TRPC4/5 inhibitors: Phase I results and proof of concept studies.

Transient receptor potential canonical (TRPC) ion channels are expressed in areas of the brain responsible for processing emotion and mood and have been implicated in the pathophysiology of internalizing disorders such as major depressive disorder and anxiety disorders. This review outlines the rationale for targeting TRPC ion channels for drug development, with specific focus on TRPC4 and TRPC5. We provide preclinical evidence that the lack of TRPC4 and TRPC5 channels or its pharmacological inhibition attenuate fear and anxiety without impairing other behaviors in mice.

Aberrant associations between neuronal resting-state fluctuations and working memory-induced activity in major depressive disorder.

Previous investigations have revealed performance deficits and altered neural processes during working-memory (WM) tasks in major depressive disorder (MDD). While most of these studies used task-based functional magnetic resonance imaging (fMRI), there is an increasing interest in resting-state fMRI to characterize aberrant network dynamics involved in this and other MDD-associated symptoms. It has been proposed that activity during the resting-state represents characteristics of brain-wide functional organization, which could be highly relevant for the efficient execution of cognitive tasks.

Negative emotionality shapes the modulatory effects of ketamine and lamotrigine in subregions of the anterior cingulate cortex.

Neuroimaging studies have identified the anterior cingulate cortex (ACC) as one of the major targets of ketamine in the human brain, which may be related to ketamine's antidepressant (AD) mechanisms of action. However, due to different methodological approaches, different investigated populations, and varying measurement timepoints, results are not consistent, and the functional significance of the observed brain changes remains a matter of open debate. Inhibition of glutamate release during acute ketamine administration by lamotrigine provides the opportunity to gain additional insight into the functional significance of ketamine-induced brain changes.

Neural signatures of shared subjective affective engagement and disengagement during movie viewing.

When watching a negative emotional movie, we differ from person to person in the ease with which we engage and the difficulty with which we disengage throughout a temporally evolving narrative. We investigated neural responses of emotional processing, by considering inter-individual synchronization in subjective emotional engagement and disengagement. The neural underpinnings of these shared responses are ideally studied in naturalistic scenarios like movie viewing, wherein individuals emotionally engage and disengage at their own time and pace throughout the course of a narrative.

Investigating the impact of rumination and adverse childhood experiences on resting-state neural activity and connectivity in depression.

Background: Both ruminative thought processes and adverse childhood experiences (ACEs) are well-established risk factors for the emergence and maintenance of depression. However, the neurobiological mechanisms underlying these associations remain poorly understood.

Methods: We examined resting-state functional magnetic resonance imaging data (3 T Tim Trio MR scanner; Siemens, Erlangen) of 44 individuals diagnosed with an acute depressive episode.

Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder - study protocol for a randomized clinical trial.

Background: Anhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated.

The influence of electroconvulsive therapy on reconsolidation of autobiographical memories: A retrospective quasi-experimental study in patients with depression.

Background/objective: Electroconvulsive therapy (ECT) is effective for treatment-resistant and psychotic depression. One previously reported side effect of ECT is the disruption of memory reconsolidation. This study examines whether this disruption induced by ECT can be detected in routine neuropsychological assessments.

Effects of Psychotherapy on Glutamatergic Neurotransmission.

Introduction: Psychodynamic psychotherapy is an effective and widely used treatment for major depressive disorder (MDD); however, little is known about neurobiological changes associated with induced symptom improvement.

Methods: Proton magnetic resonance spectroscopy with a two-dimensional J-resolved sequence served to test the relationship between glutamate (Glu) and glutamine (Gln) levels, measured separately in pregenual anterior cingulate cortex (pgACC) and the anterior midcingulate cortex (aMCC) as a control region, with change in depression symptoms after 6 months of weekly psychodynamic psychotherapy sessions in MDD patients. Depressed (N = 45) and healthy (N = 30) subjects participated in a baseline proton magnetic resonance spectroscopy measurement and a subgroup of MDD subjects (N = 21) then received once-a-week psychodynamic psychotherapy and participated in a second proton magnetic resonance spectroscopy measurement after 6 months.

Region- and time- specific effects of ketamine on cerebral blood flow: a randomized controlled trial.

There is intriguing evidence suggesting that ketamine might have distinct acute and delayed neurofunctional effects, as its acute administration transiently induces schizophrenia-like symptoms, while antidepressant effects slowly emerge and are most pronounced 24 h after administration. Studies attempting to characterize ketamine's mechanism of action by using blood oxygen level dependent (BOLD) imaging have yielded inconsistent results regarding implicated brain regions and direction of effects. This may be due to intrinsic properties of the BOLD contrast, while cerebral blood flow (CBF), as measured with arterial spin labeling, is a single physiological marker more directly related to neural activity.

Functional connectivity signatures of major depressive disorder: machine learning analysis of two multicenter neuroimaging studies.

The promise of machine learning has fueled the hope for developing diagnostic tools for psychiatry. Initial studies showed high accuracy for the identification of major depressive disorder (MDD) with resting-state connectivity, but progress has been hampered by the absence of large datasets. Here we used regular machine learning and advanced deep learning algorithms to differentiate patients with MDD from healthy controls and identify neurophysiological signatures of depression in two of the largest resting-state datasets for MDD.

Modulatory Effects of Ketamine and Lamotrigine on Cognition: Emotion Interaction in the Brain.

