Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus

Tinnitus Clinical Trial

Official title:

Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03336398
• Other study ID #: 7432
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 1, 2019
• Est. completion date: December 2025

Study information

• Verified date: August 2023
• Source: New York State Psychiatric Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 42
• Est. completion date: December 2025
• Est. primary completion date: June 17, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Tinnitus

Intervention

Drug:
• Ketamine Hydrochloride in saline
0.5 mg/kg IV of ketamine hydrochloride in saline will be administered with one of the MRS Scan
• Saline
Saline will be administered with the other MRS scan

Locations

Country	Name	City	State
United States	1051 Riverside Drive	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
New York State Psychiatric Institute

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in GABA and Glutamate (Glx) levels in the auditory cortex derived from 3T Magnetic Resonance Spectroscopy	The GABA and Glx peaks will be quantified as ratios	during ketamine and placebo MRS scans
Secondary	Change in The Brief Psychiatric Rating Scale (BPRS)	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.	Baseline, at the end of MRS scan, 110 minutes after ketamine or placebo infusion
Secondary	Change in The Tinnitus Handicap Inventory (THI)	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.	screening, pre and post ketamine and placebo sessions
Secondary	Change in Visual Analogue Scale (VAS)	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)	screening, pre and post ketamine and placebo sessions, then daily
Secondary	Change in the Beck Depression Inventory (BDI) Depression Inventory (BDI)	The Beck Depression Inventory (BDI) is a multiple choice inventory for depression	screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions
Secondary	Change in Profile of Mood States (POMS)	The Profile of Mood States (POMS) is used to assess mood states.	screening, pre and post ketamine and placebo sessions, daily for 10 days after the sessions