The impact of body mass index on the clinical features of bipolar disorder: A STEP-BD study.

INTRODUCTION: The effects of body mass index (BMI) on the core symptoms of bipolar disorder (BD) and its implications for disease trajectory are largely unexplored. OBJECTIVE: To examine whether BMI impacted hospitalization rate, medical and psychiatric comorbidities, and core symptom domains such as depression and suicidality in BD. METHODS: Participants (15 years and older) were 2790 BD outpatients enrolled in the longitudinal STEP-BD study; all met DSM-IV criteria for BD-I, BD-II, cyclothymia, BD NOS, or schizoaffective disorder, bipolar subtype. BMI, demographic information, psychiatric and medical comorbidities, and other clinical variables such as bipolarity index, history of electroconvulsive therapy (ECT), and history of suicide attempts were collected at baseline. Longitudinal changes in Montgomery-Åsberg Depression Rating Scale (MADRS) score, Young Mania Rating Scale (YMRS) score, and hospitalizations during the study were also assessed. Depending on the variable of interest, odds-ratios, regression analyses, factor analyses, and graph analyses were applied. RESULTS: A robust increase in psychiatric and medical comorbidities was observed, particularly for baseline BMIs >35. A significant relationship was noted between higher BMI and history of suicide attempts, and individuals with BMIs >40 had the highest prevalence of suicide attempts. Obese and overweight individuals had a higher bipolarity index (a questionnaire measuring disease severity) and were more likely to have received ECT. Higher BMIs correlated with worsening trajectory of core depression symptoms and with worsening lassitude and inability to feel. CONCLUSIONS: In BD participants, elevated BMI was associated with worsening clinical features, including higher rates of suicidality, comorbidities, and core depression symptoms.

Ketamine in neuropsychiatric disorders: an update.

The discovery of ketamine as a rapid-acting antidepressant led to a new era in the development of neuropsychiatric therapeutics, one characterized by an antidepressant response that occurred within hours or days rather than weeks or months. Considerable clinical research supports the use of-or further research with-subanesthetic-dose ketamine and its (S)-enantiomer esketamine in multiple neuropsychiatric disorders including depression, bipolar disorder, anxiety spectrum disorders, substance use disorders, and eating disorders, as well as for the management of chronic pain. In addition, ketamine often effectively targets symptom domains associated with multiple disorders, such as anxiety, anhedonia, and suicidal ideation. This manuscript: 1) reviews the literature on the pharmacology and hypothesized mechanisms of subanesthetic-dose ketamine in clinical research; 2) describes similarities and differences in the mechanism of action and antidepressant efficacy between racemic ketamine, its (S) and (R) enantiomers, and its hydroxynorketamine (HNK) metabolite; 3) discusses the day-to-day use of ketamine in the clinical setting; 4) provides an overview of ketamine use in other psychiatric disorders and depression-related comorbidities (e.g., suicidal ideation); and 5) provides insights into the mechanisms of ketamine and therapeutic response gleaned from the study of other novel therapeutics and neuroimaging modalities.

Case report: Interstitial pneumonitis after initiation of lamotrigine.

The second-generation anticonvulsant lamotrigine is widely used in the psychiatric field as a mood stabilizer or antidepressant augmentation therapy. Although particularly older anticonvulsants are known for their potential to cause hypersensitivity syndromes, newer antiepileptic drugs do hold a certain risk as well. Presenting a case of a 32-year-old male inpatient of African ethnicity suffering from a primary severe depressive episode in the course of a recurrent major depressive disorder, we report the occurrence of a rapid-onset drug-induced pneumonitis. Herewith, the interstitial pneumonitis occurred after the initiation of 25 mg lamotrigine as an augmentation therapy. Except for the clear temporal correlation between the administration of lamotrigine and the onset of pneumonitis, we did not reveal any further potentially causal diagnostic hints. Importantly, no relevant genetic variations of metabolizing enzymes or drug interactions resulting in lamotrigine overdosage as a potential cause of toxicity were identified. Our experience with a potentially life-threatening adverse drug reaction shortly after the initiation of the largely well-tolerated lamotrigine suggests a potential side effect under the second-generation anticonvulsant although similar adverse events are deemed to be very rare.

