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Olanzapine-Associated Hypothermia

Received Jan. 28, 2003; revision received July 9, 2003; accepted July 29, 2003. From the Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore. Address reprint requests to Dr. Blass, Johns Hopkins Hospital, 600 North Wolfe St., Meyer 279, Baltimore, MD 21287-7279; dmblass{at}jhmi.edu (e-mail).

Temperature dysregulation, a known side effect of antipsychotic medications, is thought to be mediated by the effects of these medications on hypothalamic neurotransmission. These agents most commonly cause hyperthermia,¹ although they can also cause hypothermia, a fact that highlights the complexity of the temperature regulation system.^2,3 Ambient temperature may be a factor in whether hypothermia or hyperthermia is the outcome, at least in animals.⁴ 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.⁵ Neuroleptic malignant syndrome has been described in patients treated with typical antipsychotic agents,⁶ as well as in patients treated with the newer atypical antipsychotics.^7–11

Hypothermia, traditionally defined as a drop in core body temperature below 35°C (95°F), is also a known side effect of both typical and atypical antipsychotic agents.^3,12,13 Chlorpromazine had been used in the past to induce hypothermia for the purposes of general anesthesia.¹⁴ In clinical practice the most common causes of hypothermia are prolonged exposure to cold temperature and general medical conditions such as infection and hypothyroidism, but exposure to antipsychotic medications is a notable cause of the condition as well.¹⁵

The atypical antipsychotic olanzapine was introduced into the United States market in 1996. Since its introduction into clinical use, only three case reports of hypothermia associated with olanzapine use have been published.^16–18 We present here a fourth case in which there is an association between olanzapine use and hypothermia.

Case Report

Brief History
Ms. A, a 64-year-old African American woman with a 40-year history of bipolar disorder, was admitted to the Johns Hopkins Hospital Geriatric Psychiatry Inpatient Service due to irritability, decreased sleep, pressured speech, and thought disorder that had developed over a period of weeks.

Her family history was notable for a number of first-degree relatives with unipolar major depression, one with bipolar disorder, and one with schizophrenia. Ms. A had received a diagnosis of bipolar disorder at age 24 years, and since then she had been hospitalized occasionally for both mania and depression. She had no history of substance abuse. She had been educated through the ninth grade, was a homemaker, and had been receiving disability benefits related to her psychiatric condition for about 20 years. At the time of admission, Ms. A was living with her adult children.

Her past medical history included diabetes mellitus type II, hyperlipidemia, chronic anemia, chronic lower extremity edema, glaucoma, vaginal bleeding due to a uterine cyst, and a history of right knee and left ankle fractures. Three months before this admission, she had received a diagnosis of hyperthyroidism secondary to viral thyroiditis. At that time, her unbound T₄ level was 3.2 ng/dl (compared with a normal level of 0.7–1.6 ng/dl), and her thyrotropin (TSH) level was <0.02 µU/ml (compared with a normal level of 0.50–4.50 µU/ml). The hyperthyroidism resolved without treatment. By 1 month before hospitalization, her thyroid functions had normalized (her unbound T₄ level was 0.9 ng/dl, and her TSH level was 0.32 µU/ml).

At admission, Ms. A was receiving the following medications: 2.5 mg h.s. of olanzapine, 500 mg q.a.m. and 1000 mg q.h.s. of divalproex sodium, 10 mg h.s. of glipizide, 20 mg/day of furosemide, 10 mg h.s. of atorvastatin, 20 mg/day of lisinopril, 300 mg b.i.d. of ferrous sulfate, 100 mg b.i.d. of docusate sodium, 187 mg h.s. of senna, and one drop per day of pilocarpine ophthalmic solution in each eye. She had no known drug allergies.

At admission, a mental status examination revealed a slightly obese woman who was alert and cooperative. Eye contact was normal, and there were no abnormal movements. Her speech was pressured, with flight of ideas and pronounced thought disorder. She described her mood as "top of the world," and she appeared elated. She had no suicidal or homicidal ideation. There was no evidence of hallucinations or delusions. She initially was unable to cooperate with a cognitive examination, but a few days later she was assessed with the Mini-Mental Status Examination, on which she had a normal score of 28/30. A physical examination revealed that her blood pressure was 110/60 mm Hg, her pulse was 68 bpm, her respiratory rate was 20 per minute, and her oral temperature was 36.9 °C. The results of the remainder of the physical examination were normal, except for a finding of chronic bilateral lower extremity edema.

