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.

Glutamate receptor antagonists as fast-acting therapeutic alternatives for the treatment of depression: ketamine and other compounds.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant effects in treatment-resistant major depressive disorder and bipolar depression. These effects are in direct contrast to the more modest effects seen after weeks of treatment with classic monoaminergic antidepressants. Numerous open-label and case studies similarly validate ketamine's antidepressant properties. These clinical findings have been reverse-translated into preclinical models in an effort to elucidate ketamine's antidepressant mechanism of action, and three important targets have been identified: mammalian target of rapamycin (mTOR), eukaryotic elongation factor 2 (eEF2), and glycogen synthase kinase-3 (GSK-3). Current clinical and preclinical research is focused on (a) prolonging/maintaining ketamine's antidepressant effects, (b) developing more selective NMDA receptor antagonists free of ketamine's adverse effects, and (c) identifying predictor, mediator/moderator, and treatment response biomarkers of ketamine's antidepressant effects.

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.

A single infusion of ketamine improves depression scores in patients with anxious bipolar depression.

OBJECTIVE: Patents with anxious bipolar disorder have worse clinical outcomes and are harder to treat with traditional medication regimens compared to those with non-anxious bipolar disorder. Ketamine has been shown to rapidly and robustly decrease symptoms of depression in depressed patients with bipolar disorder. We sought to determine whether baseline anxiety status reduced ketamine's ability to decrease symptoms of depression. METHODS: Thirty-six patients with anxious (n = 21) and non-anxious (n = 15) treatment-resistant bipolar depression (types I and II; concurrently treated with either lithium or valproate) received a single infusion of ketamine (0.5 mg/kg) over 40 min. Post-hoc analyses compared changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HDRS) in anxious versus non-anxious depressed patients with bipolar disorder through 14 days post-infusion. Anxious bipolar depression was defined as DSM-IV bipolar depression plus a HDRS Anxiety/Somatization Factor score of ≥ 7. RESULTS: A linear mixed model revealed a significant effect of anxiety group on the MADRS (p = 0.04) and HDRS (p = 0.04). Significant drug effects (all p < 0.001) suggested that both anxious and non-anxious groups had an antidepressant response to ketamine. The drug-by-anxiety interactions were not significant (all p > 0.28). CONCLUSIONS: Both anxious and non-anxious patients with bipolar depression had significant antidepressant responses to ketamine, although the anxious depressed group did not show a clear antidepressant response disadvantage over the non-anxious group. Given that anxiety has been shown to be a predictor of poor treatment response in bipolar depression when traditional treatments are used, our findings suggest a need for further investigations into ketamine's novel role in the treatment of anxious bipolar depression.

NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia.

Glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain's global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate's role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.

Lithium and Valproate Levels Do Not Correlate with Ketamine's Antidepressant Efficacy in Treatment-Resistant Bipolar Depression.

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.

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.

Ketamine's antidepressant efficacy is extended for at least four weeks in subjects with a family history of an alcohol use disorder.

BACKGROUND: A single subanesthetic infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has rapid and potent antidepressant properties in treatment-resistant major depressive disorder (TRD). As a family history of an alcohol use disorder is a positive predictor of ketamine's antidepressant response and the strength of the association increases over time, we hypothesized that depressed subjects with a family history of an alcohol use disorder would have greater antidepressant durability and that riluzole would augment and/or extend ketamine's antidepressant efficacy. METHODS: Fifty-two TRD subjects received an open-label infusion of ketamine (0.5mg/kg over 40 minutes), and, four to six hours post-infusion, were randomized to either flexible-dose (100-200mg/day) riluzole or placebo in the following proportions: Family History Positive (FHP) riluzole (n = 10), FHP placebo (n = 9), Family History Negative (FHN) riluzole (n = 16), and FHN placebo (n = 17). RESULTS: FHP subjects randomized to placebo had a greater antidepressant response than FHN subjects; however, contrary to our initial hypothesis, there was no significant difference in antidepressant efficacy with riluzole. Although potentially underpowered, there was no difference in overall time-to-relapse based on randomization status (riluzole responders: n = 15, placebo responders: n = 17). Yet, time-to-relapse was longer in FHP placebo responders (n = 8) compared to FHN placebo responders (n = 9) with, again, no significant difference in time-to-relapse in FHP riluzole responders (n = 6) compared to FHN riluzole responders (n = 9). CONCLUSIONS: Ketamine's extended antidepressant durability in FHP TRD should be considered in the design and analysis of ketamine depression trials.