Body mass index and clinical outcomes in individuals with major depressive disorder: Findings from the GSRD European Multicenter Database.

BACKGROUND: Individuals with major depressive disorder (MDD) are at higher risk for obesity. In turn, weight gain is a predisposing factor for depression. Although clinical data are sparse, suicide risk also appears to be elevated in obese patients. This study used data from the European Group for the Study of Resistant Depression (GSRD) to investigate clinical outcomes associated with body mass index (BMI) in MDD. METHODS: Data were drawn from 892 participants with MDD over the age of 18 years (580 female, 50.5 ± 13.6 years). Response and resistance to antidepressant medication, depression rating scale scores, and further clinical and sociodemographic variables were compared using multiple logistic and linear regressions controlled for age, sex, and risk of weight gain due to psychopharmacotherapy. RESULTS: Of the 892 participants, 323 were categorized as treatment-responsive and 569 as treatment-resistant. Within this cohort, 278 (31.1 %) were overweight (BMI = 25-29.9 kg/m2) and 151 (16.9 %) were obese (BMI > 30 kg/m2). Elevated BMI was significantly associated with higher suicidality, longer duration of psychiatric hospitalizations over their lifetimes, earlier age of onset of MDD, and comorbidities. There was a trend-wise association of BMI with treatment resistance. LIMITATIONS: Data were analyzed in a retrospective, cross-sectional design. BMI was used as an exclusive measure of overweight and obesity. CONCLUSIONS: Participants with comorbid MDD and overweight/obesity were at risk for worse clinical outcomes, suggesting that weight gain should be closely monitored in individuals with MDD in daily clinical practice. Further studies are needed to explore the neurobiological mechanisms linking elevated BMI to impaired brain health.

Inflammation, stress and depression: An exploration of ketamine's therapeutic profile.

Well-established animal models of depression have described a proximal relationship between stress and central nervous system (CNS) inflammation - a relationship mirrored in the peripheral inflammatory biomarkers of individuals with depression. Evidence also suggests that stress-induced proinflammatory states can contribute to the neurobiology of treatment-resistant depression. Interestingly, ketamine, a rapid-acting antidepressant, can partially exert its therapeutic effects via anti-inflammatory actions on the hypothalamic-pituitary adrenal (HPA) axis, the kynurenine pathway or by cytokine suppression. Further investigations into the relationship between ketamine, inflammation and stress could provide insight into ketamine's unique therapeutic mechanisms and stimulate efforts to develop rapid-acting, anti-inflammatory-based antidepressants.

Increased left dorsolateral prefrontal cortex density following escitalopram intake during relearning: a randomized, placebo-controlled trial in healthy humans.

Background: Serotonergic agents affect brain plasticity and reverse stress-induced dendritic atrophy in key fronto-limbic brain areas associated with learning and memory. Objectives: The aim of this study was to investigate effects of the antidepressant escitalopram on gray matter during relearning in healthy individuals to inform a model for depression and the neurobiological processes of recovery. Design: Randomized double blind placebo control, monocenter study. Methods: In all, 76 (44 females) healthy individuals performed daily an associative learning task with emotional or non-emotional content over a 3-week period. This was followed by a 3-week relearning period (randomly shuffled association within the content group) with concurrent daily selective serotonin reuptake inhibitor (i.e., 10 mg escitalopram) or placebo intake. Results: Via voxel-based morphometry and only in individuals that developed sufficient escitalopram blood levels over the 21-day relearing period, an increased density of the left dorsolateral prefrontal cortex was found. When investigating whether there was an interaction between relearning and drug intervention for all participants, regardless of escitalopram levels, no changes in gray matter were detected with either surfaced-based or voxel-based morphometry analyses. Conclusion: The left dorsolateral prefrontal cortex affects executive function and emotional processing, and is a critical mediator of symptoms and treatment outcomes of depression. In line, the findings suggest that escitalopram facilitates neuroplastic processes in this region if blood levels are sufficient. Contrary to our hypothesis, an effect of escitalopram on brain structure that is dependent of relearning content was not detected. However, this may have been a consequence of the intensity and duration of the interventions. Registration: ClinicalTrials.gov Identifier: NCT02753738; Trial Name: Enhancement of learning associated neural plasticity by Selective Serotonin Reuptake Inhibitors; URL: https://clinicaltrials.gov/ct2/show/NCT02753738.

