Washington Center For Psychiatry

Medical Hypotheses (2008) 70, 497-500

By Alen J. Salerian, MD, Nansen G. Saleri, PhD, Justin Salerian

Summary
Lowering core body and brain temperature has been shown to be beneficial for multiple sclerosis, cardiovascular accidents, traumatic brain injuries and myocardial infarction. Svante Arrhenius’ rate law – governs human thermoregulation and all biochemical reactions including complex chemical processes involved in mood disorders.

We reviewed the studies on core body and brain temperature’s influence on mood, mood disorders and their treatment. Our review suggests the majority of therapeutic strategies against mania are hypothermic while thermogenic strategies are used to combat depressive disorders.

We hypothesize that therapeutic manipulation of brain temperature may represent a key mechanism in the treatment of mood disorders possibly because of brain temperature’s profound influence on human biology governed by Svante Arrhenius’ rate law. We postulate that brain temperature may rise with mania and fall with depression

Introduction
The influence of temperature in the physiopathology of various neurodegenerative and psychiatric disorders has been of increasing scientific interest in the last decade. Two areas in which brain and body temperature may have a crucial impact are neurodegenerative and mood disorders. Salerian and Saleri have proposed a temperature-dependent biochemical system in humans governed by the Arrhenius rate law. We postulated that due to the exponential relationship between temperature and biochemical reactions, a relatively minor alteration in core body or brain temperature may be of significant therapeutic benefit in combating neurodegenerative disorders and prolonging lifespan (1). We further speculated that this small alteration may be as little as a drop of 1°C in core body temperature.

Many failures in temperature control have been observed in psychiatric disorders. It has been reported that patients with schizophrenia exhibit dysregulation of body temperature, including different baseline temperatures, abnormal daily range of temperatures and diurnal variation showing an early peak, an impaired ability to compensate to heat stress and compensating more effectively to cold stress (2).

”Wehr, et al (1989) suggested that chronic treatment with antidepressants decreased hypothalamic temperature in Syrian hamsters resulting in a cold defense reaction (thermogenesis) that may contribute to the behavior-activating properties of antidepressant drugs (3). Evidence suggests the antidepressant effect of sleep deprivation can be influenced by psychotropic medications (antidepressants or neuroleptics) and by ambient temperatures (3). Wehr hypothesized that the antidepressant effect of these diverse factors may be because of their common thermoregulatory influence.
In this review, we examine the brain temperature’s influence on mood, mood disorders and their treatments. The premise of our review is stated in the form of a hypothesis, hereafter referred to as the Salerian Mood Hypothesis (SMH), is that: The therapeutic manipulation of brain temperature may represent a key modality in the treatment of mood disorders as brain temperature may rise with mania and fall with depression.

Lithium is Hypothermic
1. Studies with rats suggest that lithium increases heat shock proteins that are hypothermic (4).
2. Studies with rats suggest that lithium increases brain cholinergic activity that is
hypothermic (5).
3. Lithium toxicity in mice is associated with severe hypothermia prior to death (6).

Neuroleptics are Hypothermic
Experimental studies with cats, mice and rats have shown that various neuroleptics are hypothermic and that clozapine, olanzapine and Risperdal produce a dose-dependent drop of colonic temperature in adult male Wistar rats (7). Similarly, it has been demonstrated that chlorpromazine induces a drop in colonic temperature in monkeys (8).

Neuroleptics, with a few exceptions, seem to be hypothermic in humans (9). Haloperidol, olanzapine and risperdal reduce axillary temperature of psychotic patients (9). It has been show that neuroleptic-induced hypothermia is associated with amelioration of psychosis in schizophrenic patients (9). Clozapine decreases core body temperature, improves BPRS and displays a linear but weak relationship between the degree of hypothermia and improvement of psychosis (9).

Antidepressants are Hyperthermic
Sibutramine, duloxetine and bupropion increase colonic temperature in female Wistar rats (10). In support of the thermogenic effects of antidepressants, it has been demonstrated that 12 antidepressant drugs including butriptyline, protriptyline and nortriptyline were highly thermogenic in rats (11). It has also been shown that bupropion, a dopamine/norepinephrine reuptake inhibitor, increases brain and colonic temperature in rats (12). Similarly, studies indicate that many antidepressants currently in clinical use have marked thermogenic properties and could therefore cause reduction in body weight without altering the food intake in mice (11). Soubri, et al, 1989, demonstrated that food restriction decreases responsiveness to antidepressant drugs in rats (13). This study may explain the findings of Duncan, Johnson and Wehr (1995) that fluoxetine and clorgyline reduced hypothalamic and body temperature in hamsters (14). The fluoxetine-induced hypothermia may be caused by the caloric restriction and not its direct neurochemical effect.

The studies on the effects of antidepressants on humans have been contradictory; yet there is one study that suggests chronic administration of antidepressants elevates tympanic membrane temperature (15).

Single Electroconvulsive Shock is Hypothermic Whereas Chronic Electroconvulsive Shock is Hyperthermic
Investigations of the effect of electroconvulsive shock (ECS) on body temperature have been contradictory. A single ECS has been demonstrated to reduce colonic temperature in mice. However, repeated ECS attenuates the hypothermia produced by single ECS (16).

Nicotine-Induced Hypothermia, Antidepressants and Bright Artificial Light
Is there any evidence to suggest that a nicotinic mechanism is involved in the regulation
of core body temperature and mood? Although not all the interactions between nicotine, body temperature and various antidepressants are fully understood, nicotine has been demonstrated to induce hypothermia following intracerebral nicotine administration in cats, monkeys and rats (17). Further, chronic administration of nicotine induces tolerance supporting a receptor mediated process (17). Other studies suggest that nicotine-induced alterations in body temperature are influenced by genetic factors. Differential sensitivity towards dependent nicotine-induced hypothermia is identified as the key factor for different strains of inbred mice (18). A recent study in mice deficient in beta-2 and in AChR subunit reduced hypothermic response to low doses of nicotine suggesting that this subunit partially mediates nicotine-induced hypothermia (18).

Fluoxetine, phenelzine sulfate, desipramine and bright artificial light have been shown to produce reduced sensitivity to the hypothermic effects of nicotine (17). Mendelsohn, et al, in 2005, speculated that the capacity of three chemically distant classes of antidepressants and bright artificial light (a treatment for seasonal depression) to produce this result suggests that nicotine’s thermoregulatory influence may be involved in the mechanism of action in these treatments.

Clinical Manifestations Associated With Hypothermia and Hyperthermia
Transient and reversible psychosis with auditory and visual hallucinations that appear when core body temperature rises above 39°C and disappear after core body temperature normalizes and has been documented (19).

Patients with moderate (34-30°C) hypothermia experience brady cardia and hypotension (following early and brief tachycardia and hypertension) as well as progressive depression of mental functions starting with apathy, psychomotor retardation, and silence (20).

Synopsis
Body and brain temperature’s influence on mood can be summarized as follows:
1. Most neuroleptics, lithium and single ECT are hypothermic and they improve mania.
2. Chronic ECT and chronic administration of antidepressants are thermogenic and they improve depression.

Successful treatment strategies with biologically opposing influence and opposing thermal properties suggest that temperature change may represent a critical mechanism in the pathophysiology of mood disorders and may promise an avenue for therapeutic exploitation. Therefore, it is logical to induce hypothermia for mania and thermogenesis for depression.

Further studies are necessary to confirm SMH. Of importance will be studies to measure core body and brain temperature during and after treatment for various mood disorders. If clinical studies validate SMH, there could be novel approaches in the treatment of mood disorders specifically designed with temperature-altering prowess.

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