Glutamate and its receptors in the pathophysiology and treatment of major depressive disorder.

Monoaminergic neurotransmitter (serotonin, norepinephrine and dopamine) mechanisms of disease dominated the research landscape in the pathophysiology and treatment of major depressive disorder (MDD) for more than 50 years and still dominate available treatment options. However, the sum of all brain neurons that use monoamines as their primary neurotransmitter is <20%. In addition, most patients treated with monoaminergic antidepressants are left with significant residual symptoms and psychosocial disability not to mention side effects, e.g., sexual dysfunction. In the past several decades, there has been greater focus on the major excitatory neurotransmitter in the human brain, glutamate, in the pathophysiology and treatment of MDD. Although several preclinical and human magnetic resonance spectroscopy studies had already implicated glutamatergic abnormalities in the human brain, it was rocketed by the discovery that the N-methyl-D-aspartate receptor antagonist ketamine has rapid and potent antidepressant effects in even the most treatment-resistant MDD patients, including those who failed to respond to electroconvulsive therapy and who have active suicidal ideation. In this review, we will first provide a brief introduction to glutamate and its receptors in the mammalian brain. We will then review the clinical evidence for glutamatergic dysfunction in MDD, the discovery and progress-to-date with ketamine as a rapidly acting antidepressant, and other glutamate receptor modulators (including proprietary medications) for treatment-resistant depression. We will finally conclude by offering potential future directions necessary to realize the enormous therapeutic promise of glutamatergic antidepressants.

Decreased occipital cortical glutamate levels in response to successful cognitive-behavioral therapy and pharmacotherapy for major depressive disorder.

BACKGROUND: Previous studies have demonstrated that antidepressant medication and electroconvulsive therapy increase occipital cortical γ-aminobutyric acid (GABA) in major depressive disorder (MDD), but a small pilot study failed to show a similar effect of cognitive-behavioral therapy (CBT) on occipital GABA. In light of these findings we sought to determine if baseline GABA levels predict treatment response and to broaden the analysis to other metabolites and neurotransmitters in this larger study. METHODS: A total of 40 MDD outpatients received baseline proton magnetic resonance spectroscopy (1H-MRS), and 30 subjects completed both pre- and post-CBT 1H-MRS; 9 CBT nonresponders completed an open-label medication phase followed by an additional/3rd 1H-MRS. The magnitude of treatment response was correlated with occipital amino acid neurotransmitter levels. RESULTS: Baseline GABA did not predict treatment outcome. Furthermore, there was no significant effect of CBT on GABA levels. However, we found a significant group × time interaction (F1, 28 = 6.30, p = 0.02), demonstrating reduced glutamate in CBT responders, with no significant glutamate change in CBT nonresponders. CONCLUSIONS: These findings corroborate the lack of effect of successful CBT on occipital cortical GABA levels in a larger sample. A reduction in glutamate levels following treatment, on the other hand, correlated with successful CBT and antidepressant medication response. Based on this finding and other reports, decreased occipital glutamate may be an antidepressant response biomarker. Healthy control comparator and nonintervention groups may shed light on the sensitivity and specificity of these results.

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.

Rigor and reproducibility in human brain organoid research: Where we are and where we need to go.

Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.

Neurobiology of anxious depression: a review.

