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.

Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects.

Ketamine's mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5 mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine's mechanism of action from studies of healthy controls alone.

Metacognition and emotion - How accurate perception of own biases relates to positive feelings and hedonic capacity.

Metacognition refers to awareness of one's own cognitive processes, including examining own biases and decision making. Metacognitive self (MCS), defined as accuracy in perception of own biases, is associated with pro-health behaviors and desire for feedback, including negative information. Two studies investigated MCS in relation to emotion and hedonic capacity. First, in a longitudinal study of college students, MCS measure was stable over time, and correlated with feelings of love and joy. In the second study, MCS, mood, and hedonic capacity ratings were collected prior to evaluating stimuli for pleasure from engagement during an fMRI. Higher MCS was associated with greater hedonic capacity and increased signal in cortical areas involved in self-reflection and decision making. Our findings implicate self-awareness of biases as a cognitive process supporting positive emotional state and hedonic capacity. Future studies should explore how MCS relates to changes in mood and vulnerability to mood disorders.

Multimodal imaging reveals a complex pattern of dysfunction in corticolimbic pathways in major depressive disorder.

Major depressive disorder (MDD) is highly prevalent and associated with considerable morbidity, yet its pathophysiology remains only partially understood. While numerous studies have investigated the neurobiological correlates of MDD, most have used only a single neuroimaging modality. In particular, diffusion tensor imaging (DTI) studies have failed to yield uniform results. In this context, examining key tracts and using information from multiple neuroimaging modalities may better characterize potential abnormalities in the MDD brain. This study analyzed data from 30 participants with MDD and 26 healthy participants who underwent DTI, magnetic resonance spectroscopy (MRS), resting-state functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Tracts connecting the subgenual anterior cingulate cortex (sgACC) and the left and right amygdala, as well as connections to the left and right hippocampus and thalamus, were examined as target areas. Reduced fractional anisotropy (FA) was observed in the studied tracts. Significant differences in the correlation between medial prefrontal glutamate concentrations and FA were also observed between MDD and healthy participants along tracts connecting the sgACC and right amygdala; healthy participants exhibited a strong correlation but MDD participants showed no such relationship. In the same tract, a correlation was observed between FA and subsequent antidepressant response to ketamine infusion in MDD participants. Exploratory models also suggested group differences in the relationship between DTI, fMRI, and MEG measures. This study is the first to combine MRS, DTI, fMRI, and MEG data to obtain multimodal indices of MDD and antidepressant response and may lay the foundation for similar future analyses.

Neurophysiological Changes Associated with Antidepressant Response to Ketamine Not Observed in a Negative Trial of Scopolamine in Major Depressive Disorder.

Background: This randomized, placebo-controlled, crossover trial examined the antidepressant efficacy of the muscarinic antagonist scopolamine in major depressive disorder subjects with more severe and refractory forms of major depressive disorder relative to previous reports. Methods: Participants included 23 medication-free major depressive disorder subjects (12 F/11 M, 20-55 years) currently experiencing a major depressive episode. Subjects had scored ≥20 on the Montgomery-Asberg Depression Rating Scale. Following a single-blind, placebo lead-in, participants were randomized to receive 2 counterbalanced blocks of 3 i.v. infusions of scopolamine (4 µg/kg) and placebo in a double-blind manner. The primary and secondary outcomes were the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale, respectively. Magnetoencephalography and plasma brain-derived neurotrophic factor concentrations were obtained prior to and after each treatment phase. Results: As assessed by both the Montgomery-Asberg Depression Rating Scale and Hamilton Anxiety Rating Scale, scopolamine had no significant antidepressant or anxiolytic effects relative to placebo. No significant drug vs placebo effects were seen in magnetoencephalography gamma power or brain-derived neurotrophic factor plasma concentrations, and brain-derived neurotrophic factor changes did not correlate with change in Montgomery-Asberg Depression Rating Scale score in response to scopolamine. Conclusions: These results do not support the efficacy of scopolamine for more severe or refractory forms of depression. No pre- to post-infusion changes in plasma brain-derived neurotrophic factor were detected, and magnetoencephalography gamma power changed only in the placebo lead-in, suggesting that these biomarker measures were not affected by scopolamine in this cohort. While difficult to interpret given the lack of antidepressant response, the findings suggest that the neurobiological effects of ketamine and scopolamine are at least partly distinct.

