HNK for Treatment-Resistant Depression
Recruiting in Palo Alto (17 mi)
Overseen byCarlos A Zarate, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Institute of Mental Health (NIMH)
Must not be taking: MAOIs, Fluoxetine, Aripiprazole, others
Disqualifiers: Psychotic disorders, Substance use, Cardiovascular, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?Background:
Major depressive disorder (MDD) is a serious mental illness that can put people at risk of self-harm and death. Many drugs are used to treat MDD, but it can take a long time for them to be effective. Researchers want to know if a faster-acting drug, (2R,6R)-hydroxynorketamine (HNK), can better treat the symptoms of MDD.
Objective:
To test a study drug (HNK) in people with MDD.
Eligibility:
People aged 18 to 70 years with MDD. They must have had a screening assessment under protocol 01-M-0254.
Design:
Participants will be tapered off their current MDD drugs over 2 to 5 weeks. They will stay off of the drugs for up to 2 weeks prior to starting the study medication and procedures. They will have a physical exam with blood tests. They will have tests of their heart function, mood, and thinking. They will answer questions about their symptoms. They may choose to have imaging scans and scans of their brain activity.
HNK is given through a tube attached to a needle inserted into a vein. Participants will receive infusions on this schedule:
They will receive 4 infusions over 2 weeks. They will stay in the clinical center overnight after each infusion or for the duration of the study.
They will receive no drugs for 2 to 3 weeks.
They will have 4 more infusions over 2 weeks, with overnight stays after each or for the duration of the study.
One set of 4 infusions will be the HNK. The other set of 4 infusions will be a placebo. A placebo looks just like the real drug but contains no medicine. Participants will not know when they are getting the HNK or placebo.
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Will I have to stop taking my current medications?
Yes, participants will need to gradually stop taking their current depression medications over 2 to 5 weeks and remain off them for up to 2 weeks before starting the study drug.
What evidence supports the effectiveness of the drug (2R,6R)-HNK for treatment-resistant depression?
The research suggests that (2R,6R)-HNK, a metabolite of ketamine, does not show antidepressant effects in a specific depression model, unlike (R)-ketamine, which does. Additionally, higher levels of (2R,6R)-HNK in the blood were associated with less improvement in depression symptoms in a study on suicidal depression.
12345Is (2R,6R)-hydroxynorketamine safe for humans?
(2R,6R)-hydroxynorketamine, a metabolite of ketamine, shows promise as a treatment for depression without the side effects and abuse potential associated with ketamine. Preclinical studies suggest it has a favorable safety profile, but clinical trials are needed to confirm its safety in humans.
56789What makes the drug (2R,6R)-HNK unique for treating treatment-resistant depression?
The drug (2R,6R)-HNK is unique because it is a derivative of ketamine that may offer antidepressant effects without the dissociative side effects commonly associated with ketamine, potentially providing a safer alternative for patients with treatment-resistant depression.
1011121314Eligibility Criteria
This trial is for adults aged 18 to 70 with Major Depressive Disorder (MDD) who haven't responded well to standard treatments. They must have completed a screening assessment and be able to stop their current MDD medications for the duration of the study.Inclusion Criteria
Ability of participant to understand and willingness to sign a written informed consent document. Participants must score >= 80% on the consent quiz.
I am willing and able to follow all study requirements.
Undergone a screening assessment under protocol 01-M-0254.
+9 more
Exclusion Criteria
Contraindications to MRS (metal in body, claustrophobia, etc. for imaging).
Inability to read and understand English.
My thyroid condition is not stable.
+20 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-5 weeks
Drug Tapering
Participants are tapered off their current MDD drugs
2-5 weeks
Washout
Participants stay off drugs for up to 2 weeks prior to starting the study medication
2 weeks
Treatment Session 1
Participants receive 4 infusions of either HNK or placebo over 2 weeks
2 weeks
4 visits (in-person, overnight stays)
No Drug Period
Participants receive no drugs for 2-3 weeks
2-3 weeks
Treatment Session 2
Participants receive 4 infusions of either HNK or placebo over 2 weeks
2 weeks
4 visits (in-person, overnight stays)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
(2R,6R)-hydroxynorketamine (HNK), a potential fast-acting antidepressant, is being tested against a placebo in people with treatment-resistant depression. Participants will receive infusions over two weeks, take no drugs for another few weeks, then get another set of infusions.
2Treatment groups
Experimental Treatment
Group I: 2Experimental Treatment2 Interventions
Individuals in Arm 2 will receive double-blinded placebo infusions four times over two weeks during Test Session 2 and double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise.
