrome (CFS) compared to a control population. METHODS: Thirty-two CFS and eighteen healthy controls (HC) participated in 2 weeks of a SS + WBC programme. This programme was composed of five sessions per week, 10 sessions in total. RESULTS: A significant decrease in fatigue was noted in the CFS group in response to SS + WBC. Some domains of cognitive functioning (speed of processing visual information and set-shifting) also improved in response to SS + WBC in both CFS and HC groups. Our study has confirmed that WBC is well tolerated by those with CFS and leads to symptomatic improvements associated with changes in cardiovascular and autonomic function. CONCLUSIONS: Given the preliminary data showing the beneficial effect of cryotherapy, its relative ease of application, good tolerability, and proven safety, therapy with cold exposure appears to be an approach worth attention. Further studies of cryotherapy as a potential treatment in CFS is important in the light of the lack of effective therapeutic options for these common and often disabling symptoms.

The Potential Use of Ebselen in Treatment-Resistant Depression.

Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere's Disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro screening studies show that ebselen is also an effective inhibitor of the enzyme inositol monophosphatase (IMPase), which is a key target of the mood-stabilising drug lithium. Further, in animal experimental studies, ebselen produces effects on the serotonin system very similar to those of lithium and also decreases behavioural impulsivity. The antidepressant effects of lithium in treatment-resistant depression (TRD) have been attributed to its ability to facilitate presynaptic serotonin activity; this suggests that ebselen might also have a therapeutic role in this condition. Human studies utilising magnetic resonance spectroscopy support the notion that ebselen, at therapeutic doses, inhibits IMPase in the human brain. Moreover, neuropsychological studies support an antidepressant profile for ebselen based on positive effects on emotional processing and reward seeking. Ebselen also lowers a human laboratory measure of impulsivity, a property that has been associated with lithium's anti-suicidal effects in patients with mood disorders. Current clinical studies are directed towards assessment of the neuropsychological effects of ebselen in TRD patients. It will also be important to ascertain whether ebselen is able to lower impulsivity and suicidal behaviour in clinical populations. The objective of this review is to summarise the developmental history, pre-clinical and clinical psychopharmacological properties of ebselen in psychiatric disorders and its potential application as a treatment for TRD.

Effective connectivity between resting-state networks in depression.

RATIONALE: Although depression has been widely researched, findings characterizing how brain regions influence each other remains scarce, yet this is critical for research on antidepressant treatments and individual responses to particular treatments. OBJECTIVES: To identify pre-treatment resting state effective connectivity (rsEC) patterns in patients with major depressive disorder (MDD) and explore their relationship with treatment response. METHODS: Thirty-four drug-free MDD patients had an MRI scan and were subsequently treated for 6 weeks with an SSRI escitalopram 10 mg daily; the response was defined as ≥50% decrease in Hamilton Depression Rating Scale (HAMD) score. RESULTS: rsEC networks in default mode, central executive, and salience networks were identified for patients with depression. Exploratory analyses indicated higher connectivity strength related to baseline depression severity and response to treatment. CONCLUSIONS: Preliminary analyses revealed widespread dysfunction of rsEC in depression. Functional rsEC may be useful as a predictive tool for antidepressant treatment response. A primary limitation of the current study was the small size; however, the group was carefully chosen, well-characterized, and included only medication-free patients. Further research in large samples of placebo-controlled studies would be required to confirm the results.

Neurochemical abnormalities in chronic fatigue syndrome: a pilot magnetic resonance spectroscopy study at 7 Tesla.