Research on the pathophysiology, treatment, and prevention of suicide: practical and ethical issues.

BACKGROUND: Despite decades of research, the rate of death from suicide is rising in the United States. Suicide is a complex and multifactorial phenomenon and, to date, no validated biomarkers that predict suicidal behavior have been identified. Only one FDA-approved drug to prevent suicide exists, and it is approved only for patients with schizophrenia. Although anti-suicide psychotherapeutic techniques exist, treatment takes time, and only preliminary data exist for rapid-acting therapies. DISCUSSION: While more research into suicidal ideation and acute suicidal behavior is clearly needed, this research is fraught with both practical and ethical concerns. As a result, many investigators and bioethicists have called for restrictions on the types of research that individuals with suicidal behavior can participate in, despite the fact that the available empirical evidence suggests that this research can be done safely. This manuscript presents background information on the phenomenology of suicide, discusses the current state of treatment and prevention strategies, and reviews the practical and ethical issues surrounding suicide research in the context of available empirical data. Currently, the causes of suicide are poorly understood, in part due to the fact that very few studies have investigated the acute suicidal crisis. Although some biomarkers for predicting risk have been developed, none have been sufficiently validated. The most successful current interventions involve means restriction. However, while numerous hurdles face researchers, these are not insurmountable. The available evidence suggests that research into suicide can be conducted both safely and ethically.

Glutamatergic Signaling Drives Ketamine-Mediated Response in Depression: Evidence from Dynamic Causal Modeling.

BACKGROUND: The glutamatergic modulator ketamine has rapid antidepressant effects in individuals with major depressive disorder and bipolar depression. Thus, modulating glutamatergic transmission may be critical to effectively treating depression, though the mechanisms by which this occurs are not fully understood. METHODS: This double-blind, crossover, placebo-controlled study analyzed data from 18 drug-free major depressive disorder subjects and 18 heathy controls who received a single i.v. infusion of ketamine hydrochloride (0.5 mg/kg) as well as an i.v. saline placebo. Magnetoencephalographic recordings were collected prior to the first infusion and 6 to 9 hours after both ketamine and placebo infusions. During scanning, participants passively received tactile stimulation to the right index finger. Antidepressant response was assessed across timepoints using the Montgomery-Asberg Depression Rating Scale. Dynamic causal modeling was used to measure changes in α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-mediated connectivity estimates in major depressive disorder subjects and controls using a simple model of somatosensory evoked responses. RESULTS: Both major depressive disorder and healthy subjects showed ketamine-mediated NMDA-blockade sensitization, with major depressive disorder subjects showing enhanced NMDA connectivity estimates in backward connections and controls showing enhanced NMDA connectivity estimates in forward connections in our model. Within our major depressive disorder subject group, ketamine efficacy, as measured by improved mood ratings, correlated with reduced NMDA and AMPA connectivity estimates in discrete extrinsic connections within the somatosensory cortical network. CONCLUSIONS: These findings suggest that AMPA- and NMDA-mediated glutamatergic signaling play a key role in antidepressant response to ketamine and, further, that dynamic causal modeling is a powerful tool for modeling AMPA- and NMDA-mediated connectivity in vivo. CLINICALTRIALS.GOV: NCT#00088699.

Clinical Trial of the Potassium Channel Activator Diazoxide for Major Depressive Disorder Halted Due to Intolerability.