Repeating patterns: Predictive processing suggests an aesthetic learning role of the basal ganglia in repetitive stereotyped behaviors.

Recurrent, unvarying, and seemingly purposeless patterns of action and cognition are part of normal development, but also feature prominently in several neuropsychiatric conditions. Repetitive stereotyped behaviors (RSBs) can be viewed as exaggerated forms of learned habits and frequently correlate with alterations in motor, limbic, and associative basal ganglia circuits. However, it is still unclear how altered basal ganglia feedback signals actually relate to the phenomenological variability of RSBs. Why do behaviorally overlapping phenomena sometimes require different treatment approaches-for example, sensory shielding strategies versus exposure therapy for autism and obsessive-compulsive disorder, respectively? Certain clues may be found in recent models of basal ganglia function that extend well beyond action selection and motivational control, and have implications for sensorimotor integration, prediction, learning under uncertainty, as well as aesthetic learning. In this paper, we systematically compare three exemplary conditions with basal ganglia involvement, obsessive-compulsive disorder, Parkinson's disease, and autism spectrum conditions, to gain a new understanding of RSBs. We integrate clinical observations and neuroanatomical and neurophysiological alterations with accounts employing the predictive processing framework. Based on this review, we suggest that basal ganglia feedback plays a central role in preconditioning cortical networks to anticipate self-generated, movement-related perception. In this way, basal ganglia feedback appears ideally situated to adjust the salience of sensory signals through precision weighting of (external) new sensory information, relative to the precision of (internal) predictions based on prior generated models. Accordingly, behavioral policies may preferentially rely on new data versus existing knowledge, in a spectrum spanning between novelty and stability. RSBs may then represent compensatory or reactive responses, respectively, at the opposite ends of this spectrum. This view places an important role of aesthetic learning on basal ganglia feedback, may account for observed changes in creativity and aesthetic experience in basal ganglia disorders, is empirically testable, and may inform creative art therapies in conditions characterized by stereotyped behaviors.

Ketamine for Depression: Advances in Clinical Treatment, Rapid Antidepressant Mechanisms of Action, and a Contrast with Serotonergic Psychedelics.

The approval of ketamine for treatment-resistant depression has created a model for a novel class of rapid-acting glutamatergic antidepressants. Recent research into other novel rapid-acting antidepressants - most notably serotonergic psychedelics (SPs) - has also proven promising. Presently, the mechanisms of action of these substances are under investigation to improve these novel treatments, which also exhibit considerable side effects such as dissociation. This chapter lays out the historical development of ketamine as an antidepressant, outlines its efficacy and safety profile, reviews the evidence for ketamine's molecular mechanism of action, and compares it to the proposed mechanism of SPs. The evidence suggests that although ketamine and SPs act on distinct primary targets, both may lead to rapid restoration of synaptic deficits and downstream network reconfiguration. In both classes of drugs, a glutamate surge activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) throughput and increases in brain-derived neurotrophic factor (BDNF) levels. Taken together, these novel antidepressant mechanisms may serve as a framework to explain the rapid and sustained antidepressant effects of ketamine and may be crucial for developing new rapid-acting antidepressants with an improved side effect profile.

Setting Up a Successful Vagus Nerve Stimulation Service for Patients With Difficult-to-Treat Depression.