Group II: 1Experimental Treatment2 Interventions
Individuals in Arm 1 will receive double-blinded (2R,6R)-HNK infusions four times over two weeks during Test Session 1 and daily double-blinded placebo infusions four times over two weeks during Test Session 2. The starting dose will be 0.25 mg/kg and the treatment target for all participants will be 2.0 mg/kg. If response criteria is not met by the morning of the next infusion, the dose may be increased. Doses will be decreased if tolerability issues arise.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Institute of Mental Health (NIMH)Lead Sponsor
References
Ketamine metabolite pilot study in a suicidal depression trial. [2023]Ketamine shows promise as a rapidly-acting treatment for depression and suicidal ideation, but side effects and abuse potential limit its use. Understanding its mechanism of action could help develop analogous but safer drugs. This post hoc study explored relationships of ketamine and metabolites, including hydroxynorketamine enantiomers, (2S,6S)- and (2R,6R)-HNK, to clinical response in a subgroup from a published trial in suicidal depression. Depressed adults with clinically significant suicidal ideation were randomized to double-blind infusion of sub-anesthetic ketamine or midazolam. Ketamine and metabolites were measured after infusion (N = 53). Plasma (2R,6R)-HNK was associated with change (higher levels correlated with less clinical improvement) from baseline to 24 h post-infusion of depression (HDRS-24: Spearman r = 0.37, p = 0.009) and suicidal thoughts (SSI: Spearman r = 0.29, p = 0.041). There were similar correlations with weekly follow-up clinical rating scores for both HNK enantiomers and dehydronorketamine (DHNK). Ketamine and norketamine were not associated with change in depression or suicidal ideation (unadjusted p > 0.28).
Lack of metabolism in (R)-ketamine's antidepressant actions in a chronic social defeat stress model. [2019]Since the metabolism of (R,S)-ketamine to (2R,6R)-hydroxynorketamine (HNK) is reported to be essential for ketamine's antidepressant effects, there is an increasing debate about antidepressant effects of (2R,6R)-HNK. Using pharmacokinetic and behavioral techniques, we investigated whether intracerebroventricular (i.c.v.) infusion of (R)-ketamine or (2R,6R)-HNK show antidepressant effects in a chronic social defeat stress (CSDS) model of depression. Low levels of (2R,6R)-HNK in the brain after i.c.v. infusion of (R)-ketamine were detected, although brain levels of (2R,6R)-HNK were markedly lower than those after i.c.v. infusion of (2R,6R)-HNK. Furthermore, high levels of (2R,6R)-HNK in the blood and liver after i.c.v. infusion of (R)-ketamine or (2R,6R)-HNK were detected. A single i.c.v. infusion of (R)-ketamine showed rapid and long-lasting (7 days) antidepressant effects in a CSDS model. In contrast, i.c.v. infusion of (2R,6R)-HNK did not show any antidepressant effect in the same model, although brain concentration of (2R,6R)-HNK was higher than after i.c.v. infusion of (R)-ketamine. This study suggest that (R)-ketamine in the periphery after washout from the brain is metabolized to (2R,6R)-HNK in the liver, and subsequently, (2R,6R)-HNK enters into brain tissues. Furthermore, it is unlikely that (2R,6R)-HNK is essential for the antidepressant actions of (R)-ketamine in a CSDS model.
Assessment of health-related quality of life and health status in patients with treatment-resistant depression treated with esketamine nasal spray plus an oral antidepressant. [2023]Patients with treatment-resistant depression (TRD) report significant deficits in physical and mental health, as well as severely impaired health-related quality of life (HRQoL) and functioning. Esketamine effectively enhances the daily functioning in these patients while also improving their depressive symptoms. This study assessed HRQoL and health status of patients with TRD, who were treated with esketamine nasal spray and an oral antidepressant (ESK + AD) vs. placebo nasal spray and an AD (AD + PBO).
The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine. [2022]Treatment-resistant depression is a pleomorphic phenomenon occurring in 30% of patients with depression. The chance to achieve remission decreases with every subsequent episode. It constitutes a significant part of the global disease burden, causes increased morbidity and mortality, and is associated with poor quality of life. It involves multiple difficult-to-treat episodes, with increasing resistance over time. The concept of staging captures the process of changes causing increasing treatment resistance and global worsening of functioning in all areas of life. Ketamine is a novel rapid-acting antidepressant with neuroplastic potential. Here, we argue that ketamine use as an add-on treatment of resistant major depressive disorder, based on its unique pharmacological properties, can reverse this process, give hope to patients, and prevent therapeutic nihilism.
Effects of subanesthetic ketamine and (2R,6R) hydroxynorketamine on working memory and synaptic transmission in the nucleus reuniens in mice. [2023]Acute cognitive impairment and abuse potential of ketamine incentivizes the search for alternatives to ketamine for clinical management of treatment-resistant depression. Recently, (2R,6R) hydroxynorketamine ((2R,6R)-HNK), a metabolite of ketamine, has shown promise due to its reported lack of ketamine-like reinforcing properties. Nonetheless, the effect of (2R,6R)-HNK on cognition has not been reported.
Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search. [2023]The off-label use of racemic ketamine and the FDA approval of (S)-ketamine are promising developments for the treatment of depression. Nevertheless, racemic ketamine and (S)-ketamine are controlled substances with known abuse potential and their use is associated with undesirable side effects. For these reasons, research efforts have focused on identifying alternatives. One candidate is (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), a ketamine metabolite that in preclinical models lacks the dissociative and abuse properties of ketamine while retaining its antidepressant-like behavioral efficacy. (2R,6R)-HNK's mechanism of action however is unclear. The main goals of this study were to perform an in-depth pharmacological characterization of (2R,6R)-HNK at known ketamine targets, to use target deconvolution approaches to discover novel proteins that bind to (2R,6R)-HNK, and to characterize the biodistribution and behavioral effects of (2R,6R)-HNK across several procedures related to substance use disorder liability. We found that unlike (S)- or (R)-ketamine, (2R,6R)-HNK did not directly bind to any known or proposed ketamine targets. Extensive screening and target deconvolution experiments at thousands of human proteins did not identify any other direct (2R,6R)-HNK-protein interactions. Biodistribution studies using radiolabeled (2R,6R)-HNK revealed non-selective brain regional enrichment, and no specific binding in any organ other than the liver. (2R,6R)-HNK was inactive in conditioned place preference, open-field locomotor activity, and intravenous self-administration procedures. Despite these negative findings, (2R,6R)-HNK produced a reduction in immobility time in the forced swim test and a small but significant increase in metabolic activity across a network of brain regions, and this metabolic signature differed from the brain metabolic profile induced by ketamine enantiomers. In sum, our results indicate that (2R,6R)-HNK does not share pharmacological or behavioral profile similarities with ketamine or its enantiomers. However, it could still be possible that both ketamine and (2R,6R)-HNK exert antidepressant-like efficacy through a common and previously unidentified mechanism. Given its pharmacological profile, we predict that (2R,6R)-HNK will exhibit a favorable safety profile in clinical trials, and we must wait for clinical studies to determine its antidepressant efficacy.
Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications. [2023]Hydroxynorketamines (HNKs) are formed in vivo after (R,S)-ketamine (ketamine) administration. The 12 HNK stereoisomers are distinguished by the position of cyclohexyl ring hydroxylation (at the 4, 5, or 6 position) and their unique stereochemistry at two stereocenters. Although HNKs were initially classified as inactive metabolites because of their lack of anesthetic effects, more recent studies have begun to reveal their biologic activities. In particular, (2R,6R)- and (2S 6)-HNK exert antidepressant-relevant behavioral and physiologic effects in preclinical models, which led to a rapid increase in studies seeking to clarify the mechanisms by which HNKs exert their pharmacological effects. To date, the majority of HNK research has focused on the actions of (2R,6R)-HNK because of its robust behavioral actions in tests of antidepressant effectiveness and its limited adverse effects. This review describes HNK pharmacokinetics and pharmacodynamics, as well as the putative cellular, molecular, and synaptic mechanisms thought to underlie their behavioral effects, both following their metabolism from ketamine and after direct administration in preclinical studies. Converging preclinical evidence indicates that HNKs modulate glutamatergic neurotransmission and downstream signaling pathways in several brain regions, including the hippocampus and prefrontal cortex. Effects on other neurotransmitter systems, as well as possible effects on neurotrophic and inflammatory processes, and energy metabolism, are also discussed. Additionally, the behavioral effects of HNKs and possible therapeutic applications are described, including the treatment of unipolar and bipolar depression, post-traumatic stress disorder, chronic pain, neuroinflammation, and other anti-inflammatory and analgesic uses. SIGNIFICANCE STATEMENT: Preclinical studies indicate that hydroxynorketamines (HNKs) exert antidepressant-relevant behavioral actions and may also have analgesic, anti-inflammatory, and other physiological effects that are relevant for the treatment of a variety of human diseases. This review details the pharmacokinetics and pharmacodynamics of the HNKs, as well as their behavioral actions, putative mechanisms of action, and potential therapeutic applications.
Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine. [2021]Label="BACKGROUND">(R,S)-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, (2R,6R)-hydroxynorketamine, exerts rapid antidepressant effects, without ketamine's adverse effects and abuse potential, in rodents.
