Current pharmacotherapies for major depressive disorder (MDD) and bipolar depression (BDep) have a distinct lag of onset that can generate great distress and impairment in patients. Furthermore, as demonstrated by several real-world effectiveness trials, their efficacy is limited. All approved antidepressant medications for MDD primarily act through monoaminergic mechanisms, agonists or antagonists with varying affinities for serotonin, norepinephrine and dopamine. The glutamate system has received much attention in recent years as an avenue for developing novel therapeutics. A single subanesthetic dose infusion of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has been shown to have rapid and potent antidepressant effects in treatment-resistant MDD and BDep. In a reverse translational framework, ketamine's clinical efficacy has inspired many preclinical studies to explore glutamatergic mechanisms of antidepressant action. These studies have revealed enhanced synaptic plasticity/synaptogenesis via numerous molecular and cellular mechanisms: release of local translational inhibition of brain-derived neurotrophic factor and secretion from dendritic spines, mammalian target of rapamycin activation and glycogen synthase kinase-3 inhibition. Current efforts are focused on extending ketamine's antidepressant efficacy, uncovering the neurobiological mechanisms responsible for ketamine's antidepressant activity in biologically enriched subgroups, and identifying treatment response biomarkers to personalize antidepressant selection. Other NMDA receptor antagonists have been studied both preclinically and clinically, which have revealed relatively modest antidepressant effects compared with ketamine but potentially other favorable characteristics, for example, decreased dissociative or psychotomimetic effects; therefore, there is great interest in developing novel glutamatergic antidepressants with greater target specificity and/or decreased adverse effects.
The debilitating nature of psychosis may be exacerbated by societal stigma and feelings of social isolation over and above positive (e.g., hallucinations) and negative (e.g., flat affect) symptoms. Thus, recovery may be facilitated by increasing self-compassion, the ability to respond with a nonjudgmental attitude of kindness toward oneself as a result of connecting with one's own inadequacies and suffering. We conducted a stepwise regression in individuals with schizophreniaspectrum disorders (n = 92) to determine the unique contributions of cognitive variables in predicting self-compassion, such as metacognition (the ability to form complex and integrated ideas about oneself and others), mindfulness, and cognitive insight. Results indicated that increased metacognitive awareness of others and mindfulness uniquely predicted greater selfcompassion (i.e., self-kindness), whereas increased cognitive insight predicted greater lack of selfcompassion (i.e., self-judgment). These findings suggest the potential for mindfulness and metacognitive interventions to increase positive self-compassion and promote recovery in psychosis.
Humans may retrieve words from memory by exploring and exploiting in linguistic "space" similar to hownon-human animals forage for resources in physical space. This has been studied using the verbalfluency test (VFT), in which participants generate words belonging to a semantic or phonetic category in alimited time. The foraging in mind model proposes that individuals performing VFT monitor their responseproduction rate as they search through and deplete a local patch (subcategory) of items in memory andthen switch to a new patch in another part of semantic or phonetic space. An alternative model holds thatparticipants use a random walk process, and switches are merely epiphenomenal long steps reflectingthe tail of the random walk step size distribution. This study tests these competing theories by examiningwhether there is distinct neural activity during exploring between ("switching") versus exploiting within("clustering") related response groupings (foraging), or no neural differences between search phases(random walk). Thirty participants performed category and letter VFT during functional magneticresonance imaging. Responses were categorized as cluster or switch events based on computationalmetrics of similarity and participant evaluations. Findings provide neural evidence of a cognitive foragingprocess, with greater hippocampal and cerebellar activation during switching compared to clustering,even while controlling for greater semantic and phonetic distance and response times. Furthermore,these regions exhibited ramping activity leading up to switch events. These results clarify how neuralswitch processes may guide memory searches in a manner akin to foraging in patchy spatialenvironments.
The results provide neural evidence that BD is associated with disrupted sensory, attentional, and cognitive processing of auditory stimuli, which may be worsened with the presence of psychotic features.
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