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.

Impairments in category verbal fluency task (VFT) performance have been widely documented in psychosis. These deficits may be due to disturbed “cognitive foraging” in semantic space, in terms of altered salience of cues that influence individuals to search locally within a subcategory of semantically related responses (“clustering”) or globally between subcategories (“switching”). To test this, we conducted a study in which individuals with schizophrenia (n = 21), schizotypal personality traits (n = 25), and healthy controls (n = 40) performed VFT with “animals” as the category. Distributional semantic model Word2Vec computed cosine-based similarities between words according to their statistical usage in a large text corpus. We then applied a validated foraging-based search model to these similarity values to obtain salience indices of frequency-based global search cues and similarity-based local cues. Analyses examined whether diagnosis predicted VFT performance, search strategies, cue salience, and the time taken to switch between vs search within clusters. Compared to control and schizotypal groups, individuals with schizophrenia produced fewer words, switched less, and exhibited higher global cue salience, indicating a selection of more common words when switching to new clusters. Global cue salience negatively associated with vocabulary ability in controls and processing speed in schizophrenia. Lastly, individuals with schizophrenia took a similar amount of time to switch to new clusters compared to control and schizotypal groups but took longer to transition between words within clusters. Findings of altered local exploitation and global exploration through semantic memory provide preliminary evidence of aberrant cognitive foraging in schizophrenia.

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Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition, lithium and ketamine have synergistic antidepressant-like effects at individually subeffective doses in rodents. We hypothesized that ketamine's antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine's antidepressant efficacy. Thirty-six patients with treatment-resistant bipolar depression maintained on therapeutic-dose lithium (n = 23, 0.79 ± 0.15 mEq/L) or valproate (n = 13, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a randomized, double-blind, placebo-controlled, crossover trial. The primary depression outcome measure—the Montgomery-Åsberg Depression Rating Scale (MADRS)—was assessed before infusion and at numerous postinfusion time points. Both lithium (F 1,118 = 152.08, p < 0.001, and d = 2.27) and valproate (F 1,128 = 20.12, p < 0.001, and d = 0.79) significantly improved depressive symptoms, but no statistically significant difference was observed between mood stabilizer groups (F 1,28 = 2.51, p = 0.12, and d = 0.60). Serum lithium and valproate levels did not correlate with ketamine's antidepressant efficacy. Although the study was potentially underpowered, our results suggest that lithium may not potentiate ketamine's antidepressant efficacy in treatment-resistant bipolar depression.

Background: Delay eyeblink conditioning (dEBC) is widely used to assess cerebellar-dependent associative motor learning, including precise timing processes. Transcranial direct current stimulation (tDCS), noninvasive brain stimulation used to indirectly excite and inhibit select brain regions, may be a promising tool for understanding how functional integrity of the cerebellum influences dEBC behavior.Objective/Hypothesis: The aim of this study was to assess whether tDCS-induced inhibition (cathodal) or excitation (anodal) of the cerebellum impairs or facilitates, respectively, timing of dEBC.Methods: A standard 10-block dEBC paradigm was administered to 102 healthy participants. Participants were randomized to stimulation conditions in a double-blind, between-subjects shamcontrolled design. Participants received 20-minute active (anodal or cathodal) stimulation at 1.5mA (n=20 anodal, n=22 cathodal) or 2mA (n=19 anodal, n=21 cathodal) or sham (n=20) stimulation concurrently with dEBC training. Stimulation intensity and polarity effects on percent conditioned responses (CRs) and CR peak and onset latency were examined using repeated measures analyses of variance.Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. http://www.springer.com/gb/openaccess/authors-rights/aam-terms-v1