RATIONALE: Chronic fatigue syndrome (CFS) is a common and burdensome illness with a poorly understood pathophysiology, though many of the characteristic symptoms are likely to be of brain origin. The use of high-field proton magnetic resonance spectroscopy (MRS) enables the detection of a range of brain neurochemicals relevant to aetiological processes that have been linked to CFS, for example, oxidative stress and mitochondrial dysfunction. METHODS: We studied 22 CFS patients and 13 healthy controls who underwent MRS scanning at 7 T with a voxel placed in the anterior cingulate cortex. Neurometabolite concentrations were calculated using the unsuppressed water signal as a reference. RESULTS: Compared to controls, CFS patients had lowered levels of glutathione, total creatine and myo-inositol in anterior cingulate cortex. However, when using N-acetylaspartate as a reference metabolite, only myo-inositol levels continued to be significantly lower in CFS participants. CONCLUSIONS: The changes in glutathione and creatine are consistent with the presence of oxidative and energetic stress in CFS patients and are potentially remediable by nutritional intervention. A reduction in myo-inositol would be consistent with glial dysfunction. However, the relationship of the neurochemical abnormalities to the causation of CFS remains to be established, and the current findings require prospective replication in a larger sample.

Resting state functional connectivity patterns as biomarkers of treatment response to escitalopram in patients with major depressive disorder.

RATIONAL: With no available response biomarkers, matching an appropriate antidepressant to an individual can be a lengthy process. Improving understanding of processes underlying treatment responsivity in depression is crucial for facilitating work on response biomarkers. OBJECTIVES: To identify differences in patterns of pre-treatment resting-state functional connectivity (rsFC) that may underlie response to antidepressant treatment. METHODS: After a baseline MRI scan, thirty-four drug-free patients with depression were treated with an SSRI escitalopram 10 mg daily for 6 weeks; response was defined as ≥ 50% decrease in Hamilton Depression Rating Scale (HAMD) score. Thirty-one healthy controls had a baseline clinical assessment and scan. Healthy participants did not receive treatment. RESULTS: Twenty-one (62%) of patients responded to escitalopram. Treatment responsivity was associated with enhanced rsFC of the right fronto-parietal network (FPN)-with the posterior DMN, somatomotor network (SMN) and somatosensory association cortex. The lack of treatment response was characterized by reduced rsFC: of the bilateral FPN with the contralateral SMN, of the right FPN with the posterior DMN, and of the extended sensorimotor auditory area with the inferior parietal lobule (IPL) and posterior DMN. Reduced rsFC of the posterior DMN with IPL was seen in treatment responders, although only when compared with HC. CONCLUSIONS: The study supports the role of resting-state networks in response to antidepressant treatment, and in particular the central role of the frontoparietal and default mode networks.

Brain glutamate concentration in men with early psychosis: a magnetic resonance spectroscopy case-control study at 7 T.

Abnormalities in glutamate neurotransmission are linked to psychotic symptoms and cognitive dysfunction in schizophrenia. magnetic resonance spectroscopy (MRS) provides an acceptable means of measuring glutamate in the human brain but findings from patient studies at conventional magnetic field strength show considerable heterogeneity. Ultra-high-field MRS offers greater precision in glutamate measurement, particularly in delineation of glutamate from its precursor and metabolite, glutamine. This study aimed to use high-field (7 T) MRS to measure concentrations of glutamate and glutamine in three brain regions, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and putamen (PUT), in young men with early psychosis. MRS was performed in 17 male participants with early psychosis and 18 healthy age-matched controls. Neurometabolite levels were calculated with unsuppressed water signal as the reference and corrected for individual grey matter, white matter and cerebrospinal fluid concentration. Cognitive function was measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Compared to controls, patients with early psychosis had lower concentrations of glutamate and glutamine in ACC. No differences were apparent in the DLPFC and PUT. In patients with early psychosis, there was a highly significant correlation between glutamate concentration in ACC and performance on the BACS, though the numbers available for this analysis were small. Our finding of lower glutamate levels in ACC in patients with schizophrenia is consistent with a recent meta-analysis of 7 T studies and suggests that this abnormality is present in both patients with early psychosis and those with longer-established illness. The possible link between ACC glutamate and cognitive performance requires replication in larger studies.

Functional Connectivity between Task-Positive Networks and the Left Precuneus as a Biomarker of Response to Lamotrigine in Bipolar Depression: A Pilot Study.