BACKGROUND: Some glutamatergic modulators have demonstrated rapid and relatively sustained antidepressant properties in patients with major depressive disorder. Because the potassium channel activator diazoxide increases glutamate uptake via potassium channel activation, we hypothesized that it might exert antidepressant effects by increasing the removal of glutamate from the synaptic cleft, thereby reducing excessive glutamate transmission. METHODS: This randomized, double-blind, placebo-controlled, crossover, single-site inpatient clinical study was conducted at the National Institute of Mental Health to assess the efficacy and safety of a 3-week course of diazoxide (200-400 mg daily, twice a day) versus a 3-week course of placebo in 6 participants with treatment-refractory major depressive disorder. The primary clinical outcome measure was change in Montgomery-Asberg Depression Rating Scale score from baseline to posttreatment. Quantitative insulin sensitivity check index, as well as concomitant imaging measures (electroencephalography, proton magnetic resonance spectroscopy, magnetoencephalography), were used as potential surrogate markers of target (KATP channel) engagement. RESULTS: The study was halted due to severe adverse effects. Given the small sample size, statistical evaluation of the effect of diazoxide on Montgomery-Asberg Depression Rating Scale scores or the imaging measures was not pursued. Visual inspection of the quantitative insulin sensitivity check index test revealed no evidence of target engagement. CONCLUSIONS: Although the results are negative, they are an important addition to the literature in this rapidly changing field.

Deriving frequency-dependent spatial patterns in MEG-derived resting state sensorimotor network: A novel multiband ICA technique.

Recently, independent components analysis (ICA) of resting state magnetoencephalography (MEG) recordings has revealed resting state networks (RSNs) that exhibit fluctuations of band-limited power envelopes. Most of the work in this area has concentrated on networks derived from the power envelope of beta bandpass-filtered data. Although research has demonstrated that most networks show maximal correlation in the beta band, little is known about how spatial patterns of correlations may differ across frequencies. This study analyzed MEG data from 18 healthy subjects to determine if the spatial patterns of RSNs differed between delta, theta, alpha, beta, gamma, and high gamma frequency bands. To validate our method, we focused on the sensorimotor network, which is well-characterized and robust in both MEG and functional magnetic resonance imaging (fMRI) resting state data. Synthetic aperture magnetometry (SAM) was used to project signals into anatomical source space separately in each band before a group temporal ICA was performed over all subjects and bands. This method preserved the inherent correlation structure of the data and reflected connectivity derived from single-band ICA, but also allowed identification of spatial spectral modes that are consistent across subjects. The implications of these results on our understanding of sensorimotor function are discussed, as are the potential applications of this technique. Hum Brain Mapp 38:779-791, 2017. © 2016 Wiley Periodicals, Inc.

The Ethics of Clinical Trials Research in Severe Mood Disorders.

Mood disorders, including major depressive disorder (MDD) and bipolar disorder (BD), are highly prevalent, frequently disabling, and sometimes deadly. Additional research and more effective medications are desperately needed, but clinical trials research in mood disorders is fraught with ethical issues. Although many authors have discussed these issues, most do so from a theoretical viewpoint. This manuscript uses available empirical data to inform a discussion of the primary ethical issues raised in mood disorders research. These include issues of consent and decision-making capacity, including patients' motivations for participating in research. We also address drug withdrawals, placebo controls, and the overall safety of research. Finally, we examine the extant literature for studies discussing potential indirect benefits of clinical trials research to participants. Taken together, the evidence suggests that clinical trials research incorporating drug withdrawals and placebo controls can be conducted safely and ethically, even in patients with severe or treatment-resistant mood disorders. In fact, given the dearth of effective treatment options for this population, it is our opinion that a moral imperative exists to extend the offer of research participation to severely ill or treatment-resistant groups.

Reliability of 7T (1) H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation.

PURPOSE: To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy ((1) H-MRS) can noninvasively measure glutamatergic function. Evidence suggests that aberrant glutamatergic signaling plays a role in numerous psychopathologies. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. MATERIALS AND METHODS: At 7T MR, we acquired (1) H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (n = 26) twice on two separate days. An adapted echo time optimized point-resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 ppm, was used to excite and acquire the spectra. In-house software was used to model glutamate, glutamine, and glutathione, among other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. RESULTS: Within-session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs ≥0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC >0.62). A negative correlation was observed between glutathione concentration and age (r(24) = -0.37; P < 0.05), and a gender effect was noted on glutamine and glutathione. CONCLUSION: The adapted sequence provides good reliability to measure glutamate, glutamine, and glutathione signals.

