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. Furthermore, the assessment of trait negative emotionality holds promise to link findings in healthy participants to potential AD mechanisms of ketamine. In this double-blind, placebo-controlled, randomized, single dose, parallel-group study, we collected resting-state fMRI data before, during, and 24 h after ketamine administration in a sample of 75 healthy male and female participants who were randomly allocated to one of three treatment conditions (ketamine, ketamine with lamotrigine pre- treatment, placebo). Spontaneous brain activity was extracted from two ventral and one dorsal subregions of the ACC. Our results showed activity decreases during the administration of ketamine in all three ACC subregions. However, only in the ventral subregions of the ACC this effect was attenuated by lamotrigine. 24 h after administration, ACC activity returned to baseline levels, but group differences were observed between the lamotrigine and the ketamine group. Trait negative emotionality was closely linked to activity changes in the subgenual ACC after ketamine administration. These results contribute to an understanding of the functional significance of ketamine effects in different subregions of the ACC by combining an approach to modulate glutamate release with the assessment of multiple timepoints and associations with trait negative emotionality in healthy participants.

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. METHODS: This is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow. DISCUSSION: This study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options. TRIAL REGISTRATION: ClinicalTrials.gov NCT05347199. April 12, 2022.

Transdiagnostic phenomena of psychopathology in the context of the RDoC: protocol of a multimodal cross-sectional study.

In the past, affective and cognitive processes related to psychopathology have been examined within the boundaries of phenotype-based diagnostic labels, which has led to inconsistent findings regarding their underlying operating principles. Investigating these processes dimensionally in healthy individuals and by means of multiple modalities may provide additional insights into the psychological and neuronal mechanisms at their core. The transdiagnostic phenomena Neuroticism and Rumination are known to be closely linked. However, the exact nature of their relationship remains to be elucidated. The same applies to the associations between Hedonic Capacity, Negativity Bias and different Emotion Regulation strategies.This multimodal cross-sectional study examines the relationship of the transdiagnostic phenomena Neuroticism and Rumination as well as Hedonic Capacity, the Negativity Bias and Emotion Regulation from a RDoC (Research Domain Criteria) perspective. A total of 120 currently healthy subjects (past 12 months) will complete several questionnaires regarding personality, emotion regulation, hedonic capacity, and psychopathologies as well as functional magnetic resonance imaging (fMRI) during cognitive and emotional processing, to obtain data on the circuit, behavioral and self-report level.This study aims to contribute to the understanding of the relationship between cognitive and affective processes associated with psychopathologies as well as their neuronal correlates. Ultimately, a grounded understanding of these processes could guide improvement of diagnostic labels and treatments. Limitations include the cross-sectional design and the limited variability in psychopathology scores due to the restriction of the sample to currently healthy subjects.

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. As effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release, a combination of these approaches should be particularly suited to offer novel insights. In total, 75 healthy participants were investigated in a double blind, placebo-controlled, randomized, parallel-group study and underwent two scanning sessions (acute/post 24 h.). Acute ketamine administration was associated with higher perfusion in interior frontal gyrus (IFG) and dorsolateral prefrontal cortex (DLPFC), but no other investigated brain region. Inhibition of glutamate release by pretreatment with lamotrigine abolished ketamine's effect on perfusion. At the delayed time point, pretreatment with lamotrigine was associated with lower perfusion in IFG. These findings underscore the idea that regionally selective patterns of CBF changes reflect proximate effects of modulated glutamate release on neuronal activity. Furthermore, region- specific sustained effects indicate both a swift restoration of disturbed homeostasis in DLPFC as well changes occurring beyond the immediate effects on glutamate signaling in IFG.

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. Effects of acute ketamine challenge are sensitive to modulation by pretreatment with lamotrigine, which inhibits glutamate release. Accordingly, a combination of these approaches should be particularly suited to investigate cognition-emotion interaction. METHODS: Seventy five healthy subjects were investigated in a double-blind, placebo-controlled, randomized, single-dose, parallel-group study with three treatment conditions. All subjects underwent two scanning sessions (acute/post 24 h). RESULTS: Compared to placebo, acute ketamine administration induced significant dissociative, psychotomimetic, and cognitive effects, as well as an increase in neural activity during WM for positive stimuli. Inhibition of glutamate release by pretreatment with lamotrigine did not influence ketamine's subjective effects, but significantly attenuated its impact on emotional WM and associated neural activity. There was no effect on these measures 24 h after ketamine administration. CONCLUSION: Our results demonstrate differential acute effects of modulated glutamate release and a swift restoration of disturbed neurobehavioral homeostasis in healthy subjects.

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. A random-effects model was used to calculate odds ratios and confidence intervals. Differences in efficacy between intranasal and intravenous application were statistically assessed by calculating a z-test. A total of eleven studies, comprising 1340 patients, were included. Results showed, that while both IN and IV ketamine were associated with increased response rates, efficacy did not differ significantly between these routes. Heterogeneity and funnel plot asymmetry was found in the intranasal sample only. The results of the present meta-analysis corroborate the efficacy of both IN and IV application of ketamine for the treatment of MDD but suggest no difference between both routes of administration. Accordingly, future large-scale trials as well as direct comparative trials are needed to further investigate this question.