Treatment of bipolar depression poses a significant clinical challenge. Lamotrigine is one of a few efficacious drugs, however, it needs to be titrated very slowly and response can only be assessed after 10-12 weeks. With only a proportion of patients responding, an exploration of factors underlying treatment responsivity is of paramount clinical importance, as it may lead to an allocation of the drug to those most likely to respond to it. This study aimed at identifying differences in patterns of pre-treatment resting state functional connectivity (rsFC) that may underlie response to lamotrigine in bipolar depression. After a baseline MRI scan, twenty-one patients with bipolar depression were treated with lamotrigine in an open-label design; response, defined as ≥50% decrease in Hamilton Depression Rating Scale (HAMD) score, was assessed after 10-12 weeks of treatment. Twenty healthy controls had a baseline clinical assessment and scan but did not receive any treatment. Fifteen out of 21 (71%) patients responded to lamotrigine. Treatment responsivity was associated with enhanced pre-treatment rsFC of the right fronto-parietal network (FPN) and dorsal attention network (DAN) with left precuneus. The lack of treatment response was additionally characterised by reduced rsFC: of the DAN with right middle temporal gyrus; of the default mode network (DMN) with left precuneus; of the extended sensory-motor area with areas including the left hippocampus/left amygdala and left subcallosal cortex/nucleus accumbens; and of the left FPN with left inferior temporal gyrus/occipital fusiform gyrus/lateral occipital cortex. The results suggest that preserved rsFC between the FPN and DAN, the networks involved in cognitive control, and the hub of the posterior DMN, the left precuneus, may be critical for good response to lamotrigine as an add-on treatment in patients with bipolar depression. The study also suggests a more general decrease in rsFC to be related to poor treatment responsivity.

Brain aging in major depressive disorder: results from the ENIGMA major depressive disorder working group.

Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.

Cognitive neuropsychological theory of antidepressant action: a modern-day approach to depression and its treatment.

Depression is a leading cause of disability worldwide and improving its treatment is a core research priority for future programmes. A change in the view of psychological and biological processes, from seeing them as separate to complementing one another, has introduced new perspectives on pathological mechanisms of depression and treatment mode of action. This review presents a theoretical model that incorporated this novel approach, the cognitive neuropsychological hypothesis of antidepressant action. This model proposes that antidepressant treatments decrease the negative bias in the processing of emotionally salient information early in the course of antidepressant treatment, which leads to the clinically significant mood improvement later in treatment. The paper discusses the role of negative affective biases in the development of depression and response to antidepressant treatments. It also discusses whether the model can be applied to other antidepressant interventions and its potential translational value, including treatment choice, prediction of response and drug development.

Translating the promise of 5HT4 receptor agonists for the treatment of depression.

Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.

Brain structural correlates of insomnia severity in 1053 individuals with major depressive disorder: results from the ENIGMA MDD Working Group.

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

A phase 2a randomised, double-blind, placebo-controlled, parallel-group, add-on clinical trial of ebselen (SPI-1005) as a novel treatment for mania or hypomania.

RATIONALE: Lithium is an effective prophylactic and anti-manic treatment in bipolar disorder; however, its use is declining through perceived poor tolerance and toxicity. Lithium inhibits inositol monophosphatase (IMPase), a probable key therapeutic mechanism. The anti-inflammatory drug, ebselen, also inhibits IMPase and appears well-tolerated and safe. OBJECTIVES: To assess the efficacy of adjunctive ebselen in mania using the Young Mania Rating Scale (YMRS) (primary outcome) and the Altman Self-Rating Mania (ASRM) Scale and Clinical Global Impression-Severity Scale (CGI-S) among the secondary outcomes. METHODS: Randomised, double-blind, placebo-controlled, parallel-group trial conducted between October 2017 and June 2019, at Oxford Health NHS Foundation Trust. Pharmacy-controlled randomisation was computer-generated, with full allocation concealment. In/outpatients (n = 68) aged 18-70, experiencing mania or hypomania, were assigned to 3 weeks ebselen (600 mg bd) (n = 33) or placebo (n = 35). Participants received usual clinical care and psychotropic medication. RESULTS: Ebselen was numerically, but not statistically, superior to placebo in lowering scores on the YMRS (adjusted mean difference and 95% confidence interval, - 1.71 (- 5.34 to 1.91), p = 0.35) and ASRM (- 1.36 (- 3.75 to 1.17), p = 0.29). However, scores on the CGI-S were significantly lower at week 3 in ebselen-treated participants (adjusted mean difference, - 0.58 (- 1.14 to - 0.03), p = 0.04). A post hoc analysis excluding patients taking concomitant valproate treatment magnified the difference between ebselen and placebo on the YMRS. Adverse events were comparable between groups, and mild. CONCLUSIONS: Ebselen merits further investigation where concomitant psychotropic medication is better controlled and participants taking valproate are excluded. If effective, ebselen's superior tolerance and safety could make it a useful alternative to lithium. TRIAL REGISTRATION: Trial Registry: www.clinicaltrials.gov , Identifier: NCT03013400.