Anxious depression is a common, distinct clinical subtype of major depressive disorder (MDD). This review summarizes current neurobiological knowledge regarding anxious depression. Peer-reviewed articles, published January 1970 through September 2012, were identified via PUBMED, EMBASE, and Cochrane Library, using the following key words: anxious depression electroencephalography (EEG), anxious depression functional magnetic resonance imaging (fMRI), anxious depression genetics, anxious depression neurobiology, and anxious melancholia neurobiology. Despite a general dearth of neurobiological research, the results suggest that anxious depression-when defined either syndromally or dimensionally-has distinct neurobiological findings that separate it from nonanxious depression. Structural neuroimaging, EEG, genetics, and neuropsychiatric studies revealed differences in subjects with anxious depression compared to other groups. Endocrine differences between individuals with anxious depression and those with nonanxious depression have also been noted, as evidenced by abnormal responses elicited by exogenous stimulation of the system. Despite these findings, heterogeneity in the definition of anxious depression complicates the results. Because exploring the neurobiology of this depressive subtype is important for improving diagnosis, prognosis, and treatment, enrichment strategies to decrease heterogeneity within the field should be employed for future research.

Defining anxious depression: a review of the literature.

The diagnosis of anxious depression is presently inconsistent. The many different definitions of anxious depression have complicated its diagnosis, leading to clinical confusion and inconsistencies in the literature. This article reviewed the extant literature in order to identify the varying definitions of anxious depression, which were then compared using Feighner's diagnostic criteria. Notably, these suggest a different clinical picture of patients with anxious depression. For instance, relying on The International Classification of Diseases (ICD) or Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnoses yields a clinical picture of a comparatively mild or transient disorder; in contrast, using dimensional criteria such as DSM criteria combined with additional rating scales-most commonly the anxiety somatization factor score from the Hamilton Depression Rating Scale (HAM-D)-yields a more serious clinical picture. The evidence reviewed here suggests that defining anxious depression in a dimensional manner may be the most useful and clinically relevant way of differentiating it from other types of mood and anxiety disorders, and of highlighting the most clinically significant differences between patients with anxious depression versus depression or anxiety alone.

Second messenger/signal transduction pathways in major mood disorders: moving from membrane to mechanism of action, part I: major depressive disorder.

The etiopathogenesis and treatment of major mood disorders have historically focused on modulation of monoaminergic (serotonin, norepinephrine, dopamine) and amino acid [γ-aminobutyric acid (GABA), glutamate] receptors at the plasma membrane. Although the activation and inhibition of these receptors acutely alter local neurotransmitter levels, their neuropsychiatric effects are not immediately observed. This time lag implicates intracellular neuroplasticity as primary in the mechanism of action of antidepressants and mood stabilizers. The modulation of intracellular second messenger/signal transduction cascades affects neurotrophic pathways that are both necessary and sufficient for monoaminergic and amino acid-based treatments. In this review, we will discuss the evidence in support of intracellular mediators in the pathophysiology and treatment of preclinical models of despair and major depressive disorder (MDD). More specifically, we will focus on the following pathways: cAMP/PKA/CREB, neurotrophin-mediated (MAPK and others), p11, Wnt/Fz/Dvl/GSK3ß, and NFκB/ΔFosB. We will also discuss recent discoveries with rapidly acting antidepressants, which activate the mammalian target of rapamycin (mTOR) and release of inhibition on local translation via elongation factor stimulation. Throughout this discourse, we will highlight potential intracellular targets for therapeutic intervention. Finally, future clinical implications are discussed.

Second messenger/signal transduction pathways in major mood disorders: moving from membrane to mechanism of action, part II: bipolar disorder.

