An Open-Label Study of Adjunctive Dextromethorphan/Quinidine in Treatment-Resistant Depression.

BACKGROUND: Approximately one third of individuals with major depressive disorder have treatment-resistant depression (TRD). Glutamatergic modulators such as the N -methyl- d -aspartate receptor antagonist ketamine have rapid and robust antidepressant effects, but their use has been limited by accessibility and route of administration. This open-label pilot study assessed the adjunctive antidepressant efficacy of dextromethorphan/quinidine (DM/Q) in TRD. METHODS: Inpatients with TRD (n = 17, 40.8 ± 12.3 years; 9 females/8 males) received adjunctive open-label DM/Q (20 mg/10 mg) up to 3 times daily. The study had no set endpoint; participants were followed until they discontinued DM/Q or were discharged. Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained at baseline (before DM/Q administration) and regularly during hospitalization. Full response was defined as a ≥50% reduction in baseline MADRS score, partial response as a 25% to 50% decrease in baseline MADRS score, and nonresponse as a <25% reduction or an increase in baseline MADRS score. RESULTS: The 17 inpatients received open-label DM/Q for 5.1 ± 2.7 weeks. Forty-seven percent of participants responded to DM/Q-12% achieved a full response and 35% achieved a partial response. The largest MADRS difference observed at any time point was -6.4 ± 8.4 (-21.0% ± 29.9%), and the MADRS difference observed at time of DM/Q discontinuation or hospital discharge was -4.8 ± 8.4 (-15.9% ± 29.7%). Twenty-four percent of participants experienced a nonserious adverse event; none experienced a serious adverse event. CONCLUSIONS: In this open-label pilot study, 47% of participants responded to adjunctive DM/Q, which was well tolerated. Larger placebo-controlled trials are needed to determine the real-world efficacy of DM/Q.

Assessing geographic disparities in mental health research participation.

BACKGROUND: Large geographic health disparities are well-documented within the U.S. Although approximately 60 million Americans-or roughly 20% of the total U.S. population-live in rural areas, rural residents may be less likely to participate in health research, including mental health research, due to multiple barriers. This retrospective analysis evaluated the urbanity and rurality of inpatient research participants and potential research participants over a five-year period at the Experimental Therapeutics and Pathophysiology Branch (ETPB), NIMH-NIH (Bethesda, Maryland), which conducts experimental medicine and neurobiological research in mood disorders. METHODS: Participant and potential participant zip codes were converted to Rural Urban Commuting Area (RUCA) codes (1-3 urban, 4-10 rural). These results were compared with each other and with U.S. population data. RESULTS: The analysis included 182 research participants and 1864 potential research participants; the former were admitted to an in-person research unit and the latter were screened by phone or online. ETPB research participants had an urban residence rate of 93.4% and a rural residence rate of 6.6%. Potential ETPB research participants had an urban residence rate of 90.9% and a rural residence rate of 9.1%. In comparison, the U.S. urban residence rate is 80% and the rural rate is 20%. CONCLUSION: At the ETPB, both research participants with mood disorders admitted to an in-person research unit and potential research participants screened online or by phone from rural areas were under-represented relative to participants from more urban areas. Further study of research recruitment barriers in rural areas of the U.S is needed.

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.

κ-Opioid Receptor Plasma Levels Are Associated With Sex and Diagnosis of Major Depressive Disorder But Not Response to Ketamine.

BACKGROUND: Preclinical evidence indicates that the κ-opioid receptor (KOR)/dynorphin pathway is implicated in depressive-like behaviors. Ketamine is believed to partly exert its antidepressant effects by modulating the opioid system. This post hoc study examined the following research questions: (1) at baseline, were there differences in KOR or dynorphin plasma levels between individuals with major depressive disorder (MDD) and healthy volunteers (HVs) or between men and women? (2) in individuals with MDD, did KOR or dynorphin baseline plasma levels moderate ketamine's therapeutic effects or adverse effects? and (3) in individuals with MDD, were KOR or dynorphin plasma levels affected after treatment with ketamine compared with placebo? METHODS: Thirty-nine unmedicated individuals with MDD (23 women) and 25 HVs (16 women) received intravenous ketamine (0.5 mg/kg) and placebo in a randomized, crossover, double-blind trial. Blood was obtained from all participants at baseline and at 3 postinfusion time points (230 minutes, day 1, day 3). Linear mixed model regressions were used. RESULTS: At baseline, participants with MDD had lower KOR plasma levels than HVs ( F1,60 = 13.16, P < 0.001), and women (MDD and HVs) had higher KOR plasma levels than men ( F1,60 = 4.98, P = 0.03). Diagnosis and sex had no significant effects on baseline dynorphin levels. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects. Compared with placebo, ketamine was not associated with postinfusion changes in KOR or dynorphin levels. CONCLUSIONS: In humans, diagnosis of MDD and biological sex are involved with changes in components of the KOR/dynorphin pathway. Neither KOR nor dynorphin levels consistently moderated ketamine's therapeutic effects or adverse effects, nor were levels altered after ketamine infusion. TRIAL REGISTRATION: NCT00088699 ( ClinicalTrials.gov ).

