Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus

• ClinicalTrials.gov Identifier: NCT03336398
• Recruitment Status: Recruiting
• First Posted: November 8, 2017
• Last Update Posted: June 1, 2023
• Sponsor: New York State Psychiatric Institute
• Information provided by (Responsible Party): Diana Martinez, New York State Psychiatric Institute

Study Description

Brief Summary:

Tinnitus, or ringing in the ears, is a very common problem that often accompanies hearing loss. It affects up to 1 in 10 adults, and about 30% of people who experience chronic tinnitus find it very distressing. In these patients, symptoms of depression and anxiety often accompany tinnitus and there are no approved treatments. Clinical trials are ongoing to test a glutamate NMDA receptor antagonist (called esketamine), which is injected into the inner ear. However, the preliminary results with this medication show that it only works for tinnitus that results from acute injury. It does not treat tinnitus resulting from progressive hearing loss.

Research in humans and animals suggest that the neurotransmitters glutamate and GABA are important in the development and maintenance of tinnitus. This data shows that over-activation of the NMDA receptor and a decrease in GABA signaling in the brain play a crucial role. Previous studies show that ketamine, which an antagonist at the NMDA receptor, increases GABA levels in the brain in participants with depression. Thus, in this experiment, this study will test the effect of ketamine on tinnitus, since it blocks the NMDA glutamate receptor and increase GABA levels.

Two groups of participants will be included in this study: those who experience distress (symptoms of anxiety or depression) with tinnitus and those who have tinnitus but do not experience distress. Each participant will receive both ketamine and placebo on different days. Magnetic Resonance Spectroscopy (MRS) scans will be

Condition or disease	Intervention/treatment	Phase
Tinnitus	Drug: Ketamine Hydrochloride in saline; Drug: Saline	Phase 2

Detailed Description:

Tinnitus has a prevalence of approximately 1 in 10 adults in the United States. Among those with tinnitus, 36% had nearly constant symptoms and almost 30% of those report that their tinnitus as a big or a very big problem. Currently there are few effective treatments for tinnitus, and no approved medications. Cognitive behavioral and retraining therapy provide some relief, but many patients fail to respond.

Animal research and human studies indicate that maladaptive plasticity plays a role in tinnitus, which involves glutamatergic signaling largely at the NMDA and AMPA receptors. Additionally, GABA signaling has been shown to be impaired in tinnitus. Rodent models show a diminished sensitivity to GABA signaling and human magnetic resonance spectroscopy (MRS) studies show decreased GABA levels in the auditory cortex.

Ketamine is a non-competitive NMDA receptor antagonist that has also been shown to activate AMPA receptors, and modulates ongoing plasticity. Additionally, ketamine activates a subpopulation of cortical GABAergic interneurons and projection neurons and increases GABA levels in the human brain, measured with MRS. Ketamine is FDA approved as an anesthetic, and recent work has demonstrated its efficacy in treating refractory depression and chronic pain. Importantly, these demonstrate that low dose ketamine, at doses lower than those required for anesthesia, are effective in lifting depressed mood and improving the sensation of chronic pain.

For many, tinnitus has an important affective component to it, with distress and co-morbid symptoms of depression and anxiety. The onset and severity of tinnitus can correlate with stressful events, and it has been posited that stress lowers the threshold of perception, and unmasks tinnitus. Tinnitus then triggers more anxiety and depressed mood, which in turn reinforces the symptoms. An advantage of ketamine may be its effect on depression and anxiety, in addition to tinnitus, to interrupt this cycle.

The goal of this study is to perform a proof-of-concept preliminary study of ketamine in tinnitus associated with sensori-neural hearing loss. This will be studied both in participants who report depressed mood and anxiety and those who do not. MRS imaging will be used to assess ketamine-induced changes in GABA in the auditory cortex.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus
• Actual Study Start Date: September 1, 2019
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tinnitus Distressed Patients; Tinnitus distressed patients are patients who experience symptoms of anxiety or depression with tinnitus. This group will receive both 0.5 mg/kg ketamine hydrochloride in saline and placebo, saline, with Magnetic Resonance Spectroscopy scans and audiometry testing and scales.	Drug: Ketamine Hydrochloride in saline; 0.5 mg/kg IV of ketamine hydrochloride in saline will be administered with one of the MRS Scan; Other Name: Ketamine HCI; Drug: Saline; Saline will be administered with the other MRS scan; Other Name: Saline solution
Experimental: Tinnitus Patients; Tinnitus patients are patients who do not experience symptoms of anxiety or depression with tinnitus. This group will receive both 0.5 mg/kg ketamine hydrochloride in saline and placebo, saline, with Magnetic Resonance Spectroscopy scans and audiometry testing and scales.	Drug: Ketamine Hydrochloride in saline; 0.5 mg/kg IV of ketamine hydrochloride in saline will be administered with one of the MRS Scan; Other Name: Ketamine HCI; Drug: Saline; Saline will be administered with the other MRS scan; Other Name: Saline solution