In this second of two articles on second messenger/signal transduction cascades in major mood disorders, we will review the evidence in support of intracellular dysfunction and its rectification in the etiopathogenesis and treatment of bipolar disorder (BD). The importance of these cascades is highlighted by lithium's (the gold standard in BD psychopharmacology) ability to inhibit multiple critical loci in second messenger/signal transduction cascades including protein kinase C (involved in the IP3/PIP2 pathway) and GSK-3ß (canonically identified in the Wnt/Fz/Dvl/GSK-3ß cascade). As a result, and like major depressive disorder (MDD), more recent pathophysiological studies and rational therapeutic targets have been directed at these and other intracellular mediators. Even in the past decade, intracellular dysfunction in numerous neuroprotective/apoptotic cascades appears important in the pathophysiology and may be a future target for pharmacological interventions of BD.

Alcohol inhibits sociability via serotonin inputs to the nucleus accumbens.

Social interaction is a core component of motivational behavior that is perturbed across multiple neuropsychiatric disorders, including alcohol use disorder (AUD). Positive social bonds are neuroprotective and enhance recovery from stress, so reduced social interaction in AUD may delay recovery and lead to alcohol relapse. We report that chronic intermittent ethanol (CIE) induces social avoidance in a sex-dependent manner and is associated with hyperactivity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). While 5-HT DRN neurons are generally thought to enhance social behavior, recent evidence suggests that specific 5-HT pathways can be aversive. Using chemogenetic iDISCO, the nucleus accumbens (NAcc) was identified as one of 5 regions that were activated by 5-HT DRN stimulation. We then employed an array of molecular genetic tools in transgenic mice to show that 5-HT DRN inputs to NAcc dynorphin neurons drive social avoidance in male mice after CIE by activating 5-HT 2C receptors. NAcc dynorphin neurons also inhibit dopamine release during social interaction, reducing the motivational drive to engage with social partners. This study reveals that excessive serotonergic drive after chronic alcohol can promote social aversion by inhibiting accumbal dopamine release. Drugs that boost brain serotonin levels may be contraindicated for individuals with AUD.

(Es)Ketamine for Suicidal Ideation and Behavior: Clinical Efficacy.

Suicidal ideation and behavior are among the most severe psychiatric presentations, warranting emergency room visits and psychiatric admission for higher levels of care. In the United States, suicide rates continue to climb, especially in younger patients, and the continued psychosocial stressors of the COVID-19 pandemic may further exacerbate this crisis. Suicidal ideation and behavior are core features of a major depressive episode, but there are limited treatment options to rapidly redress these life-threatening symptoms. Racemic ketamine and its S-enantiomer, esketamine, are N-methyl-D-aspartate receptor antagonists and glutamate modulators that have robust antidepressant efficacy in treatment-resistant major depressive disorder and bipolar depression. Additionally, both ketamine and esketamine have demonstrated rapid-acting antisuicidal efficacy in major mood disorders. In August 2020, this culminated in a first-in-class approval of Spravato® (intranasal esketamine) for the treatment of major depressive disorder with acute suicidal ideation and behavior. In this article, we review the literature in support of the antisuicidal efficacy of ketamine and esketamine.

Biomarkers of ketamine's antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology.

Major depressive disorder (MDD) is one of the leading causes of morbidity and all-cause mortality (including suicide) worldwide, and, unfortunately, first-line monoaminergic antidepressants and evidence-based psychotherapies are not effective for all patients. Subanesthetic doses of the N-methyl-D-aspartate receptor antagonists and glutamate modulators ketamine and S-ketamine have rapid and robust antidepressant efficacy in such treatment-resistant depressed patients (TRD). Yet, as with all antidepressant treatments including electroconvulsive therapy (ECT), not all TRD patients adequately respond, and we are presently unable to a priori predict who will respond or not respond to ketamine. Therefore, antidepressant treatment response biomarkers to ketamine have been a major focus of research for over a decade. In this article, we review the evidence in support of treatment response biomarkers, with a particular focus on genetics, functional magnetic resonance imaging, and neurophysiological studies, i.e. electroencephalography and magnetoencephalography. The studies outlined here lay the groundwork for replication and dissemination.