Cerebrospinal fluid exploratory proteomics and ketamine metabolite pharmacokinetics in human volunteers after ketamine infusion.

Ketamine is a treatment for both refractory depression and chronic pain syndromes. In order to explore ketamine's potential mechanism of action and whether ketamine or its metabolites cross the blood brain barrier, we examined the pharmacokinetics of ketamine and its metabolites-norketamine (NK), dehydronorketamine (DHNK), and hydroxynorketamines (HNKs)-in cerebrospinal fluid (CSF) and plasma, as well as in an exploratory proteomic analysis in the CSF of nine healthy volunteers who received ketamine intravenously (0.5 mg/kg IV). We found that ketamine, NK, and (2R,6R;2S,6S)-HNK readily crossed the blood brain barrier. Additionally, 354 proteins were altered in the CSF in at least two consecutive timepoints (p < 0.01). Proteins in the classes of tyrosine kinases, cellular adhesion molecules, and growth factors, including insulin, were most affected, suggesting an interplay of altered neurotransmission, neuroplasticity, neurogenesis, synaptogenesis, and neural network functions following ketamine administration.

Ketamine treatment for depression: a review.

This manuscript reviews the clinical evidence regarding single-dose intravenous (IV) administration of the novel glutamatergic modulator racemic (R,S)-ketamine (hereafter referred to as ketamine) as well as its S-enantiomer, intranasal esketamine, for the treatment of major depressive disorder (MDD). Initial studies found that a single subanesthetic-dose IV ketamine infusion rapidly (within one day) improved depressive symptoms in individuals with MDD and bipolar depression, with antidepressant effects lasting three to seven days. In 2019, esketamine received FDA approval as an adjunctive treatment for treatment-resistant depression (TRD) in adults. Esketamine was approved under a risk evaluation and mitigation strategy (REMS) that requires administration under medical supervision. Both ketamine and esketamine are currently viable treatment options for TRD that offer the possibility of rapid symptom improvement. The manuscript also reviews ketamine's use in other psychiatric diagnoses-including suicidality, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse, and social anxiety disorder-and its potential adverse effects. Despite limited data, side effects for antidepressant-dose ketamine-including dissociative symptoms, hypertension, and confusion/agitation-appear to be tolerable and limited to around the time of treatment. Relatively little is known about ketamine's longer-term effects, including increased risks of abuse and/or dependence. Attempts to prolong ketamine's effects with combined therapy or a repeat-dose strategy are also reviewed, as are current guidelines for its clinical use. In addition to presenting a novel and valuable treatment option, studying ketamine also has the potential to transform our understanding of the mechanisms underlying mood disorders and the development of novel therapeutics.

Comparative metabolomic analysis in plasma and cerebrospinal fluid of humans and in plasma and brain of mice following antidepressant-dose ketamine administration.