Outcome Measures

Primary Outcome Measures :

1. Change in GABA and Glutamate (Glx) levels in the auditory cortex derived from 3T Magnetic Resonance Spectroscopy [ Time Frame: during ketamine and placebo MRS scans ]
   The GABA and Glx peaks will be quantified as ratios

Secondary Outcome Measures :

1. Change in The Brief Psychiatric Rating Scale (BPRS) [ Time Frame: Baseline, at the end of MRS scan, 110 minutes after ketamine or placebo infusion ]
   The Brief Psychiatric Rating Scale (BPRS) is a rating scale used by a clinician to measure psychiatric symptoms. The scores range from a minimum 16 to maximum of 112. Higher scores indicate a more severe disorder.
2. Change in The Tinnitus Handicap Inventory (THI) [ Time Frame: screening, pre and post ketamine and placebo sessions ]
   The Tinnitus Handicap Inventory is a self-administered test to determine the degree of distress in tinnitus patients. Scores range from 0 to 100 with higher scores indicating a greater degree of distress from tinnitus.
3. Change in Visual Analogue Scale (VAS) [ Time Frame: screening, pre and post ketamine and placebo sessions, then daily ]

   Visual Analogue Scale (VAS) is a scale that consists of a straight line with gradients from 0 (no tinnitus) to 10 (severe tinnitus).

   (maximal experience of tinnitus)

4. Change in the Beck Depression Inventory (BDI) Depression Inventory (BDI) [ Time Frame: screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions ]
   The Beck Depression Inventory (BDI) is a multiple choice inventory for depression
5. Change in Profile of Mood States (POMS) [ Time Frame: screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions ]
   The Profile of Mood States (POMS) is used to assess mood states.

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Participant aged 21-60
• Tinnitus associated with at least mild sensori-neural hearing loss of at least 6 months duration
• Score at least 32 on the Tinnitus Handicap Inventory and a score of 5dB or greater on the minimum masking level
• Tinnitus not due to medical disease (other than sensorineural hearing loss)
• Score of at least 14 on the Hamilton Depression Rating Scales with a score of at least 2 on the Hamilton Anxiety Rating Scale (in the distressed group).

Exclusion Criteria:

• DSM-V psychiatric disorders other than mild-moderate depression and anxiety, including substance use disorder.
• History of recreational ketamine use, recreational PCP use,exposure to ketamine as an anesthetic, or an adverse reaction to ketamine
• Currently taking psychotropic medication (e.g.antipsychotics, antidepressants, benzodiazepines)
• Presence or positive history of significant medical or neurological illness, including high blood pressure (SBP >140, DBP > 90), cardiac illness, abnormality on EKG, head injury.
• Pregnancy, abortion, or lack of effective birth control during 15 days before the scan
• Metal implants, pacemaker, other metal (e.g. shrapnel or surgical prostheses) or paramagnetic objects contained within the
• Medicinal patch that cannot be removed for the scans.

Contacts and Locations

Contacts

Contact: Diana Martinez, MD; 646-774-6160; dm437@cumc.columbia.edu

Locations

United States, New York

1051 Riverside Drive; Recruiting

New York, New York, United States, 10032

Principal Investigator: Diana Martinez, M.D.

Sponsors and Collaborators

New York State Psychiatric Institute

Investigators

• Principal Investigator: Diana Martinez; NYSPI/Columbia University

More Information

• Responsible Party: Diana Martinez, Medical Doctor, New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT03336398
• Other Study ID Numbers: 7432
• First Posted: November 8, 2017
• Last Update Posted: June 1, 2023
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Tinnitus; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action