HNK for Treatment-Resistant Depression

Overseen By Solaleh Azimipour

Age: 18+

Sex: Any

Trial Phase: Phase 2

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 All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 8

50 Participants Needed

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. ...

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. ^{1 2 3 4 5}

Is (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. ^{5 6 7 8 9}

What 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. ^{10 11 12 13 14}

Research Team

Carlos A Zarate, M.D.

Principal Investigator

National Institute of Mental Health (NIMH)

Eligibility 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.

Exclusion Criteria

Contraindications to MRS (metal in body, claustrophobia, etc. for imaging).

Inability to read and understand English.

My thyroid condition is not stable.

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

Treatment Details

Interventions

• (2R,6R)-hydroxynorketamine

Trial Overview (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.

Participant Groups

Group I: 2 Experimental Treatment 2 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: 1 Experimental Treatment 2 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.

Who Is Running the Clinical Trial?

National Institute of Mental Health (NIMH)

Lead Sponsor

Trials

3,007

Recruited

2,852,000+

Findings from Research

In a study of 53 depressed adults with suicidal thoughts, higher levels of the ketamine metabolite (2R,6R)-HNK were linked to less improvement in depression and suicidal ideation after treatment, suggesting a complex relationship between this metabolite and clinical outcomes.

Ketamine itself and other metabolites like norketamine did not show a significant association with changes in depression or suicidal thoughts, indicating that the efficacy of ketamine may not solely depend on these metabolites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine metabolite pilot study in a suicidal depression trial. Grunebaum, MF., Galfalvy, HC., Choo, TH., et al.[2023]

Intracerebroventricular (i.c.v.) infusion of (R)-ketamine produced rapid and long-lasting antidepressant effects in a chronic social defeat stress model, lasting up to 7 days.

In contrast, (2R,6R)-hydroxynorketamine (HNK) did not demonstrate any antidepressant effects despite higher brain concentrations compared to (R)-ketamine, suggesting that (2R,6R)-HNK is not essential for the antidepressant actions of (R)-ketamine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of metabolism in (R)-ketamine's antidepressant actions in a chronic social defeat stress model. Zhang, K., Fujita, Y., Hashimoto, K.[2019]

In a study of 223 patients with treatment-resistant depression, those treated with esketamine nasal spray combined with an oral antidepressant showed significantly better health-related quality of life (HRQoL) and functioning compared to those receiving a placebo nasal spray with an antidepressant.

At Day 28, patients in the esketamine group reported less impairment across various health dimensions, including mobility and anxiety, and demonstrated greater improvements in health status and daily functioning, indicating esketamine's efficacy in enhancing overall well-being in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Jamieson, C., Popova, V., Daly, E., et al.[2023]

Approximately 30% of patients with depression experience treatment-resistant depression, which worsens with each episode and significantly impacts quality of life.

Ketamine, a rapid-acting antidepressant with neuroplastic effects, may serve as an effective add-on treatment for resistant major depressive disorder, potentially reversing treatment resistance and improving patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine. Wilkowska, A., Cubała, WJ.[2022]

(2R,6R)-HNK, a metabolite of ketamine, does not impair spatial working memory (SWM) in mice, unlike ketamine, which at a higher dose (32 mg/kg) significantly reduces SWM performance.

Both single and repeated doses of (2R,6R)-HNK alter the intrinsic properties of neurons in the midline thalamic nucleus but do not lead to cognitive deficits, suggesting it may be a safer alternative for treating treatment-resistant depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of subanesthetic ketamine and (2R,6R) hydroxynorketamine on working memory and synaptic transmission in the nucleus reuniens in mice. Goswamee, P., Rice, R., Leggett, E., et al.[2023]

(2R,6R)-hydroxynorketamine (HNK) is a promising ketamine metabolite that shows antidepressant-like effects without the dissociative and abuse potential associated with racemic ketamine and (S)-ketamine, as demonstrated through various behavioral tests.

Despite not binding to known ketamine targets or showing addictive properties in preclinical models, (2R,6R)-HNK produced a significant reduction in immobility in the forced swim test, suggesting it may have a unique mechanism of action that warrants further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search. Bonaventura, J., Gomez, JL., Carlton, ML., et al.[2023]

Hydroxynorketamines (HNKs), metabolites of ketamine, have been found to exert significant antidepressant effects in preclinical models, particularly (2R,6R)-HNK, which shows robust behavioral actions and limited side effects.