Subanesthetic-dose racemic (R,S)-ketamine (ketamine) produces rapid, robust, and sustained antidepressant effects in major depressive disorder (MDD) and bipolar disorder (BD) and has also been shown to effectively treat neuropathic pain, complex regional pain syndrome, and post-traumatic stress disorder (PTSD). However, to date, its mechanism of action remains unclear. Preclinical studies found that (2 R,6 R;2 S,6 S)-hydroxynorketamine (HNK), a major circulating metabolite of ketamine, elicits antidepressant effects similar to those of ketamine. To help determine how (2 R,6 R)-HNK contributes to ketamine's mechanism of action, an exploratory, targeted, metabolomic analysis was carried out on plasma and CSF of nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg). A parallel targeted metabolomic analysis in plasma, hippocampus, and hypothalamus was carried out in mice receiving either 10 mg/kg of ketamine, 10 mg/kg of (2 R,6 R)-HNK, or saline. Ketamine and (2 R,6 R)-HNK both affected multiple pathways associated with inflammatory conditions. In addition, several changes were unique to either the healthy human volunteers and/or the mouse arm of the study, indicating that different pathways may be differentially involved in ketamine's effects in mice and humans. Mechanisms of action found to consistently underlie the effects of ketamine and/or (2 R,6 R)-HNK across both the human metabolome in plasma and CSF and the mouse arm of the study included LAT1, IDO1, NAD+, the nitric oxide (NO) signaling pathway, and sphingolipid rheostat.

Prospective association of psychological pain and hopelessness with suicidal thoughts.

BACKGROUND: Early markers preceding suicide ideation (SI) may provide valuable information for both assessment and treatment. The glutamatergic modulator ketamine has rapid, transient effects on SI, creating an opportunity to observe potential antecedents of the re-emergence of SI. This analysis evaluated whether the interaction between two suicide risk factors-psychological pain and hopelessness-were prospectively associated with SI post-ketamine administration. METHODS: Data were drawn from three ketamine clinical trials of participants with treatment-resistant major depressive disorder or bipolar disorder (n = 108) with short- and/or long-term follow-up (three or 11 days). A random intercept cross-lagged panel model evaluated the longitudinal relationship between the correlated concepts, specifically whether the interaction between hopelessness and psychological pain was associated with future SI. RESULTS: Psychological pain and hopelessness were not prospectively associated with SI in short-term or long-term analyses; rather, long-term analyses found that SI was associated with later psychological pain and hopelessness. Similarly, no relationship was observed for other suicide risk factors, including anhedonia, depressed mood, and impaired sleep. LIMITATIONS: Secondary analysis of clinical trial data not collected for this purpose; hopelessness and psychological pain were assessed via proxy measures from existing depression rating scales; the small sample size required a restricted statistical model. CONCLUSIONS: Psychological pain and hopelessness were not associated with the re-emergence of SI post-ketamine. These results may be due to limited variability in the data. The re-emergence of SI post-ketamine may also not follow patterns typically seen in non-pharmacologic contexts. Individuals with a history of SI warrant careful monitoring post-ketamine administration.

The mental health impact of contact with COVID-19 patients on healthcare workers in the United States.

This study assessed the relationship between contact with COVID-19 patients and the mental health of healthcare workers (HCWs) in the United States (US). In a convenience sample of 957 HCWs who completed an anonymous online survey between April-May 2020, HCWs who provided direct care to confirmed or suspected COVID-19 patients reported increased depressive and posttraumatic symptoms compared to HCWs with no COVID-19 patient contact. Additionally, more frequent contact was associated with higher distress. More data drawn from diverse samples that better represent US HCWs are needed to fully assess the scope of this association.

The relationship between the HDRS insomnia items and polysomnographic (PSG) measures in individuals with treatment-resistant depression.

The Hamilton Depression Rating Scale (HDRS), which includes several insomnia-related items, is potentially valuable in evaluating both depressive and sleep symptoms. However, the HDRS insomnia items have not been fully assessed by objective measures. This study compared the three HDRS insomnia items (Early, Middle, and Late) with the corresponding objective polysomnography (PSG) measures of Sleep Latency (SL), middle wakefulness, and late wakefulness. The study used HDRS and PSG data from 130 baseline nights, drawn from 80 participants enrolled in clinical trials for treatment-resistant depression (TRD). Mixed models evaluated the relationship between the HDRS and PSG, and primary analyses examined the Early, Middle, and Late Insomnia HDRS items and the PSG variables SL and Waking After Sleep Onset (WASO). To approximate the Middle and Late HDRS Insomnia items more closely, WASO was divided into WASO before 4:00 a.m. (waking between Sleep Onset and 0400 h) and WASO after 4:00 a.m. (waking between 0400 h and 0700 h). Secondary analyses included summed HDRS Global Insomnia score. HDRS Early and Late Insomnia items predicted objective PSG measures of early and late wakefulness. For Early Insomnia, each additional point in severity was associated with 61% [95%CI: 35%, 93%] longer SL. For Late Insomnia, each additional point was associated with a 35% [95% CI: 13%, 63%] increase in WASO after 4:00 a.m. Middle Insomnia was marginally related to WASO before 4:00 a.m. HDRS Early and Late Insomnia items may thus provide an index of wakefulness in TRD and help monitor treatment response when objective measures such as PSG are not feasible. CLINICAL TRIALS IDENTIFIER: www.clinicaltrials.gov (NCT01204918, NCT00054704, NCT00088699).

