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Biological Consistency. JBRF-supported investigators have defined a subtype of bipolar disorder which is bolstered by a hypothesis that can explain both the physiology that causes it and the broad range of symptoms which accompany it. Further, this logical and parsimonious hypothesis is strengthened by the fact that a corresponding treatment has prompted a reversal of symptoms. This is the gold standard of medical research. In contrast, no other classification of a mental illness, proposed or established, is associated with more than one or two physiological characteristics. Those studies continue to accept, as a starting point, the DSM conceptualization of disorders in which observable symptoms are allocated into ever-more refined, separate disorders in the belief that, by so doing, extraneous factors will be eliminated and the specific biology which causes the disorder will be discoverable. Indeed, post hoc comparisons of disorders defined in this way have identified some physiological differences. These findings seem to lend credibility to the distinction drawn between the conditions. However, without a greater context in which to understand any particular difference, its meaningfulness is undetermined. For instance, investigators who have proposed the new classification of Temper Dysregulation with Dysphoria report that the pathophysiological correlates of frustration differ between children with TDD and children with bipolar disorder. This unto itself may be interesting, but certainly doesn’t prove that these conditions are distinct from each other in a meaningful way. While the investigators do not claim that this difference is proof, it is nevertheless used as a point of credibility that they are on the right path towards validation of the classification. This is a very inefficient approach however and is more like going on a fishing expedition than following a road map. Case in point; when they explored the ability of the two populations to label emotions, another area in which they suspected variation, they found none. The process of random comparison does not provide the justification as to why one example is more important than the other. What has allowed JBRF-supported investigators to arrive at a significantly different outcome derives from the fact that they did not follow a DSM constrained conceptualization of the disorder. Instead, they adopted one which is consistent with concepts born out by recent advances in genetics, neuroimaging, and neurology. This new knowledge, which does much to show us how neurological functioning creates behavior, has caused investigators across many fields to question the operating concept of the DSM. We now know that gene expression and the neurological pathways or systems that create our behavior do not function in a manner which would result in single types of behavior, i.e. depression, that are able to be separated from each other. Instead, these pathways interconnect a network of functional brain areas which are inextricably tied together in complex relationships. Activity in any pathway causes numerous neurological responses which result in a variety of associated changes in body physiology and behavioral expressions. Hence, disorder within a pathway will result in a much broader array of primary and downstream impairments than previously considered. Many of those impairments would seem unrelated to each other by observation alone. Therefore, to separate observable symptoms into unique categories such as ADHD, TDD, or bipolar disorder is at odds with the underlying physiology and perhaps counterproductive to further discovery. It prevents the consideration of a more accurate orchestration of symptoms which would provide better clues to the part(s) of the brain involved in the problem. In their approach, JBRF-supported investigators analyzed the comprehensive range of symptoms experienced by children who had received a bipolar diagnosis, regardless of whether the symptoms were, by definition, part of bipolar disorder. Another important characteristic of their non-traditional analysis is that it accommodated for varying degrees of severity of those symptoms rather than count them as categorically “present” or “absent”. Both of these aspects more accurately reflect our natural biology. The combined approach allowed the research to identify the disruption of a very important pathway in the brain which causes a broad range of behavioral impairments including, but certainly not limited to, mania and depression. That pathway is called the orexigenic neuropeptide pathway. This pathway uses a class of transmitters called orexins, which, either directly or indirectly, integrate very basic homeostatic systems of survival: temperature regulation, metabolic signals, and arousal, as well as all the downstream behaviors and responses which support those systems. Downstream effects would include everything from blood pressure and shivering to reward seeking and eating, to fear response and sleeping, and so much more. Many of the symptoms which were critical to the discovery of the pathway demonstrate no observable relationship to mania and depression and would not be considered in traditional investigations of bipolar disorder. Nevertheless, this study allowed those symptoms to assert their inclusion and importance. Only when looked at through the new lens of the physiology that they helped to reveal, can one see the inextricable tie that these symptoms have to both mania and depression. Investigators call the condition caused by this disrupted pathway Fear of Harm (FOH) due to the strong and distorted perception of threat which is part of the symptom profile. This disorder, like most things that occur naturally, presents itself on a spectrum. Children who have some degree of this disorder represent about 2/3 of the children who today would probably receive a diagnosis of BP I, II or NOS. One half of those children are highly affected. Children with strong FOH profiles have severe levels of mania and depression and higher rates of hospitalization than the children with low or no FOH. Additionally, there is a high correlation between FOH and aggressive behavior and risk of suicide. Children with FOH are unified by a particular underlying biology, but do not, as a group, belong to either the classifications Bipolar I or II (in which (hypo)mania criteria are satisfied) or the classification of Bipolar-NOS (in which (hypo)mania criteria are not satisfied). There is no particular pattern to their mania; some of them have moods which fluctuate episodically while others have moods which fluctuate abruptly and rapidly. During the course of this study, both the research and anecdotal evidence indicated that children in this group experience anomalies in their body temperature. Further research found that indeed, these children either conserve too much heat, or do not dissipate enough heat. Since thermoregulatory signals play a crucial role in the orexigenic pathway and proper arousal regulation, and these children demonstrated a thermoregulatory deficit, investigators sought a treatment regimen which would address body temperature. The combination of ventilation with fans at night to promote heat dissipation, exogenous melatonin prior to sleep to help lower core body temperature and promote the onset of sleep, and use of a pharmacological agent also known to dose-dependently lower body temperature has resulted in a sustained and significant elimination of symptoms in 12 out of 12 severely ill children. The thinking that led to, and the results that derive from, this research are as different from others as apples are to oranges. We all know that existing treatments are both unreliable and insufficient. The selection of which drug to use is often referred to as a guessing game. Unfortunately, that is the best you can do when you don’t really know what causes the problem. The key to the development of effective and predictable treatment is in knowing what you want to target and why. This preliminary trial tells us that, while there is still much to be learned and filled in, we have taken a giant step in the right direction. It is of utmost importance that the investigators be able to follow up this research with a controlled, double blind placebo study of the treatment. Looking forward, now that we have a basic road map to follow, we are confident that our journey will continue to provide insights that will reduce the burden of this disorder. In addition to learning more about the role of thermoregulation to this disorder, we have already identified several other areas that deserve further inquiry. Notably, our hypothesis tells us that we must learn more about the neural mechanisms which interpret circadian and circannual signals from the environment as these inputs have a large influence on the orexigenic pathway.
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New: Are you interested in finding out if your children qualify to participate in the JBRF's research studies? Learn more here. Context and Summary of JBRF Sponsored Research Clinical Phenomenological Study of Childhood-onset Bipolar Disorder Neuropsychological Testing in Juvenile-onset Bipolar Disorder |
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