Hydroxynorketamine Blocks N-Methyl-d-Aspartate Receptor Currents by Binding to Closed Receptors. [2023]Ketamine, a dissociative anesthetic, is experiencing a clinical resurgence as a fast-acting antidepressant. In the central nervous system, ketamine acts primarily by blocking NMDA receptor currents. Although it is generally safe in a clinical setting, it can be addictive, and several of its derivatives are being investigated as preferable alternatives. 2R,6R-Hydroxynorketamine (HNK), a ketamine metabolite, reproduces some of the therapeutic effects of ketamine and appears to lack abuse liability. Here, we report a systematic investigation of the effects of HNK on macroscopic responses elicited from recombinant NMDA receptors expressed in human embryonic kidney 293 cells. We found that, like ketamine, HNK reduced NMDA receptor currents in a dose-, pH-, and voltage-dependent manner. Relative to ketamine, it had 100-fold-lower potency (46 µM at pH 7.2), 10-fold-slower inhibition onset, slower apparent dissociation rate, weaker voltage dependence, and complete competition by magnesium. Notably, HNK inhibition was fully effective when applied to resting receptors. These results revealed unexpected properties of hydroxynorketamine that warrant its further investigation as a possible therapeutic in pathologies associated with NMDA receptor dysfunction. SIGNIFICANCE STATEMENT: NMDA receptors are excitatory ion channels with fundamental roles in synaptic transmission and plasticity, and their dysfunction associates with severe neuropsychiatric disorders. 2R,6R-Hydroxynorketamine, a metabolite of ketamine, mimics some of the neuroactive properties of ketamine and may lack its abuse liability. Results show that 2R,6R-hydroxynorketamine blocks NMDA receptor currents with low affinity and weak voltage dependence and is effective when applied to resting receptors. These properties highlight its effectiveness to a subset of NMDA receptor responses and recommend it for further investigation.
Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors. [2021]Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1st-generation (reversible) EGFR TKI and later the 2nd -generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI.
NTRK fusion-positive cancers and TRK inhibitor therapy. [2021]NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.
Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence. [2019]In the era of personalized medicine, the identification of targetable genetic alterations represented a major step forward in anticancer therapy. NTRK rearrangements represent the molecular driver of a subset of solid tumors, including 3% of non-small-cell lung cancers (NSCLCs). Preliminary data indicate that molecularly selected NSCLC patients harboring NTRK fusions derive an unprecedented clinical benefit from Trk-directed targeted therapies. The aim of this review is to describe the molecular biology of NTRK signaling pathway and to summarize the preclinical data on novel Trk inhibitors, touching upon the clinical development of these inhibitors for the treatment of advanced NSCLC, which have already shown encouraging anticancer activity and acceptable safety profile in early phase I clinical trials.
Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants. [2021]Due to the critical tumorigenic role of fused NTRK genes in multiple cancers, TRK kinases have attracted extensive attention as a drug discovery target. Starting from an indazole based scaffold, through the type II kinase inhibitor fragments hybrid design approach with a ring closure strategy, we discovered a novel potent type II TRK kinase inhibitor compound 34 (IHMT-TRK-284), which exhibited IC50 values of 10.5 nM, 0.7 nM and 2.6 nM to TRKA, B, and C respectively. In addition, it displayed great selectivity profile in the kinome when tested among 468 kinases and mutants (S score (1) = 0.02 at 1 μM). Importantly, 34 could overcome drug resistant mutants including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region. In vivo, 34 exhibited good PK profiles in different species including mice, rats, and dogs. It also displayed good in vivo antitumor efficacies in the TRKA/B/C, TRKA mutants, and KM-12-LUC cells mediated mouse models. The potent activity against clinically important TRK mutants combined with the good in vivo PK and efficacy properties of 34 indicated that it might be a new potential therapeutic candidate for TRK kinase fusion or mutants driven cancers.
Identification of harmine and β-carboline analogs from a high-throughput screen of an approved drug collection; profiling as differential inhibitors of DYRK1A and monoamine oxidase A and for in vitro and in vivo anti-cancer studies. [2023]DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1a) is highly expressed in glioma, an aggressive brain tumor, and has been proposed as a therapeutic target for cancer. In the current study, we have used an optimized and validated time-resolved fluorescence energy transfer (TR-FRET)-based DYRK1A assay for high-throughput screening (HTS) in 384-well format. A small-scale screen of the FDA-approved Prestwick drug collection identified the β-carboline, harmine, and four related analogs as DYRK1A inhibitors. Hits were confirmed by dose response and in an orthogonal DYRK1A assay. Harmine's potential therapeutic use has been hampered by its off-target activity for monoamine oxidase A (MAO-A) which impacts multiple nervous system targets. Selectivity profiling of harmine and a broader collection of analogs allowed us to map some divergent SAR (structure-activity relationships) for the DYRK1A and MAO-A activities. The panel of harmine analogs had varying activities in vitro in glioblastoma (GBM) cell lines when tested for anti-proliferative effects using a high content imaging assay. In particular, of the identified analogs, harmol was found to have the best selectivity for DYRK1A over MAO-A and, when tested in a glioma tumor xenograft model, harmol demonstrated a better therapeutic window compared to harmine.