Confused, cold, and lethargic

Ms. K is admitted and rewarmed passively and with warm IV fluids; by day 10 of hospitalization, temperature is stable (>35.1ºC [95.2ºF]). Thrombocytopenia, transaminitis, and altered mental status resolve.

Ms. K’s oral medications, including citalopram and paliperidone, have been held since admission because of her altered mental status. The psychiatry service is consulted to evaluate whether her presentation could be related to her change of medication.

A literature search reveals no report of paliperidone-induced hypothermia, but we consider it a possible explanation for Ms. K’s presentation. Lamotrigine (titrated to 50 mg/d), a benzodiazepine (oral lorazepam as needed), and discontinuing antipsychotics are recommended. After she returns to her baseline functioning, Ms. K is discharged to a skilled nursing facility.

Ms. K presents to the ED 2 days after discharge with altered mental status. Vital signs are: blood pressure, 90/55 mm Hg; pulse, 59 bpm; respiratory rate, 14/min; and temperature, 34.4ºC (93.9ºF) via bladder probe (Figure). Laboratory tests were significant for hepatic transaminitis (aspartate aminotransferase, 75 U/L; alanine aminotransferase, 122 U/L) and elevated alkaline phosphatase (226 U/L). A review of records from the nursing facility revealed that Ms. K was receiving paliperidone because of an error in the discharge summary, which recommended restarting all prior medications.

The authors’ observations

The Naranjo Causality Scale,⁶ which categorizes the probability that an adverse event is related to a drug (based on several variables, including timing of the drug administration with the onset of event, drug dosage and levels, response relationships to a drug, including re-challenge when possible, and previous patient experience with the medication), often is used to evaluate whether an adverse clinical event has been caused by a drug (Table 2). We applied the Scale to Ms. K’s case, which revealed a score of 7—indicating a probable adverse drug reaction. The sequence of events in Ms. K’s case that led to a paliperidone challenge-dechallenge-rechallenge, and the resulting hypothermia, are, we concluded, evidence of an adverse drug reaction.

Using the World Health Organization database for adverse drug reactions, van Marum et al⁷ found 480 reports hypothermia with antipsychotics as of 2007 (compared with 524 reports of hyperthermia in the same period); 55% involved atypical antipsychotics, mainly risperidone. There are no case reports of paliperidone-induced hypothermia; however, several reports of hypothermia have been attributed to risperidone, and paliperidone is the primary active metabolite of risperidone.⁵

To identify risk factors for hypothermia with antipsychotic use, van Marum et al⁷ performed a literature search for case reports of antipsychotic-induced hypothermia, which revealed no association with age or sex. The most common diagnosis in cases of antipsychotic-induced hypothermia was schizophrenia (51%). In 73% of the cases, hypothermia followed the start or dosage increase of the antipsychotic. These observations have been noted in case reports and case series of hypothermia associated with antipsychotic use.^8-12

Mechanism of action

One proposed mechanism for antipsychotic-induced hypothermia includes preferential 5-HT2A receptor antagonism over D2 receptor antagonism.^7,12 It has been believed that, under normal conditions, the action of dopamine to reduce body temperature and the action of serotonin to elevate it are in balance.⁹

Another possible mechanism is peripheral á2-adrenergic blockade, which might increase the hypothermic effect by inhibiting peripheral responses to cooling, such as vasoconstriction and shivering.^7,8 Boschi et al¹³ found that antipsychotics cause hypothermia in rats when the drug is administered intraperitoneally but not when given intrathecally. Perhaps for these reasons, in the early 1950s, before its psychotropic properties were known, chlorpromazine was used during surgery to induce artificial hibernation and suppress the body’s response to cooling.⁷ The therapeutic activity of paliperidone is mediated though a D2, 5-HT2A, and á2-receptor antagonism⁵; these mechanisms could, therefore, be contributing to Ms. K’s hypothermia.

Patients with preexisting brain damage— such as Ms. K—might be at increased risk of antipsychotic-induced hypothermia.^7,8 This includes focal damage to central thermoregulatory centers, such as the pre-optic anterior hypothalamic region,¹⁴ and more diffuse damage seen in patients with cognitive impairment or a seizure disorder.⁸

Studies of people with schizophrenia show a decrease in core temperature after administration of an antipsychotic,¹⁵ raising the possibility of an impairment of baseline thermoregulatory control. Such thermal dysregulation in patients with schizophrenia might be explained by changes in neurotensin levels.⁷

The neuropeptide neurotensin has been implicated in the regulation of prolactin release and interacts to a significant degree with the dopaminergic system.¹⁶ When administered to animals, neurotensin suppresses heat production and increases heat loss.¹⁷ The neurotensin level in CSF was found to be lower in non-medicated patients with schizophrenia than in healthy controls, with an inverse correlation between the severity of symptoms and the neurotensin level.¹⁸