Preliminary Data on the Effects of Intranasal Ketamine on Cold Thermal Sensitivity and fMRI Response to Threat in Individuals with Fear of Harm Phenotype of Bipolar Disorder

Kyoko Ohashi, PhD

McLean Hospital – Faculty

Scientific Abstract

Background: The Fear of Harm (FOH) bipolar phenotype is characterized by early onset, severe mood swings, fearful-aggressive obsessions, insensitivity to cold, heat intolerance and extreme anxiety. Patients are typically resistant to standard treatments but are often responsive to ketamine. We hypothesized that patients with FOH misinterpret neutral stimuli as threatening, and physiologically insensitive to cool temperatures, and that these deficits would be normalized following ketamine.

Methods: Participants were 8 (4M/3F/1T, 22.5±4.1 years) individuals with FOH who had an excellent long-term response to intranasal ketamine administered 2-3 times per week. We measured fMRI response to subliminal (17 ms) and supraliminal (500 ms) fearful, neutral and happy faces and response in the insula to 6 different temperatures (20, 24, 26, 28, 30, 33°C) on their palm. Participants were tested after they had been withdrawn from ketamine and again 2 hours post administration. 

Results: Off ketamine there were no differences in response to supraliminal fearful versus neutral faces in amygdala, insula or inferior frontal gyrus (IFG). Following ketamine fearful > neutral responses were observed in these regions. Off ketamine subliminal fearful faces activated the insula, IFG, dorsal anterior cingulate and ventromedial prefrontal cortex. This response was lost following ketamine. In addition, there was no association between palm temperature and BOLD activity in the insula off ketamine but there was the expected linear association between cold stimulation and insula activity after ketamine.

Conclusions: Off ketamine it appeared that individuals with FOH found neutral faces to be as neurobiologically threatening as fearful faces, which fits clinically with their strong tendency to misperceive people or events as threatening. Ketamine appeared to normalize response so that neutral faces produced less activation than fearful faces and also markedly reduce BOLD response to fearful subliminal faces. Ketamine also appeared to restore their ability to detect varying degree of non-noxious cold. These findings are consistent with the marked improvement they experienced on ketamine.

Live Zoom Session – March 9th

research Areas


Kyoko Ohashi, PhD, Elizabeth A. Bolger, Alaptagin Khan, MBSS, Cynthia E. McGreenery, Martin H. Teicher, MD, PhD

Principal Investigator

Martin H. Teicher, MD, PhD

Affiliated Website