Stress, inflammation and hippocampal subfields in depression: A 7 Tesla MRI Study.

Experiencing stressful events throughout one's life, particularly childhood trauma, increases the likelihood of being diagnosed with Major Depressive Disorder (MDD). Raised levels of cortisol, and markers of inflammation such as Interleukin (IL-6) and C-reactive protein (CRP), have been linked to both early life stress and MDD. We aimed to explore the biological stress signatures of early stress and MDD on hippocampal sub regional volumes using 7 Tesla MRI imaging. A cohort of 71 MDD patients was compared against 46 age and sex-matched healthy volunteers. MDD subjects had higher averages of IL-6 and CRP levels. These differences were significant for IL-6 levels and trended for CRP. There were no significant group differences in any of the hippocampal subfields or global hippocampal volumes; further, there were no hippocampal subfield differences between MDD subjects with high levels of our biological stress measures and MDDs with normal levels.

Changes in brain Glx in depressed bipolar patients treated with lamotrigine: A proton MRS study.

BACKGROUND: Lamotrigine is a useful treatment in bipolar depression but requires several weeks of dose titration before its clinical effects can be assessed. Animal experimental studies suggest that lamotrigine lowers glutamate release. The aim of the current study was to assess the effect of lamotrigine on brain glutamate in depressed bipolar patients and to determine whether baseline glutamate could be used to predict clinical response. METHODS: We studied 21 bipolar patients who received lamotrigine treatment for a current episode of depression. Before starting lamotrigine and after 10-12 weeks treatment, patients underwent proton magnetic resonance spectroscopy (MRS) scanning at 3 Tesla where levels of glutamate (measured as Glx) were determined in anterior cingulate cortex (ACC). RESULTS: Overall, lamotrigine treatment had no significant effect on Glx levels in ACC. However, in patients who responded clinically to lamotrigine treatment Glx concentrations were significantly increased. Baseline levels of Glx did not predict response to lamotrigine. LIMITATIONS: The main limitation of the study was the modest sample size. Most patients were medicated which may have modified the effect of lamotrigine on glutamate activity. MRS at 3T cannot give a reliable estimate of glutamate separate from its main metabolite, glutamine, and thus changes in Glx may not give a precise estimate of effects of lamotrigine on glutamate itself. CONCLUSION: Lamotrigine does not appear to have a direct effect on glutamate levels in ACC in bipolar patients. However, therapeutic improvement during lamotrigine was associated with increased Glx, suggesting that alterations in glutamatergic activity might be related to recovery from bipolar depression.

Cognitive neuropsychological theory: Reconciliation of psychological and biological approaches for depression.

New antidepressants and individualized approaches to treatment, matching specific therapies to individual patients, are urgently needed. For this, a better understanding of processes underpinning the development of depressive symptoms and response to medications are required. The cognitive neuropsychological model offers a novel approach uniquely combining biological and psychological approaches to explain how antidepressants exert their effect, why there is a delay in the onset of their clinical effect, and how changes in emotional processing are an essential step for a clinical antidepressant effect to take place. The paper presents the model and its underpinnings in the form of research in both healthy and depressed individuals, as well as the potential for its practical use.