The results of admission laboratory testing were normal for CBC, liver function tests, and electrolyte levels. Her serum glucose level was elevated to 190 mg/dl, and her BUN level was elevated to 39 mg/dl, which was her baseline. Her serum creatinine level was also at its baseline level of 1.2 mg/dl. The results of laboratory studies for thyroid function showed a TSH level of 1.27 µU/ml and an unbound T₄ level of 1.1 ng/dl. The results of a urinalysis were normal. Her plasma level of valproic acid was 127 mg/liter.

Hospital Course
Ms. A was admitted to the hospital, and her condition was formulated as a manic episode of bipolar disorder. She initially continued to receive the medications she was receiving at admission. Lithium carbonate was not used because of concerns about a low calculated creatinine clearance rate (34 ml/minute). Gabapentin was added to her regimen on hospital day 8 and titrated up to a dose of 300 mg p.o. three times a day by hospital day 11.

The patient's dose of olanzapine was gradually titrated up to 5 mg q.a.m. and 6.25 mg h.s. by hospital day 17, and her manic symptoms gradually improved. Between hospital days 1 and 23 her oral temperature in the morning and evening (checked between 6:00 a.m. and 9:00 a.m. and between 3:00 p.m. and 7:00 p.m. on most days) ranged between 36.4°C and 37.0°C and between 36.4°C and 37.1°C, respectively. On hospital day 24 (day 7 of this dose of olanzapine), the patient's morning temperature dropped below 34°C (three readings averaged 33.7°C). For the next week her temperature ranged between 33.4°C and 36.7°C in both oral and rectal measurements. Ms. A reported no symptoms during this period, and she was entirely unaware of her hypothermia. Routine laboratory tests performed during this period revealed no change from the previous results of the CBC and liver function tests and no change in electrolyte levels, except for a mildly elevated potassium level (5.2–5.6 meq/liter). On hospital day 29, her 7:00 a.m. serum cortisol level was normal (13.7 g/dl). Her TSH level was elevated (16.99 µU/ml), but her level of unbound T₄ was normal (0.9 ng/dl).

Hypothermia was presumed to be due either to olanzapine or to thyroid abnormalities. On hospital day 31, olanzapine was discontinued, and treatment with 0.05 mg/day of levothyroxine was started to address the patient's subclinical hypothyroidism. Gabapentin was discontinued the following day, and treatment with 0.5 mg b.i.d. of risperidone was started. Over the next few days, Ms. A's daily temperatures started to rise. After hospital day 32, no further rectal temperature measurements were below 35.0°C, and after hospital day 37, no further oral temperature measurements were below 35.0°C. Ms. A continued to improve clinically and was discharged to the geriatric day hospital on hospital day 38. She remained in the geriatric day hospital for another 4 weeks (through hospital day 68). There were no further episodes of hypothermia (Figure 1).

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FIGURE 1.  Body Temperature Measurements and Olanzapine Doses Over a 68-Day Period in a 64-Year-Old Woman With Bipolar Disorder and Subclinical Hypothyroidism aAverage of three temperature measurements.

We compared Ms. A's mean daily temperatures for the days during which she took the highest dose of olanzapine (11.25 mg/day) with all other hospital days (days 18–31 versus days 1–17 and 32–68). There were a total of 49 days for which at least one temperature reading was available. Her mean temperature was 35.53°C during the highest-dose olanzapine days, and 36.45°C on the other days. Analysis with a Student t test showed that the difference between these means was statistically significant (t=4.03, df=47, p<0.01).

Discussion

This case demonstrates a possible relationship between olanzapine treatment and hypothermia in a single patient. In general, an antipsychotic medication can be the sole cause of hypothermia, or it can be one of a number of possible causes coexisting in the individual patient who develops hypothermia. The few previously reported cases of hypothermia associated with olanzapine reflect both of these patterns. In one case, a 73-year-old woman with schizophrenia developed profound hypothermia (31.7°C) 4 hours after the administration of a single 10-mg dose of olanzapine.¹⁶ Her temperature returned to normal after cessation of the olanzapine. On other occasions the same patient had developed hypothermia while taking haloperidol or thioridazine. The patient had no known general medical causes of hypothermia other than the medications.

