Clozapine-Induced Hypothermia in an Elderly Female
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.
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Case Presentation
Brief History
Mrs. D is a 79-year-old, widowed, African-American female who has been residing in a nursing home for three years. She has a 40-year history of schizophrenia, chronic paranoid type, and was admitted voluntarily to the geriatric psychiatry inpatient unit due to an abrupt 48-hour decompensation characterized by withdrawal, food and fluid refusal, extreme intense paranoia, and occasional verbalization of desire to kill herself.
Mrs. D received a diagnosis of schizophrenia, chronic paranoid type, more than 40 years prior, with a first psychiatric inpatient admission at age 25. She has been admitted more than 20 times to different hospitals due to exacerbation of schizophrenia. She had no history of substance abuse, and her family history was non-contributory. Her primary support was her daughter. Her past medical history included hypothyroidism, type 2 diabetes mellitus, hypertension, right-eye blindness, chronic venous insufficiency, and mild dementia.
At admission, Mrs. D was receiving the following medications: bupropion 100 mg in the morning, ziprasidone 80 mg twice a day, glyburide 1.25 mg in the morning, levothyroxine sodium 0.15 mg daily, lithium carbonate 300 mg alternating with 450 mg per day, amlodipine besylate 5 mg per day, and senna 8.6 mg per day. She had no known drug allergies.
Mental status examination revealed a well-nourished female who appeared stated age, was alert but uncooperative, and guarded. She had psychomotor retardation and intermittent eye contact. Mrs. D appeared tremulous with a slow gait. Speech was very sparse with low volume and slow rate. She described her mood as “I wanna die,” and she appeared depressed and dysphoric. Thought process was impoverished. Thought content revealed auditory and visual hallucinations, paranoid ideation, and preoccupation with death. Cognitive function was difficult to evaluate due to poor cooperation. She was oriented only to person; her insight and judgment were extremely impaired.
Mrs. D’s physical examination revealed a blood pressure (BP) of 126/70, pulse of 100, respiratory rate of 20, and oral temperature of 36.7 degrees C. Her weight was 174 pounds, and her height was 5 feet 10 inches. The rest of her physical examination was normal except for bilateral edema due to chronic venous disease. The results of admission laboratory tests showed a normal complete blood count (hemoglobin: 13.7, hematocrit: 40.4, white blood cell [WBC] count: 8600, absolute neutrophil count [ANC]: 6000, and platelets: 207,000), and normal electrolyte levels. BUN was slightly increased at 25, and creatinine was within normal limits (WNL). Her serum glucose level was 120 and HbA1c was 5.6. Folic acid levels were increased in 15.7, and B12 levels were WNL. Urinalysis, lipid profile, thyroid-stimulating hormone, and liver function tests were ordered later on during hospitalization, and results were WNL, except for reduced albumin of 3.3 and increased globulin in 3.5. Her plasma level of lithium was 0.9, and baseline electrocardiogram was WNL.
Hospital Course
Mrs. D initially continued receiving the medications she was taking prior to admission, except for the lithium that was discontinued due to tremors. On hospital day 4, ziprasidone was increased to 100 mg twice daily and maximized on hospital day 10 to 120 mg twice daily. Bupropion was gradually tapered until discontinued on hospital day 14. At this time, she continued to be isolated with active visual hallucinations and a passive wish to die. She was still very paranoid and displayed disorganized thought process. At that point, ziprasidone was discontinued, and it was determined that a clozapine trial was indicated. Her WBC count was 5800, and ANC was 2900. Clozapine was started on a dose of 12.5 mg per day. Clozapine was titrated at a rate of 25 mg every other day. Clozapine dose on day 40 was 12.5 mg in the morning and 200 mg at bedtime. WBC count for this day was 3.8; ANC was not available. Clinically, the patient was still symptomatic, very paranoid, and uncooperative.
Between hospital days 1 to 43, Mrs. D’s oral temperatures in the morning (checked between 6:00 AM and 9:00 AM ) ranged between 35.4 degrees C and 37.1 degrees C. On hospital day 44 (day 4 of clozapine 12.5 mg in morning, 200 mg at bedtime), her morning temperature was recorded as 31.0 degrees C. She was confused, with slurred speech and was unable to be awakened. Her other vital signs were: BP: 100/60, heart rate: 66, respiratory rate: 18, pulse oximetry : 99%, and fasting blood glucose: 101. Patient was immediately evaluated by the Internal Medicine team. Her temperature one hour later was 30.8 degrees C; she was treated with warming blankets and warmed intravenous fluids. Septic work-up was ordered including blood cultures, urine cultures, urinalysis, chest x-ray, thyroid panel, electrocardiogram, creatinine phosphokinase, cortisol levels, and computed tomography scan. By that time, clozapine was discontinued and the patient was transferred to a medical floor for further work-up and monitoring. She spent two days on the medical floor with temperatures ranging from 34.0 degrees C to 36.4 degrees C, during which she received intravenous hydration and prophylactic antibiotics consisting of cefepime, metronidazole, and vancomycin. All of the previous laboratory tests came back WNL, except for mild anemia, low platelets, and WBC of 2100. ANC was not available. The medical team was unable to find a medical cause to explain Mrs. D’s hypothermia. The hydration and antibiotics were discontinued prior to her transfer to the psychiatric unit.
On hospital day 46, Mrs. D was transferred back to the geriatric psychiatry inpatient unit. At this time her WBC was 7200, and her ANC was 4300. On hospital day 48, haloperidol was introduced due to her ongoing psychotic symptoms. While taking haloperidol she became catatonic, necessitating the discontinuation of the lorazepam. Mrs. D had an immediate positive response to the intramuscular lorazepam. The symptoms were felt to be due to catatonia rather than severe extrapyramidal side effects, given the patient response to the intramuscular lorazepam and her history of one previous catatonic decompensation. She remained on the intramuscular lorazepam throughout the remainder of her hospital stay. The dose was reduced but not eliminated prior to discharge to the nursing facility. No other psychotropic medications were initiated. At no time during the remaining 26 days of her hospitalization did she become hypothermic. She returned to her previous level of functioning at the nursing facility, which entailed independent self-care and participation in church and music groups.
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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.