BACKGROUND: A substantial number of patients with major depressive disorder (MDD) do not sufficiently remit after the first lines of antidepressant treatments, making them vulnerable to poor clinical outcomes. Patients who have not had adequate resolution of their depressive symptoms after four antidepressant treatments and/or have been experiencing their current episode of MDD for two years or more (with insufficient responses to adequate antidepressant treatments) should be evaluated for antidepressant vagus nerve stimulation (VNS Therapy). Adjunctive VNS Therapy is a promising long-term treatment option for patients with difficult-to-treat depression (DTD), offering significantly improved remission rates in comparison with usual treatments. However, VNS Therapy requires specialized treatment centers to support patients. MATERIALS AND METHODS: In this narrative review, we aim to outline the necessary steps for setting up an antidepressant VNS Therapy service in an efficient manner. RESULTS: Establishing a VNS Therapy service requires several high-level considerations: initiation of a collaborative multidisciplinary team of health care professionals; developing a surgical pathway for implantation; consideration of reimbursement and health care coverage; setting up a specialist clinic to identify optimal candidates for VNS Therapy; educating patients and their families about VNS Therapy; and training health care providers on patient-specific VNS Therapy treatment and long-term treatment management. CONCLUSIONS: Antidepressant VNS Therapy is a promising treatment option for the long-term treatment of patients with DTD. We have successfully initiated four VNS Therapy service centers for DTD in the United States, Austria, and Germany. Based on our experiences and lessons learned, herein, we have provided advice to psychiatric centers planning to set up a VNS Therapy service for their patients with DTD.

Serotonergic modulation of effective connectivity in an associative relearning network during task and rest.

An essential core function of one's cognitive flexibility is the use of acquired knowledge and skills to adapt to ongoing environmental changes. Animal models have highlighted the influence serotonin has on neuroplasticity. These effects have been predominantly demonstrated during emotional relearning which is theorized as a possible model for depression. However, translation of these mechanisms is in its infancy. To this end, we assessed changes in effective connectivity at rest and during associative learning as a proxy of neuroplastic changes in healthy volunteers. 76 participants underwent 6 weeks of emotional or non-emotional (re)learning (face-matching or Chinese character-German noun matching). During relearning participants either self-administered 10 mg/day of the selective serotonin reuptake inhibitor (SSRI) escitalopram or placebo in a double-blind design. Associative learning tasks, resting-state and structural images were recorded before and after both learning phases (day 1, 21 and 42). Escitalopram intake modulated relearning changes in a network encompassing the right insula, anterior cingulate cortex and right angular gyrus. Here, the process of relearning during SSRI intake showed a greater decrease in effective connectivity from the right insula to both the anterior cingulate cortex and right angular gyrus, with increases in the opposite direction when compared to placebo. In contrast, intrinsic connections and those at resting-state were only marginally affected by escitalopram. Further investigation of gray matter volume changes in these functionally active regions revealed no significant SSRI-induced structural changes. These findings indicate that the right insula plays a central role in the process of relearning and SSRIs further potentiate this effect. In sum, we demonstrated that SSRIs amplify learning-induced effective connections rather than affecting the intrinsic task connectivity or that of resting-state.

Dynamic Causal Modeling of the Prefrontal/Amygdala Network During Processing of Emotional Faces.

Introduction: The importance of the amygdala/medial orbitofrontal cortex (OFC) network during processing of emotional stimuli, emotional faces in particular, is well established. This premise is supported by converging evidence from animal models, human neuroanatomical results, and neuroimaging studies. However, there is missing evidence from human brain connectivity studies that the OFC and no other prefrontal brain areas such as the dorsolateral prefrontal cortex (DLPFC) or ventrolateral prefrontal cortex (VLPFC) are responsible for amygdala regulation in the functional context of emotional face stimuli. Methods: Dynamic causal modeling of ultrahigh-field functional magnetic resonance imaging data acquired at 7 Tesla in 38 healthy subjects and a well-established paradigm for emotional face processing were used to assess the central role of the OFC to provide empirical validation for the assumed network architecture. Results: Using Bayesian model selection, it is demonstrated that indeed the OFC, and not the VLPFC and the DLPFC, downregulates amygdala activation during the emotion discrimination task. In addition, Bayesian model averaging group results were rigorously tested using bootstrapping, further corroborating these findings and providing an estimator for robustness and optimal sample sizes. Discussion: While it is true that VLPFC and DLPFC are relevant for the processing of emotional faces and are connected to the OFC, the OFC appears to be a central hub for the prefrontal/amygdala interaction. Impact statement Using dynamic causal modeling (DCM), abnormal effective connectivity in the orbitofrontal cortex (OFC)/amygdala network has been repeatedly observed in the pathophysiology of psychiatric disorders. However, it has to be considered that these findings are all based on the a priori assumption of the OFC being the central area for prefrontal control regulating amygdala activation. This is particularly important, as DCM results conditionally depend on the underlying model space used for model selection. Using Bayesian model comparison methods, it is shown that the OFC (and not the dorsolateral prefrontal cortex or ventrolateral prefrontal cortex) engages in amygdala downregulation in the context emotional face processing.

