Introduction

Hypothermia is defined as a core temperature below 35 degrees C (95 degrees F), and can be further classified by severity1 (Table I). Fever is the most commonly encountered disorder of thermoregulation; however, hypothermia was the reported cause of death of 16,655 persons in the United States between 1979 and 2002 (average, 689 persons/yr). Nearly one-half of these deaths involved patients older than age 65 years, with an overall male-to-female ratio of 2.5:1.2,3 In addition, researchers have speculated that hypothermia could explain some of the unexpected sudden deaths that have been observed in patients treated with neuroleptic drugs.4,5

Important risk factors that predispose the body to poor temperature regulation include very young or advanced age, the presence of comorbid conditions such as infections, and hypothyroidism.2 Additional comorbid conditions, which often occur in the psychiatric population, increase the risk of hypothermia. These include nocturnal enuresis, seizure disorder, debilitating physical illness, and mental retardation. The risk of hypothermia in this population is further increased by the use of several classes of medications used to treat psychiatric disorders, such as typical and atypical antipsychotics, beta-adrenergic antagonists, benzodiazepines, and other sedatives.4,6

Multiple potential etiologies of hypothermia include environmental exposure, hypothyroidism, adrenal insufficiency, sepsis, neuromuscular disease, malnutrition, and hypoglycemia. Certain medications such as beta-blockers, clonidine, meperidine, and general anesthetic agents can impair a patient’s ability to compensate for a low ambient temperature and increase the risk of accidental hypothermia.1 Hypothermia has been described previously as an adverse reaction to neuroleptic drugs, particularly to phenothiazines, but also to haloperidol and olanzapine.5

Differential diagnosis of hypothermia in psychiatric patients should include primary accidental hypothermia, central nervous system (CNS) disorders, metabolic disorders, infections, and medications7 (Table II).

This article presents a case of a geriatric patient with multiple comorbidities, who was presumed to have experienced clozapine-induced hypothermia.

Discussion

The body temperature regulation center is located in the hypothalamus. Dopamine, noradrenaline, and serotonin systems are considered to be involved in temperature regulation. Blockade of alpha-receptors involved in peripheral vasodilation is also important.5 Medications can alter the body temperature by acting on any component of the thermoregulatory system, including heat production, heat conservation, heat loss, and thermosensors.8

Dopaminergic mechanisms are involved in both the genesis and the dissipation of body heat. This can explain why neuroleptic medications can cause temperature dysregulation and produce either hypothermia or hyperthermia.6,9 In animals, and possibly in humans, ambient temperature may be a factor in determining whether hypothermia or hyperthermia is produced. The most dramatic and devastating syndrome of temperature dysregulation due to antipsychotics is neuroleptic malignant syndrome, a life-threatening emergency typically presenting as hyperthermia, muscle rigidity, delirium, and autonomic instability. Neuroleptic malignant syndrome has been described in patients treated with typical antipsychotic agents, as well as in patients treated with the newer atypical antipsychotics.6

In addition, antipsychotic blockade of skin alpha-1 receptors may reduce the shivering capability and cause peripheral vasodilatation.10,11 Some researchers have attempted to antagonize the hypothermia in animals produced by peripheral administration of two neuroleptics with phenylephrine, an alpha-adrenoceptor agonist that does not cross the blood-brain barrier. They found that hypothermia induced by both chlorpromazine and haloperidol was attenuated by phenylephrine, supporting the view that peripheral alpha-adrenoceptors may mediate neuroleptic-induced hypothermia.10

Clark and Lipton12 listed the results of all studies reporting the effects of neuroleptic medications on body temperature in various species, including man.12 There are 458 reports involving 651 trials or experiments. Neuroleptics decreased the body temperature in 321 trials, increased it in 187 cases, and had no effect in 143 instances. These include 110 reports involving 153 trials with humans. In only 26 instances did the administration of a neuroleptic medication lower body temperature; in contrast, in 127 cases the neuroleptic increased it. Due to their thermoregulatory properties, neuroleptics have been used for medicinal purposes other than psychosis. For example, chlorpromazine has been used in the past to induce hypothermia for the purposes of general anesthesia.5,9

Atypical antipsychotic agents were developed in response to problems with typical agents, including lack of efficacy in some patients, lack of improvement in negative symptoms such as flat affect, apathy, and poverty of speech, and problematic adverse effects, particularly extrapyramidal symptoms and tardive dyskinesia.

Atypical antipsychotics differ from typical antipsychotics in their “limbic-specific” dopamine type 2 (D2)-receptor binding and high ratio of serotonin type 2 (5-HT2)-receptor binding to D2 binding.13 They influence hypothalamic thermoregulation and may induce hypothermia by stimulating dopamine (mainly D2) receptors and blocking 5-HT2 receptors. Olanzapine was introduced into the United States market in 1996, and since its introduction into clinical use, very few, but some, case reports of hypothermia associated with olanzapine use have been published.6

Clozapine, a dibenzodiazepine, shows high in vitro receptor affinities for the D4, 5-HT2, alpha-adrenergic, muscarinic, and histamine H1 receptors, and a relatively weak affinity for D1, D2, and D3 receptors.14 Due to its receptor properties, clozapine is able to induce modification of body temperature, an undesirable effect. Research in animal studies has found that intraperitoneal administration of clozapine produces hypothermic effects.15

Some researchers have studied the effect of neuroleptic-induced hypothermia in the improvement of symptoms of schizophrenia. Heh et al16 studied eight individuals with chronic treatment-resistant schizophrenia in a 6-week single-blind trial of haloperidol, and then a subsequent 6-week double-blind trial of clozapine. They found that both haloperidol and clozapine significantly lowered oral body temperatures relative to baseline washout temperatures. Notably, clozapine relative to haloperidol was found to induce a greater decrement in body temperature and was associated with greater clinical improvement.16

Conclusion

Medication-induced hypothermia is quite rare, and therefore routine screening is not necessary. However, clinicians should be alert to the possibility of its development and should be familiar with its presenting signs and symptoms. Delirium, slurred speech, ataxia, fatigue, incoordination, subjective coldness, shivering, and bradycardia can all be presenting features of hypothermia. A routine monitoring of temperature in patients taking antipsychotic medications should be encouraged, as these effects can occur at any time during treatment. Currently, most of the research regarding temperature dysregulation properties of antipsychotic medications is focused on neuroleptic malignant syndrome because of its life-threatening capacity; nonetheless, hypothermia is also life-threatening. We encourage clinicians and researchers to share their experiences dealing with the spectrum of temperature dysregulation disorders.

The authors report no relevant financial relationships.