by Atmaram Yarlagadda, MD, and Anita H. Clayton, MD

Dr. Yarlagadda is from Newport News, Virginia, and Dr. Clayton is Professor, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.

Psychiatry (Edgemont) 2008;5(12):51–54


Understanding the functional capacity of the human brain at a molecular level continues to be a challenge despite modern scientific and technological advances. Extreme variations in thermoregulation, whether induced by genetic predisposition or changes in internal, external or central factors, appear to be caused by altered calcium signalling at the neurotransmitter level and are likely due to a compromised blood brain barrier (BBB) in the hypothalamic region. The objective of this hypothesis is to explore the complicated interactions between neurotransmission, calcium signalling, and thermoregulation resulting from a challenged BBB in the hypothalamic region of the brain.

Key words
blood brain barrier, calcium signalling, thermoregulation, neurotransmission


Psychiatric symptoms often can only be described subjectively unless presenting with somatization and, if not managed effectively, may have devastating outcomes. Effective management of psychiatric disorders frequently involves titration or tapering, adding, or switching psychotropic medications. Presently, there are no clinically reliable physical signs, biochemical markers, or technological tools to accurately determine the response to treatment. Adverse reactions or drug side effects, therefore, pose a threat and, in some cases, are lethal. Neuroleptic malignant syndrome (NMS) is one of the most devastating of such adverse reactions, raising the body temperature above 40?C. Hypothermia, on the other hand, is rare with no designated term like NMS. Both hyper- and hypothermia seem to result from variations in neurotransmitter levels commonly seen not only in neuropsychiatry secondary to the use of psychotropics but also in pain management involving anesthetics. Interestingly, the link between thermoregulation and neurotransmission is largely dependent on intracellular calcium homeostasis. The goal of this hypothesis is to connect the complicated yet interdependent mechanisms of thermoregulation, altered calcium signalling, and neurotransmission potentially due to a compromised blood brain barrier (BBB) in the hypothalamus.


Hyperthermia is defined as a body temperature above 37?C. There are several established causes of hyperthermia, including external (environmental), internal (metabolic), and central (chemical imbalances). Heat stress, heat fatigue, heat syncope, heat cramps, heat exhaustion, and heat stroke are a few commonly used terms. Heat exhaustion and heat stroke represent responses of the body to environmental challenges. Heat stroke is clearly an objective increase in body temperature above 40?C, whereas other entities mentioned may or may not have detectable changes in body temperature.

Hypothermia, although rare, can similarly result in response to internal, external, and central factors. Hypothermia is defined as a body temperature less than 35?C, although 37?C is the ideal body temperature. Temperatures dropping below 32?C can have lethal consequences. However, unlike NMS, there is no known or well-established medical term associated with hypothermia.

NMS and hypothermia, although rare, are considered life-threatening conditions generally potentiated by neuroleptics.[1,2] Malignant hyperthermia (MH), on the other hand, while bearing striking clinical resemblence to NMS, is a genetically distinct, hypermetabolic syndrome[3] associated commonly with anesthetics and not induced by neuroleptics.


Consideration of altered calcium regulation or homeostasis has recently begun to take precedence in psychiatry over mechanisms exclusively involving neurotransmission.[4] Calcium ions are the most important and widely used intracellular messengers[5] in the brain. The proposed role of calcium dysregulation in the pathophysiology model of schizophrenia and calcium binding proteins in bipolar disorder[6,7] have been experimentally demonstrated. Effects of lithium in regulating calcium ions by interacting with calcium binding proteins, such as neuronal calcium sensor 1 (NCS-1), have been established.[8] Importance of the regulatory role or signalling of intracellular calcium centrally in the development of NMS and MH has been thoroughly reviewed in another paper.[9]


Involvement of neurotransmitters in maintaining thermoregulation is frequently mentioned in the literature. Although an association is suggested, there are no definitive data linking any particular neurotransmitter to hyper- or hypothermia. NMS is a rare, yet well-known, phenomenon induced either by initiating, abruptly stopping, or inappropriate dosing of antipsychotics.[10] Some evidence points toward the genetic predisposition for this condition in some individuals in association with known triggers. Hypothermia, however, is less well described in the literature and is not a well-understood phenomenon. According to two reported cases,[11] adjustments in antipsychotic dose resulted in severe hypothermia, not hyperthermia, leading to intensive care unit admissions. The postulated mechanism was thought to be stimulation of dopamine (D2) receptors and blockage of serotonergic 5-HT2A receptors by risperidone. The authors, therefore, suggest ruling out hypothermia when a patient’s condition rapidly deteriorates following the initiation of antipsychotic medications. Conversely, blockage of D2 receptors could result in entirely opposite outcomes. Both hypo- and hyperthermia are associated with the use of antipsychotics and their individual mechanisms of action at the particular receptor site hypothetically by altering cellular calcium homeostasis (FIGURE 1).


