Progression: From Trait to Treatment

An Important Trait

Before getting started, we would like to acknowledge that the use of the phrase “fear of harm” gets a little confusing.  To simplify this,

  • when we discuss it as a trait, it will be written as fear-of-harm.
  • and when we refer to the phenotype for which it became the basis (click here to read the definition for phenotype), it will be written as Fear of Harm or FOH.

Investigators first identified a trait that was shared by a large number of children who were at risk for, or had a diagnosis of bipolar disorder. This trait involves a very prominent or obsessive fear that harm would come to themselves or others.  Further, these children responded to this fear with defensive, as opposed to offensive, aggression.  Investigators labeled this trait fear-of-harm. The difficulty this trait poses for those children who have it is underscored by the fact that it is correlated with a high frequency of hospitalization and suicidal behavior.

From a Trait to a Subtype

A concurrent, but separate, dimensional analysis confirmed the importance of this trait to the condition. (Click here to read about dimensional analysis) The analysis found that the symptom data from thousands of Child Bipolar Questionnaires (CBQ) (click here to read about the CBQ) sorted into ten behavioral dimensions. (click here to see the dimensional profile) Two of these dimensions describe mania and depression.  Another one described what could be called fear-of-harm.

When the ten dimensions were analyzed for heritability, the fear-of-harm dimension was found to be 9 times more heritable than either of the dimensions of mania or depression.  From a genetic point of view, this newly identified behavioral dimension was of great significance and therefore potentially more relevant than mania or depression to the identification of the biological basis of the disorder.

The high heritability of the trait prompted investigators to consider fear-of-harm, and the nine dimensions that associate with it, to represent a subtype of bipolar disorder.  They called it the Core phenotype.  (to read more about the Core phenotype click here).

From a Subtype to a Neuroanatomical Hypothesis

Further dimensional analysis of over 1000 children with high levels of fear-of-harm revealed a more refined profile of the specific behavioral and symptomatic dimensions that associate with the fear-of-harm trait. Investigators called this new dimensional profile the Fear of Harm (FOH) phenotype (click The 6 Dimensions of the Fear of Harm Phenotype to see the dimensional profile, click here to read about the FOH phenotype.)

Along with the fear-of-harm dimension, several other dimensions pointed to specific areas of the brain that might be involved in the expression of these abnormal behaviors.  Eventually, this resulted in a detailed neuroanatomical hypothesis of the pathology that may underlie the condition.

The hypothesis brings together the broad range of cognitive, behavioral and physiological symptoms experienced by these children into a framework that is logical from an evolutionary point of view.

From a Neuroanatomical Hypothesis to a Treatment

With a working hypothesis of the brain pathways involved in the condition, investigators were able to select a drug that they believed could potentially address the dysregulation.  A pilot study that used this drug to treat children and adolescents with the Fear of Harm phenotype has shown the effect to be substantial.  Children in this study have experienced a complete or significant reduction in the symptoms primary to the illness and have maintained that improved condition for as long as treatment has continued.  A few of the children have been on the regimen for several years.

From Here

This is not the end of the story.  The observations of the pilot study need to be confirmed by a double-blind controlled study. Undoubtedly, as complex as the brain is, we will learn much more in the future that will point to more and better treatments.  We have only begun to scratch the surface, but it is a welcome and exciting start.

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