Escitalopram modulates learning content-specific neuroplasticity of functional brain networks.

Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.

Give me a pain that I am used to: distinct habituation patterns to painful and non-painful stimulation.

Pain habituation is associated with a decrease of activation in brain areas related to pain perception. However, little is known about the specificity of these decreases to pain, as habituation has also been described for other responses like spinal reflexes and other sensory responses. Thus, it might be hypothesized that previously reported reductions in activation are not specifically related to pain habituation. For this reason, we performed a 3 T fMRI study using either painful or non-painful electrical stimulation via an electrode attached to the back of the left hand. Contrasting painful vs. non-painful stimulation revealed significant activation clusters in regions well-known to be related to pain processing, such as bilateral anterior and posterior insula, primary/secondary sensory cortices (S1/S2) and anterior midcingulate cortex (aMCC). Importantly, our results show distinct habituation patterns for painful (in aMCC) and non-painful (contralateral claustrum) stimulation, while similar habituation for both types of stimulation was identified in bilateral inferior frontal gyrus (IFG) and contralateral S2. Our findings thus distinguish a general habituation in somatosensory processing (S2) and reduced attention (IFG) from specific pain and non-pain related habituation effects where pain-specific habituation effects within the aMCC highlight a change in affective pain perception.

Detached empathic experience of others' pain in remitted states of depression - An fMRI study.

BACKGROUND: Major depressive disorder is strongly associated with impairments and difficulties in social interactions. Deficits in empathy, a vital skill for social interactions, have been identified as a risk factor for relapse. However, research on empathy in remitted states of depression is scarce. We chose a social neuroscience approach to investigate potentially altered neural processes involved in sub-components of empathy in remitted states of depression. We expected aberrations in cognitive components of empathy, based on previous reports regarding their role as risk factors for relapse. METHODS: Employing functional magnetic resonance imaging and a pain empathy task (video clips of painful medical treatments), we compared behavioral and neural empathic responses of unmedicated remitted depressive patients (N = 32) to those of untreated acutely depressed patients (N = 29) and healthy controls (N = 35). Self-report ratings of pain evaluation and affect-sharing were obtained. RESULTS: Compared to controls and acutely depressed patients, remitted depressive patients reported higher pain evaluation and showed increased activity in the right temporo-parietal junction. This region, which is central to self-other distinction and which has been linked to adopting a detached perspective, also exhibited reduced connectivity to the anterior insula. Furthermore, we observed reduced activity in regions involved in emotion processing (amygdala) and perception of affective facial expressions (fusiform face area, posterior superior temporal sulcus). CONCLUSIONS: Remitted states of depression are associated with a detached empathic style in response to others' pain, characterized by increased self-other distinction, lowered affective processing, and reduced connectivity between empathy-related brain regions. Although this may prevent emotional harm in specific situations, it may reduce opportunities for positive experiences in social interactions in the long run.

Translating the immediate effects of S-Ketamine using hippocampal subfield analysis in healthy subjects-results of a randomized controlled trial.