Introduction: Cognition and emotion are fundamentally integrated in the brain and mutually contribute to behavior. The relation between working memory (WM) and emotion is particularly suited to investigate cognition-emotion interaction since WM is an essential component of many higher cognitive functions. Ketamine affects not only WM but also has a profound impact on emotional processing.

Functional connectivity changes between amygdala and prefrontal cortex after ECT are associated with improvement in distinct depressive symptoms.

Electroconvulsive therapy (ECT) is one of the most effective treatments for treatment-resistant depression. However, the underlying mechanisms of action are not yet fully understood. The investigation of depression-specific networks using resting-state fMRI and the relation to differential symptom improvement might be an innovative approach providing new insights into the underlying processes.

Does route of administration affect antidepressant efficacy of ketamine? A meta-analysis of double-blind randomized controlled trials comparing intravenous and intranasal administration.

Intranasal (IN) and intravenous (IV) applications of ketamine have been proven effective for the treatment of depression, but direct comparative trials or meta-analyses on whether both differ in their antidepressant efficacy are lacking. We aimed to meta-analytically compare the short-term efficacy of a single dose of IV and IN ketamine in adult patients with major depressive disorder (MDD) and included double-blind, randomized controlled trials published until February 2022 in our analyses. The main outcome was a response 24 h after the administration of a single dose of ketamine.

The effects of transient receptor potential cation channel inhibition by BI 1358894 on cortico-limbic brain reactivity to negative emotional stimuli in major depressive disorder.

Abnormal emotional processing in major depressive disorder (MDD) has been associated with increased activation to negative stimuli in cortico-limbic brain regions. The authors investigated whether treatment with BI 1358894, a small-molecule inhibitor of the transient receptor potential cation channel subfamily C leads to attenuated activity in these areas in MDD patients. 73 MDD patients were randomized to receive a single oral dose of BI 1358894 (100 mg), citalopram (20 mg), or matching placebo.

Investigation of Neurofunctional Changes Over the Course of Electroconvulsive Therapy.

Background: Electroconvulsive therapy (ECT) is an effective treatment for patients suffering from depression. Yet the exact neurobiological mechanisms underlying the efficacy of ECT and indicators of who might respond best to it remain to be elucidated. Identifying neural markers that can inform about an individual's response to ECT would enable more optimal treatment strategies and increase clinical efficacy.

Predicting Antidepressant Effects of Ketamine: the Role of the Pregenual Anterior Cingulate Cortex as a Multimodal Neuroimaging Biomarker.

Background: Growing evidence underscores the utility of ketamine as an effective and rapid-acting treatment option for major depressive disorder (MDD). However, clinical outcomes vary between patients. Predicting successful response may enable personalized treatment decisions and increase clinical efficacy.

Acute effects of ketamine on the pregenual anterior cingulate: linking spontaneous activation, functional connectivity, and glutamate metabolism.

Ketamine exerts its rapid antidepressant effects via modulation of the glutamatergic system. While numerous imaging studies have investigated the effects of ketamine on a functional macroscopic brain level, it remains unclear how altered glutamate metabolism and changes in brain function are linked. To shed light on this topic we here conducted a multimodal imaging study in healthy volunteers (N = 23) using resting state fMRI and proton (H) magnetic resonance spectroscopy (MRS) to investigate linkage between metabolic and functional brain changes induced by ketamine.

Increase in thalamic cerebral blood flow is associated with antidepressant effects of ketamine in major depressive disorder.

Ketamine is a promising treatment option for patients with Major Depressive Disorder (MDD) and has become an important research tool to investigate antidepressant mechanisms of action. However, imaging studies attempting to characterise ketamine's mechanism of action using blood oxygen level-dependent signal (BOLD) imaging have yielded inconsistent results- at least partly due to intrinsic properties of the BOLD contrast, which measures a complex signal related to neural activity. To circumvent the limitations associated with the BOLD signal, we used arterial spin labelling (ASL) as an unambiguous marker of neuronal activity-related changes in cerebral blood flow (CBF).

Risk Assessment of Electroconvulsive Therapy in Clinical Routine: A 3-Year Analysis of Life-Threatening Events in More Than 3,000 Treatment Sessions.

Extensive research has reported that electroconvulsive therapy (ECT) can be highly effective in approximately 80% of patients suffering from depression. Its clinical use is mainly limited by historical objections and the concern about unwanted adverse effects (AEs), including serious and potentially life-threatening adverse events (pLTAEs), induced either by ECT or by anesthesia. Objective risk estimation is, therefore, a decisive factor in determining an indication for ECT.

Altered resting-state functional connectome in major depressive disorder: a mega-analysis from the PsyMRI consortium.

Major depressive disorder (MDD) is associated with abnormal neural circuitry. It can be measured by assessing functional connectivity (FC) at resting-state functional MRI, that may help identifying neural markers of MDD and provide further efficient diagnosis and monitor treatment outcomes. The main aim of the present study is to investigate, in an unbiased way, functional alterations in patients with MDD using a large multi-center dataset from the PsyMRI consortium including 1546 participants from 19 centers ( www.

EffECTively Treating Depression: A Pilot Study Examining Manualized Group CBT as Follow-Up Treatment After ECT.

There is an urgent need for effective follow-up treatments after acute electroconvulsive therapy (ECT) in depressed patients. Preliminary evidence suggests psychotherapeutic interventions to be a feasible and efficacious follow-up treatment. However, there is a need for research on the long-term usefulness of such psychotherapeutic offers in a naturalistic setting that is more representative of routine clinical practice.