Recognition of emotional facial expressions in anxious and nonanxious depression.

BACKGROUND: Anxiety and depression have each been independently associated with impairments in emotional face recognition. However, little is known about the nature of these impairments when anxiety and depression co-occur. METHODS: This post-hoc analysis evaluated the relationship between anxiety status and performance on the Emotional Expression Multimorph Task within a clinical sample of individuals with major depressive disorder (MDD). RESULTS: Participants with anxious depression (n=14) and nonanxious depression (n=14) completed the Emotional Expression Multimorph Task. Those with anxious depression required greater intensity of emotion to identify both happy (p=.01) and sad (p=.04) facial expressions than those with nonanxious depression. Severity of anxiety also correlated with greater intensity of emotion required to detect sad faces. Contrary to prediction, hypervigilance to angry and fearful facial expressions was not observed in anxious depression. LIMITATIONS: The present study did not include an anxiety-only group for comparison, and did not assess state anxiety at time of administration. In addition, the extent to which the experimental task correlates with social functioning is not fully understood. CONCLUSIONS: These findings suggest a diminished sensitivity to happy and sad facial expressions specific to anxious depression, but not a hypervigilance toward threatening facial expressions. Further research on the nature of emotion recognition in anxiety and depression may inform improved clinical interventions.

Group differences in MEG-ICA derived resting state networks: Application to major depressive disorder.

UNLABELLED: Functional magnetic resonance imaging (fMRI) studies have revealed the existence of robust, interconnected brain networks exhibiting correlated low frequency fluctuations during rest, which can be derived by examining inherent spatio-temporal patterns in functional scans independent of any a priori model. In order to explore the electrophysiological underpinnings of these networks, analogous techniques have recently been applied to magnetoencephalography (MEG) data, revealing similar networks that exhibit correlated low frequency fluctuations in the power envelope of beta band (14-30Hz) power. However, studies to date using this technique have concentrated on healthy subjects, and no method has yet been presented for group comparisons. We extended the ICA resting state MEG method to enable group comparisons, and demonstrate the technique in a sample of subjects with major depressive disorder (MDD). We found that the intrinsic resting state networks evident in fMRI appeared to be disrupted in individuals with MDD compared to healthy participants, particularly in the subgenual cingulate, although the electrophysiological correlates of this are unknown. Networks extracted from a combined group of healthy and MDD participants were examined for differences between groups. Individuals with MDD showed reduced correlations between the subgenual anterior cingulate (sgACC) and hippocampus in a network with primary nodes in the precentral and middle frontal gyri. Individuals with MDD also showed increased correlations between insulo-temporal nodes and amygdala compared to healthy controls. To further support our methods and findings, we present test/re-test reliability on independent recordings acquired within the same session. Our results demonstrate that group analyses are possible with the resting state MEG-independent component analysis (ICA) technique, highlighting a new pathway for analysis and discovery. This study also provides the first evidence of altered sgACC connectivity with a motor network. This finding, reliable across multiple sessions, suggests that the sgACC may partially mediate the psychomotor symptoms of MDD via synchronized changes in beta-band power, and expands the idea of the sgACC as a hub region mediating cognitive and emotional symptomatic domains in MDD. Findings of increased connectivity between the amygdala and cortical nodes further support the role of amygdalar networks in mediated depressive symptomatology. CLINICAL TRIALS IDENTIFIER: NCT00024635 (ZIA-MH002927-04).

Baseline working memory activation deficits in dimensional anxious depression as detected by magnetoencephalography.

OBJECTIVE: Anxiety often co-occurs with major depressive disorder (MDD). This preliminary study sought to ascertain the extent to which anxious depression drives group neurobiological differences between patients with MDD and healthy volunteers (HVs). METHODS: Magnetoencephalography beta-band frequency was used to compare differences in brain response during the N-back working memory task between 30 medication-free patients with treatment-resistant MDD (anxious depression=18; nonanxious depression=12) and 28 HVs. RESULTS: Compared to HVs, patients with anxious depression had significantly reduced desynchronisation (less activation) in the left precuneus, right cuneus, and left insula extending into the inferior and middle frontal cortex during the 2-back condition compared with the 1-back condition of the N-back working memory task--indicating less activation of these neural networks in patients with anxious depression during the condition with the highest level of task demands. No other significant group differences were found during the working memory conditions. CONCLUSION: This preliminary study suggests that a subset of patients--those with anxious depression--may be driving observed group differences between patients with MDD and HVs. Further neurobiological studies and replication experiments are necessary to determine the extent to which this subgroup has preferentially influenced our understanding of the underlying neurobiology of depression.