In a second case, an 83-year-old woman with bipolar disorder developed hypothermia (33.1°C) 3 weeks after beginning to take 5 mg/day of olanzapine.¹⁷ That case was complicated by the fact that the patient was also taking lithium carbonate, clonazepam, and trazodone. The patient's temperature normalized upon cessation of all medications. In a third case, a 37-year-old woman with Prader-Willi syndrome and psychotic symptoms developed hypothermia on two different occasions while being treated with risperidone and once after receiving a single dose of olanzapine.¹⁸ In that patient's case, there were endocrinologic abnormalities as well as infections, all of which could have contributed to the development of hypothermia. However, the same patient had previous episodes of infections while she was not taking antipsychotic medications and did not develop hypothermia during those episodes.¹⁸

In the case presented here, a patient who was taking olanzapine and who also had subclinical hypothyroidism developed hypothermia. It is possible that the hypothermia was primarily due to the thyroid abnormalities. Over the course of the hospitalization, the patient's TSH levels increased from 1.27 µU/ml to 16.99 µU/ml, and the episode of hypothermia occurred within this time interval. Moreover, her hypothermia began to resolve immediately after initiatiation of levothyroxine treatment, which was concurrent with the olanzapine discontinuation. It is well known that even in subclinical hypothyroidism there are abnormalities in peripheral indices of thyroid hormone action such as serum lipid levels and ankle reflex time.^19–21 On the other hand, hypothermia is not reported to be associated with subclinical hypothyroidism alone, and at the time that the hypothermia developed, Ms. A's unbound T₄ level was normal. Moreover, the onset of hypothermia was fairly abrupt, which might argue in favor of olanzapine's being the primary etiologic agent. Another possibility is that the presence of both olanzapine and subclinical hypothyroidism was necessary to produce hypothermia in this patient.

Hypothermia in this case may have been due to gabapentin treatment. There is some evidence that gabapentin is effective in the treatment of hot flashes,²² and a case report described a high rate of hypothermic events in a patient with preexisting hypothalamic disease who was treated with gabapentin.²³ However, gabapentin is not known to have affinity for dopaminergic or serotonergic receptors, which argues against its role as the primary etiologic agent.²⁴ Moreover, in the patient described here, the increase in olanzapine dose was more proximate to the development of hypothermia than were the last changes in gabapentin dose, suggesting that the responsible agent was olanzapine.

Olanzapine-induced hypothermia could be mediated through its effects on the dopamine system, specifically by its antagonism of the D₂ receptor,²⁵ a mechanism of hypothermia supported by animal experiments.²⁶ Alternatively, it has been suggested that the hypothermic effects of antipsychotics may be primarily mediated by effects on the serotonergic system by antagonism of the 5-HT₂ receptor,^3,27,28 also a known site of olanzapine activity.²⁵

It is noteworthy that this patient was completely asymptomatic despite significant hypothermia over a period of 1 week. In an inpatient unit where vital signs are routinely monitored, asymptomatic hypothermia will be detected, but detection cannot be assumed for outpatients. Whether the hypothermia experienced by this patient was a harbinger of a further and potentially life-threatening drop in body temperature cannot be known. Likewise, it is not yet known at what specific temperature the clinician should begin to worry about the development of clinically significant hypothermia.

Medication-induced hypothermia is quite rare, and therefore routine screening is not necessary. Nonetheless, 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. Evaluation of any of these treatment-emergent signs or symptoms should include temperature measurement.

In summary, this case describes the acute onset of asymptomatic hypothermia in a 64-year-old woman with bipolar disorder and subclinical hypothyroidism who was taking olanzapine. This case adds to the sparse literature reporting hypothermia with olanzapine use. It also illustrates that the newer antipsychotics, while generally better tolerated than the older ones, do carry significant risks and that patients treated with the newer agents require careful monitoring.

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