Thermoregulatory Fear of Harm Mood Disorder: In Depth Exploration of a Unique Juvenile-Onset Phenotype That Provides a Parsimonious Clinical Description of Certain Youths with Highly Comorbid Treatment Refractory Psychiatric Disorders

Demitri F Papolos ,Steven Mattis ,Herbert M Lachman ,Martin H Teicher

doi:10.20900/jpbs.20190004

Abstract

Among aggressive youths with severe mood lability who frequently fail to benefit from mood stabilizers and antipsychotics there is a discrete subtype called ‘Thermoregulatory Fear of Harm Mood Disorder’ (FOH). This disorder is characterized by an underlying thermoregulatory deficit, a specific prodromal sequence and a unique constellation of symptoms. The underlying problem appears to be a deficit in thermoregulation resulting in excessive heat that manifests as thermal discomfort in neutral ambient temperatures and moderate to extreme cold tolerance, and produces REM sleep-related problems and parasomnias, such as night-terrors and hypnogogic hallucinations. Clinically, FOH is associated with the advent in childhood of frequent, recurrent, vivid nightmares with themes of pursuit and abandonment. The apparent psychological sequelae of exposure to this frightening imagery is fear sensitization and auto-traumatization. A developmental sequence of fear based defensive behaviors arises and includes obsessive bedtime rituals, fear of the dark, separation anxiety, contamination fears, hypervigilance, perfectionism, misperception of neutral stimuli as threatening, as well as reactive aggression in response to limit setting and perceived threat or loss. Ketamine, chosen as a potential treatment because of its effectiveness in reducing fear sensitization and dose-dependent lowering of body temperature in preclinical studies, has been associated with sustained improvement in otherwise refractory youths. We present a detailed description of this heritable disorder, link its clinical features to a potential disturbance in brain derived neurotropic factor (BDNF) and orexin, and indicate how ketamine rapidly affects BDNF through multiple mechanisms, to produce a dramatic beneficial response in youths with this disorder

Highlights

We present a detailed description of this heritable disorder, link its clinical features to a potential disturbance in brain derived neurotropic factor (BDNF) and orexin, and indicate how ketamine rapidly affects BDNF through multiple mechanisms, to produce a dramatic beneficial response in youths with this disorder
These individuals experience intense fears related to abandonment, loss, injury and death, engage in aggressive behaviors directed toward self or others, undergo intense mood fluctuations, frequently require hospitalization and generally fail to respond to anxiolytics, antipsychotics, and mood stabilizers alone, but may experience sustained benefits from intranasal ketamine when combined with lithium salts
We recently reported in a detailed assessment of individuals receiving extended treatment with intranasal ketamine for Fear of Harm Mood Disorder (FOH), that these individuals were currently taking an average of 3 psychotropic medications prior to ketamine [4]

Summary

INTRODUCTION

We consider this thermoregulatory deficit a potential biomarker for FOH with possible causal implications These findings are consistent with our hypothesis that alterations in neural processes that underlie thermal regulation sets the stage for the development of sleep disorders, fear sensitization and poor modulation of aggression and other survival-based behaviors that are the manifest phenotypic features of FOH. Specific epigenetic modifications to Bdnf promoters during this critical period serve to regulate the emerging balance between warm and cold sensitive neurons in this region [48] These warmsensitive neurons (WSNs) within the mammalian preoptic hypothalamus function to orchestrate the homeostatic response to heat [51] as their optogenetic excitation triggers rapid hypothermia, mediated by reciprocal changes in heat production and heat dissipation, as well as dramatic cold-seeking behavior [51]. We suspect that FOH may represent a cluster of highly similar ketamine-responsive disorders involving a primary disturbance in either orx/hcrt or BDNF, though this remains to be determined

DISCUSSION

Findings

CONFLICTS OF INTEREST