Key considerations in the pharmacological management of treatment-resistant depression.

Introduction: Treatment-resistant depression (TRD) is a complex, multifactorial, and biologically heterogeneous disorder with debilitating outcomes. Understanding individual reasons why patients do not respond to treatment is necessary for improving clinical recommendations regarding medication regimens, augmentation strategies, and alternative treatments.Areas covered: This manuscript reviews evidence-based treatment strategies for the clinical management of TRD. Current developments in the field and potential future recommendations for personalized treatment of TRD are also discussed.Expert opinion: Treatment guidelines for TRD are limited by the heterogeneous nature of the disorder. Furthermore, current strategies reflect this heterogeneity by emphasizing disease characteristics as well as drug trial response or failure. Developing robust biomarkers that could one day be integrated into clinical practice has the potential to advance specific treatment targets and ultimately improve treatment and remission outcomes.

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status.

The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.

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.

The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response.

Dysfunction in a wide array of systems-including the immune, monoaminergic, and glutamatergic systems-is implicated in the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway. This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD (23 F, ages 18-65) received a single ketamine infusion (0.5 mg/kg) over 40 min. KYN pathway analytes-including plasma concentrations of indoleamine 2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)-were assessed at baseline (pre-infusion), 230 min, day 1, and day 3 post-ketamine. General linear models with restricted maximum likelihood estimation and robust sandwich variance estimators were implemented. A repeated effect of time was used to model the covariance of the residuals with an unstructured matrix. After controlling for age, sex, and body mass index (BMI), post-ketamine IDO levels were significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA levels at days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/KYN was observed at day 1. In addition, baseline levels of proinflammatory cytokines and behavioral measures predicted KYN pathway changes post ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.

Correction: Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ketamine metabolites, clinical response, and gamma power in a randomized, placebo-controlled, crossover trial for treatment-resistant major depression.

A single, subanesthetic dose of (R,S)-ketamine (ketamine) exerts rapid and robust antidepressant effects. Several groups previously reported that (2S,6S;2R,6R)-hydroxynorketamine (HNK) had antidepressant effects in rodents, and that (2R,6R)-HNK increased cortical electroencephalographic gamma power. This exploratory study examined the relationship between ketamine metabolites, clinical response, psychotomimetic symptoms, and gamma power changes in 34 individuals (ages 18-65) with treatment-resistant depression (TRD) who received a single ketamine infusion (0.5 mg/kg) over 40 min. Plasma concentrations of ketamine, norketamine, and HNKs were measured at 40, 80, 120, and 230 min and at 1, 2, and 3 days post-infusion. Linear mixed models evaluated ketamine metabolites as mediators of antidepressant and psychotomimetic effects and their relationship to resting-state whole-brain magnetoencephalography (MEG) gamma power 6-9 h post-infusion. Three salient findings emerged. First, ketamine concentration positively predicted distal antidepressant response at Day 11 post-infusion, and an inverse relationship was observed between (2S,6S;2R,6R)-HNK concentration and antidepressant response at 3 and 7 days post-infusion. Norketamine concentration was not associated with antidepressant response. Second, ketamine, norketamine, and (2S,6S;2R,6R)-HNK concentrations at 40 min were positively associated with contemporaneous psychotomimetic symptoms; post-hoc analysis revealed that ketamine was the predominant contributor. Third, increased (2S,6S;2R,6R)-HNK maximum observed concentration (Cmax) was associated with increased MEG gamma power. While contrary to preclinical observations and our a priori hypotheses, these exploratory results replicate those of a recently published study documenting a relationship between higher (2S,6S;2R,6R)-HNK concentrations and weaker antidepressant response in humans and provide further rationale for studying gamma power changes as potential biomarkers of antidepressant response.