Open Study of the Neurobiological Effects of Intranasal Ketamine in Children and Adults With Bipolar Disorder

• Conditions: Bipolar Disorder
• Interventions: Drug: Ketamine

• Registration Number: NCT05209217
• Lead Sponsor: Mclean Hospital

Brief Summary

Aim 1: Test the hypothesis that participants with Bipolar Disorder - Fear of Harm Phenotype have an enhanced amygdala fMRI response to fearful threatening stimuli, increased resting beta and gamma EEG spectral activity in temporal leads and blunted posterior insula response to cold when partially withdrawn from ketamine with normalization of these responses following intranasal administration of ketamine.

Aim 2. Test the hypothesis that ketamine alters response to fearful-threatening visual stimuli and cold sensation by altering functional connectivity of the amygdala and insula with the hypothalamus, thalamus, hippocampus and ventromedial prefrontal cortex, and identify specific alterations that correlate with degree of pre-post ketamine change.

Aim 3. Test the hypothesis that low-dose medicinal ketamine, unlike high-dose recreation ketamine, is not associated with an increase in number of focal areas of abnormality on morphometric scans based on duration of use.

Detailed Description

Clinically, the Fear of Harm phenotype is characterized by early age of onset, severe mood swings, treatment resistance, separation anxiety, fearful-aggressive obsessions, parasomnias (e.g. night-terrors) and thermal dysregulation (Papolos et al. 2009). These youth typically received little benefit from standard treatments (i.e., antipsychotic medication and mood stabilizers) often wind up home-schooled due to excessive fears of the school environment and frequently require multiple periods of inpatient care (Papolos et al. 2009; Papolos et al. 2013). Key features seen in FOH that distinguish these youths from other youths with BD include fear sensitization and thermal dysregulation. Children with FOH often experience thermal discomfort (e.g., feeling hot, excessive sweating) in neutral ambient temperature conditions, as well as no discomfort during exposure to the cold, and alternate noticeably between being excessively hot in the evening and cold in the morning (Murphy, Frei, and Papolos 2014). Ketamine, an NMDA receptor antagonist was selected as a potential treatment for FOH because of its effectiveness in the reduction of fear sensitization and capacity to dose-dependently lower body temperature in animal studies, and has been found to be clinically efficacious in the treatment of FOH (Papolos et al. 2018; Papolos et al. 2013). There are two main reasons for proposing to conduct a neuroimaging study. First, intranasal ketamine can produce an almost immediate improvement in clinical state. This makes it possible to scan a subject whose dose of ketamine has largely worn off in order to assess blood flow and functional connectivity and then to rescan the individual within hours of receiving intranasal ketamine in order to correlate degree of clinical improvement with alterations in blood flow and connectivity. This will provide information on both the neurobiological basis of ketamine response and information on the possible biological underpinnings of FOH. Second, there is some concern, based on a report of examining brain scans in chronic ketamine abusers, that ketamine in daily doses 10X higher than clinically prescribed every 3-4 days can produce some evidence for structural brain damage4. Hence, it would be valuable to scan individuals undergoing long term treatment with intranasal ketamine to rule out or monitor for pathological changes in brain structure.

Study Timeline

• Study First Submitted: 2018-10-26
• Study Start: 2019-06-04
• Status Verified: 2022-01
• Study First Submitted QC: 2022-01-25
• Study First Posted: 2022-01-26
• Last Update Submitted: 2022-01-26
• Last Update Posted: 2022-01-27
• Primary Completion: 2022-12-31
• Study Completion: 2023-01-15

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Males and Females
• Age 14 - 40 years
• Clinical diagnosis of Bipolar Disorder -Fear of Harm Phenotype
• Meets Papolos criteria for FOH based on independent interviews.
• Taking intranasal ketamine for at least 2 months.
• Must be on an every three or every four-day dosing regimen
• Dosage will not exceed 300 mg per dosing interval.
• Willing to delay ketamine dose by 2 days past their prescribed dosing interval
• Prior experience having tolerated this degree of delay.
• Willing to participate in daily assessments during period of ketamine withdrawal prior to traveling to Belmont ,MA.
• Willing to provide urine sample to screen for drugs of abuse (all participants and pregnancy in females.)

Exclusion Criteria

• Any psychiatric hospitalization within the past 6 months
• Lifetime history of suicide attempts
• Co-occurring substance use disorders
• Any change in concomitant medications within the last 2 months

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Participant Group	Ketamine	Participants will all have history of good to excellent clinical response to intranasal ketamine for at least two months and on a treatment schedule varying from use every other day to every fifth day. Participants will be tested one or two days beyond their customary administration date and again 2-3 hours after their administration of ketamine.

Primary Outcome Measures

Name	Time	Method
BOLD fMRI response in amygdala	Prior to and 2-3 hours following ketamine administration	Change in BOLD measured by functional Magnetic Resonance Imaging (fMRI) to images of threatening versus neutral facial expressions.
BOLD fMRI response in posterior insula	Prior to and 2-3 hours following ketamine administration	Correlation between BOLD measured by functional Magnetic Resonance Imaging (fMRI) and degree of cold stimulation of non-dominant hand.

Secondary Outcome Measures

Name	Time	Method
Profile of Mood State (POMS) scale.	Prior to and 2-3 hours following ketamine administration	Ratings of tension and total mood score on the POMS.
Functional connectivity between amygdala and insula	Prior to and 2-3 hours following ketamine administration	Seed-to-seed and seed-to-voxel functional connectivity analysis of rs-fMRI data.
EEG spectral activity measures	Prior to and 2-3 hours following ketamine administration	Absolute and relative power in low beta (15-26), high beta (28-40), low gamma (42-53) and high gamma (55-67) frequency bands using 32-channel Electrical Geodesics, Inc. EEG.

Trial Locations

Locations (1)

McLean Hospital; 🇺🇸 Belmont, Massachusetts, United States