Neural correlates of suicidal ideation and its reduction in depression.

BACKGROUND: The neural correlates of suicidal ideation and its reduction after treatment are unknown. We hypothesized that increased regional cerebral glucose metabolism in the infralimbic cortex (Brodmann area 25), amygdala, and subgenual anterior cingulate cortex would be associated with suicidal ideation and its reduction after ketamine infusion. METHODS: Medication-free patients (n=19) with treatment-resistant major depressive disorder underwent positron emission tomography imaging at baseline and 230 minutes after an open-label ketamine infusion (0.5 mg/kg for 40 minutes). RESULTS: Baseline suicidal ideation and regional cerebral glucose metabolism in the infralimbic cortex were significantly correlated (r=.59, P=.007); but not overall mood scores (r=-.07, P=.79). Reductions in suicidal ideation after ketamine infusion were correlated with decreased regional cerebral glucose metabolism in the infralimbic cortex (r=.54, P=.02). Metabolism in other areas of interest was not significantly correlated with suicidal ideation or depression. CONCLUSION: The infralimbic cortex may be implicated in suicidal ideation.

Neural correlates of rapid antidepressant response to ketamine in bipolar disorder.

OBJECTIVES: Ketamine, an N-methyl d-aspartate (NMDA) antagonist, has rapid antidepressant effects in depressed subjects with bipolar disorder (BD). Evidence supports a role for the glutamatergic system in the pathophysiology of BD. This double-blind, randomized, cross-over study sought to determine cerebral metabolic correlates of antidepressant response to ketamine. METHODS: Twenty-one subjects with BD currently in a depressed state underwent [(18) F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging after receiving a placebo infusion as well as after receiving a ketamine infusion. Metabolism was compared between ketamine and placebo infusions, and correlated with clinical response. Regional metabolic rate of glucose (rMRGlu) in regions of interest (ROIs) and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were the main outcome measures. RESULTS: The study found that change in metabolism between sessions was significantly correlated with percentage change in MADRS scores in the right ventral striatum; subjects who showed the greatest improvement had the largest metabolic increase after ketamine infusion compared to placebo. In a voxel-wise analysis, subjects with BD had significantly lower glucose metabolism in the left hippocampus following the ketamine infusion than following the placebo infusion. In addition, metabolism in the subgenual anterior cingulate cortex (ACC) following the placebo infusion was positively correlated with percentage improvement in MADRS score following the ketamine infusion. CONCLUSIONS: Taken together, the results suggest that higher activity in the subgenual ACC may predict antidepressant response to ketamine. Ketamine administration altered glucose metabolism in areas known to be involved in mood disorders; these alterations may partially underlie ketamine's mechanism of action.

Developing biomarkers in mood disorders research through the use of rapid-acting antidepressants.

An impediment to progress in mood disorders research is the lack of analytically valid and qualified diagnostic and treatment biomarkers. Consistent with the National Institute of Mental Health (NIMH)'s Research Domain Criteria (RDoC) initiative, the lack of diagnostic biomarkers has precluded us from moving away from a purely subjective (symptom-based) toward a more objective diagnostic system. In addition, treatment response biomarkers in mood disorders would facilitate drug development and move beyond trial-and-error toward more personalized treatments. As such, biomarkers identified early in the pathophysiological process are proximal biomarkers (target engagement), while those occurring later in the disease process are distal (disease pathway components). One strategy to achieve this goal in biomarker development is to increase efforts at the initial phases of biomarker development (i.e. exploration and validation) at single sites with the capability of integrating multimodal approaches across a biological systems level. Subsequently, resultant putative biomarkers could then undergo characterization and surrogacy as these latter phases require multisite collaborative efforts. We have used multimodal approaches - genetics, proteomics/metabolomics, peripheral measures, multimodal neuroimaging, neuropsychopharmacological challenge paradigms and clinical predictors - to explore potential predictor and mediator/moderator biomarkers of the rapid-acting antidepressants ketamine and scopolamine. These exploratory biomarkers may then be used for a priori stratification in larger multisite controlled studies during the validation and characterization phases with the ultimate goal of surrogacy. In sum, the combination of target engagement and well-qualified disease-related measures are crucial to improve our pathophysiological understanding, personalize treatment selection, and expand our armamentarium of novel therapeutics.