Antidepressant doses of ketamine rapidly facilitate synaptic plasticity and modify neuronal function within prefrontal and hippocampal circuits. However, most studies have demonstrated these effects in animal models and translational studies in humans are scarce. A recent animal study showed that ketamine restored dendritic spines in the hippocampal CA1 region within 1 h of administration. To translate these results to humans, this randomized, double-blind, placebo-controlled, crossover magnetic resonance imaging (MRI) study assessed ketamine's rapid neuroplastic effects on hippocampal subfield measurements in healthy volunteers. S-Ketamine vs. placebo data were analyzed, and data were also grouped by brain-derived neurotrophic factor (BDNF) genotype. Linear mixed models showed that overall hippocampal subfield volumes were significantly larger (p = 0.009) post ketamine than post placebo (LS means difference=0.008, standard error=0.003). Post-hoc tests did not attribute effects to specific subfields (all p > 0.05). Trend-wise volumetric increases were observed within the left hippocampal CA1 region (p = 0.076), and trend-wise volumetric reductions were obtained in the right hippocampal-amygdaloid transition region (HATA) (p = 0.067). Neither genotype nor a genotype-drug interaction significantly affected the results (all p > 0.7). The study provides evidence that ketamine has short-term effects on hippocampal subfield volumes in humans. The results translate previous findings from animal models of depression showing that ketamine has pro-neuroplastic effects on hippocampal structures and underscore the importance of the hippocampus as a key region in ketamine's mechanism of action.

Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants.

BACKGROUND: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period. METHODS: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed. RESULTS: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. CONCLUSIONS: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.

Ketamine modulates fronto-striatal circuitry in depressed and healthy individuals.

Ketamine improves motivation-related symptoms in depression but simultaneously elicits similar symptoms in healthy individuals, suggesting that it might have different effects in health and disease. This study examined whether ketamine affects the brain's fronto-striatal system, which is known to drive motivational behavior. The study also assessed whether inflammatory mechanisms-which are known to influence neural and behavioral motivational processes-might underlie some of these changes. These questions were explored in the context of a double-blind, placebo-controlled, crossover trial of ketamine in 33 individuals with treatment-resistant major depressive disorder (TRD) and 25 healthy volunteers (HVs). Resting-state functional magnetic resonance imaging (rsfMRI) was acquired 2 days post-ketamine (final sample: TRD n = 27, HV n = 19) and post-placebo (final sample: TRD n = 25, HV n = 18) infusions and was used to probe fronto-striatal circuitry with striatal seed-based functional connectivity. Ketamine increased fronto-striatal functional connectivity in TRD participants toward levels observed in HVs while shifting the connectivity profile in HVs toward a state similar to TRD participants under placebo. Preliminary findings suggest that these effects were largely observed in the absence of inflammatory (C-reactive protein) changes and were associated with both acute and sustained improvements in symptoms in the TRD group. Ketamine thus normalized fronto-striatal connectivity in TRD participants but disrupted it in HVs independently of inflammatory processes. These findings highlight the potential importance of reward circuitry in ketamine's mechanism of action, which may be particularly relevant for understanding ketamine-induced shifts in motivational symptoms.

Prognosis and Improved Outcomes in Major Depression: A Review.

(Reprinted from Transl Psychiatry. 2019 Apr 3; 9(1):127. Open access; is licensed under a Creative Commons Attribution 4.0 International License).

Can 'floating' predict treatment response to ketamine? Data from three randomized trials of individuals with treatment-resistant depression.

Ketamine has rapid-acting antidepressant properties but also potentially concerning transient dissociative side effects (SEs). Recent studies noted a positive correlation between treatment response to ketamine and general dissociative SEs, as well as "floating", a depersonalization SE (a subtype of the dissociative SEs). This analysis sought to determine whether floating mediates treatment response to ketamine. Data were pooled from three double-blind, crossover, placebo-controlled ketamine clinical trials across which 82 participants with treatment-resistant depression (TRD) (44 with bipolar depression and 38 with major depressive disorder) received placebo and ketamine (0.5 mg/kg) infusions. SEs were actively solicited in a standardized fashion before and after ketamine infusion. The hypothesis that a post-infusion experience of floating would mediate antidepressant response to ketamine was assessed at 230 min post-infusion and at Day 1. Montgomery-Asberg Depression Rating Scale (MADRS) total score was the dependent variable in a linear mixed effects model. Ketamine significantly decreased MADRS scores (p < 0.0001), but no relationship was detected between floating and MADRS score at either 230 min or Day 1 post-infusion. The hypothesized mediation effect of floating was also not detected at either 230 min or Day 1 post-infusion. Taken together, the findings do not support the hypothesis that ketamine's antidepressant effects are mediated by the dissociative depersonalization subtype SE of floating.