Thermoregulation is a highly intercommunicative function[12] involving internal, external, and central factors, which are greatly dependent on an intact BBB. A classic example of internal factors compromising the intactness of BBB would be menopausal women in whom hormonal disturbances result in hot flashes and night sweats as a response to compensatory thermoregulatory mechanisms. An example of central factors would be neuropsychiatric disorders or neurotransmitter dyregulation, which could lead to similar compensatory thermoregulatory mechanisms (e.g., tachycardia and sweating). On the other hand, extreme environmental variations or external factors also trigger compensatory thermoregulatory responses (e.g., sweating and altered heart rate). These thermoregulatory compensatory mechanisms are almost always associated with a psychological component. Therefore, to explore the role of thermoregulation in patients with compromised BBB, we first have to understand the basics of neurotransmission and calcium signalling centrally in the brain in response to either internal or external demands. The psychiatric patient population appears more vulnerable to changes in thermoregulation as compared to others. Are these developmental changes due to increased susceptiblity or genetic make-up manifesting later in adolescence? Or are these physiological changes due to metabolic or pharmacological interventions seen with advancing age or onset of diseases? These questions necessitate further exploration.


Thermoregulation is a developmental process. According to one experimental study, development of thermoregulatory mechanisms start during the prenatal ontogeny.[13] Relevance of this study to human in-utero thermoregulatory mechanisms, however, is unclear. Febrile seizures, therefore, serve as an example of poor developmental responses to thermoregulatory mechanisms.

NMS and MH, on the other hand, are seen later, both in young adults and the elderly. Genetic predisposition seems to be one independent underlying factor for both conditions. It appears that only a certain population expresses symptoms consistent with NMS or MH.

Cell wall damage, potentially a result of medications or hypoxia due to metabolic deficiencies described in this article, is a factor that may contribute to calcium overload of cellular mitochondria[14] leading to cytotoxicity and cell death in the hypothalamis compromising the intactness of the BBB. These processes may be independent of genetic predisposition in some, and dependent genetically by cytoprotective mechanisms, such as apoptosis,[15] in others. External factors, therefore, could play a significant role by quickly unbalancing the metabolic internal mechanisms maintaining normal physiological body requirements and vice versa—all of which may result in extreme variations in body temperatures, particularly in individuals in whom the intactness of the BBB is compromised.

Minor variations in any of the factors described in this article, therefore, could generate a huge impact on body temperatures due to a shift in the neurotransmitter balance via altered calcium signalling. Resulting feedback neurotransmitter response is one example of shifting the thermoregulatory balance toward hypothermia by blocking the 5HT2 receptors and activating D2 receptors, respectively, as with the case of the second-generation, atypical antipsychotic risperidone. Conversely, the balance shifting toward thermoregulatory hyperthermia secondary to dopamine blockade and serotonergic activation has been observed with the first-generation typical antipsychotic haloperidol. This may in part explain the similarities in clinical manifestations, which are common to both NMS and serotonin syndrome (SS).
In summary, researchers have made enormous progress in their efforts to understand psychopharmacology at a molecular level; however, associating thermoregulatory feedback mechanisms in the particular context of psychopharmacology remains under-recognized. The potential of psychiatric patients being more vulnerable to thermoregulatory changes either inherently or related to unknown factors compromising the BBB in hypothalamic region warrants further exploration and research.


From a practicing psychiatrist’s point of view, monitoring vital signs routinely in outpatient settings as with inpatient settings may provide better insights into the relationship between thermoregulatory mechanisms and psychopharmacology. Secondly, use of receptor modulators capable of stabilizing CNS calcium homeostasis, such as centrally acting calcium channel blockers, in conjunction with antipsychotics may provide a safer treatment approach not only in preventing extremes in temperature variations but may also decrease the risk of stroke in elderly patients with dementia.


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