HNKs appear to work by modulating glutamatergic neurotransmission and influencing various brain regions, suggesting potential therapeutic applications for conditions like depression, PTSD, and chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications. Highland, JN., Zanos, P., Riggs, LM., et al.[2023]

(2R,6R)-hydroxynorketamine shows promising oral bioavailability, ranging from 42% to 58% across species (mice, rats, and dogs), making it a viable candidate for oral antidepressant treatment.

In mouse models, (2R,6R)-hydroxynorketamine effectively reduced depressive behaviors without causing adverse effects, indicating its potential as a safer alternative to ketamine for treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine. Highland, JN., Morris, PJ., Zanos, P., et al.[2021]

2R,6R-Hydroxynorketamine (HNK), a metabolite of ketamine, shows potential as a fast-acting antidepressant by blocking NMDA receptor currents, similar to ketamine but with lower potency and slower action.

HNK appears to lack the addictive properties associated with ketamine, making it a promising candidate for further research in treating neuropsychiatric disorders linked to NMDA receptor dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hydroxynorketamine Blocks N-Methyl-d-Aspartate Receptor Currents by Binding to Closed Receptors. Abbott, JA., Popescu, GK.[2023]

The EGFR p.T790M mutation is the primary mechanism of acquired resistance in patients treated with both reversible and irreversible EGFR tyrosine kinase inhibitors (TKIs), based on a study of 123 rebiopsy samples from patients who had progressed after at least 6 months of therapy.

Patients treated with irreversible EGFR TKI Afatinib had a lower rate of developing the T790M mutation (45%) compared to those treated with reversible TKIs (65%), suggesting that the type of TKI used may influence resistance development and could impact clinical treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors. Wagener-Ryczek, S., Heydt, C., Süptitz, J., et al.[2021]

NTRK gene fusions are significant drivers of various tumors, and first-generation TRK inhibitors like larotrectinib and entrectinib show over 75% response rates in treating NTRK fusion-positive cancers, regardless of tumor type.

While first-generation TRK inhibitors are generally well tolerated, resistance can develop in advanced cases, but second-generation TRK inhibitors like LOXO-195 and TPX-0005 may effectively target these resistant mutations, offering hope for continued treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NTRK fusion-positive cancers and TRK inhibitor therapy. Cocco, E., Scaltriti, M., Drilon, A.[2021]

NTRK rearrangements are found in about 3% of non-small-cell lung cancers (NSCLCs) and are key drivers of these tumors, making them important targets for personalized cancer therapy.

Early phase I clinical trials of Trk-directed targeted therapies for NSCLC patients with NTRK fusions have shown promising anticancer activity and an acceptable safety profile, indicating potential for effective treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence. Ricciuti, B., Brambilla, M., Metro, G., et al.[2019]

A novel TRK kinase inhibitor, compound 34 (IHMT-TRK-284), was developed with impressive potency, showing IC50 values of 10.5 nM, 0.7 nM, and 2.6 nM against TRKA, B, and C respectively, indicating strong potential for treating cancers driven by fused NTRK genes.

This compound demonstrated the ability to overcome drug-resistant mutations and showed good pharmacokinetic profiles and antitumor efficacy in various animal models, suggesting it could be a promising new treatment for TRK fusion or mutant-driven cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Wang, B., Zhang, W., Liu, X., et al.[2021]

The study identified harmine and its analogs as inhibitors of DYRK1A, a promising target for treating glioma, through a high-throughput screening of FDA-approved drugs.

Among the tested compounds, harmol showed the best selectivity for DYRK1A over the off-target enzyme MAO-A and demonstrated improved therapeutic effects in a glioma tumor model compared to harmine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Tarpley, M., Oladapo, HO., Strepay, D., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Ketamine metabolite pilot study in a suicidal depression trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Lack of metabolism in (R)-ketamine's antidepressant actions in a chronic social defeat stress model. [2019]

3. England pubmed.ncbi.nlm.nih.gov

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]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The Downstaging Concept in Treatment-Resistant Depression: Spotlight on Ketamine. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Effects of subanesthetic ketamine and (2R,6R) hydroxynorketamine on working memory and synaptic transmission in the nucleus reuniens in mice. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Hydroxynorketamine Blocks N-Methyl-d-Aspartate Receptor Currents by Binding to Closed Receptors. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors. [2021]

11. England pubmed.ncbi.nlm.nih.gov

NTRK fusion-positive cancers and TRK inhibitor therapy. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Targeting NTRK fusion in non-small cell lung cancer: rationale and clinical evidence. [2019]

13. France pubmed.ncbi.nlm.nih.gov

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]

14. Netherlands pubmed.ncbi.nlm.nih.gov

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]