Biomarkers in mood disorders research: developing new and improved therapeutics.

BACKGROUND: Recently, surrogate neurobiological biomarkers that correlate with target engagement and therapeutic response have been developed and tested in early phase studies of mood disorders. OBJECTIVE: The identification of biomarkers could help develop personalized psychiatric treatments that may impact public health. METHODS: These biomarkers, which are associated with clinical response post-treatment, can be directly validated using multimodal approaches including genetic tools, proteomics/metabolomics, peripheral measures, neuroimaging, biostatistical predictors, and clinical predictors. RESULTS: To date, early phase biomarker studies have sought to identify measures that can serve as "biosignatures", or biological patterns of clinical response. These studies have also sought to identify clinical predictors and surrogate outcomes associated with pathophysiological domains consistently described in the National Institute of Mental Health's (NIMH) new Research Domain Criteria (RDoC). Using the N-methyl-D-aspartate (NMDA) antagonist ketamine as an example, we identified changes in several domains (clinical, cognitive, and neurophysiological) that predicted ketamine's rapid and sustained antidepressant effects in individuals with treatment-resistant major depressive disorder (MDD) or bipolar depression. DISCUSSION: These approaches may ultimately provide clues into the neurobiology of psychiatric disorders and may have enormous impact Backon the development of novel therapeutics.

Hippocampal volume changes after (R,S)-ketamine administration in patients with major depressive disorder and healthy volunteers.

The hippocampus and amygdala have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Preclinical models suggest that stress-related changes in these regions can be reversed by antidepressants, including ketamine. Clinical studies have identified reduced volumes in MDD that are thought to be potentiated by early life stress and worsened by repeated depressive episodes. This study used 3T and 7T structural magnetic resonance imaging data to examine longitudinal changes in hippocampal and amygdalar subfield volumes associated with ketamine treatment. Data were drawn from a previous double-blind, placebo-controlled, crossover trial of healthy volunteers (HVs) unmedicated individuals with treatment-resistant depression (TRD) (3T: 18 HV, 26 TRD, 7T: 17 HV, 30 TRD) who were scanned at baseline and twice following either a 40 min IV ketamine (0.5 mg/kg) or saline infusion (acute: 1-2 days, interim: 9-10 days post infusion). No baseline differences were noted between the two groups. At 10 days post-infusion, a slight increase was observed between ketamine and placebo scans in whole left amygdalar volume in individuals with TRD. No other differences were found between individuals with TRD and HVs at either field strength. These findings shed light on the timing of ketamine's effects on cortical structures.

Exploring the impact of music on response to ketamine/esketamine: A scoping review.

Music and ketamine are both known to affect therapeutic outcomes, but few studies have investigated their co-administration. This scoping review describes the existing literature on the joint use of music and ketamine-or esketamine (the S(+) enantiomer of ketamine)-in humans. The review considers that extant studies have explored the intersection of ketamine/esketamine and music in healthy volunteers and in patients of various age groups, at different dosages, through different treatment processes, and have varied the sequence of playing music relative to ketamine/esketamine administration. Studies investigating the use of music during ketamine anesthesia are also included in the review because anesthesia and sedation were the early drivers of ketamine use. Studies pertaining to recreational ketamine use were omitted. The review was limited to articles published in the English language but not restricted by publication year. To the best of our knowledge, this scoping review is the first comprehensive exploration of the interplay between music and ketamine/esketamine and offers valuable insights to researchers interested in designing future studies.