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Confused, cold, and lethargic: Ms. K, age 48, presents with new-onset altered mental status, hypotension, bradycardia, and severe hypothermia. How would you manage her? L.

CASE Confused and cold

Ms. K, age 48, is brought to the emergency department (ED) by her husband because she has become increasingly lethargic over the past 2 weeks and cannot attend to activities of daily living. She is incontinent of stool and poorly responsive.

Ms. K's husband reports that lethargy culminated in his wife sleeping 30 continuous hours. She has a history of a ruptured cerebral arteriovenous malformation (AVM) complicated by a secondary infarct 7 years ago, with residual symptoms of frontal lobe syndrome. Until 2 weeks ago, however, she was in her usual state of health.

Symptoms have included depression, mood lability, impulsivity, disinhibition, poor focus, and apathy. An outpatient psychiatrist has managed these symptoms with antidepressants and atypical antipsychotics.

When Ms. K arrives in the ED, she is taking citalopram, 30 mg/d, and paliperidone, 6 mg/d. Her psychiatrist started paliperi-done 2 months ago, increasing the dosage to 6 mg/d 6 weeks before presentation because of worsening mood lability, disinhibition, and paranoia regarding her caregivers. Her husband denies any other medication changes or exposure to environmental toxins.

In the ED, Ms. K is confused and oriented only to person. Vital signs are: pulse 46 bpm; blood pressure, 66/51 mm Hg; respirations, 12/min; and temperature, 29.9[degrees]C (85.8[degrees]F) via bladder probe.

What is your differential diagnosis?

a) major depressive disorder, severe, with catatonic features

b) exposure to cold

c) hypothyroidism

d) drug-induced hypothermia

e) stroke

f) sepsis

g) delirium

The authors' observations

Hypothermia is core body temperature <35[degrees]C (95"F).1 It often is caused by exposure to low ambient temperature (Table 1, page 72),' but Ms. K's husband denied that she had been exposed to cold. Because of Ms. K's neurologic history, stroke was high on the differential diagnosis, but physical examination did not reveal evidence of focal dysfunction and was significant only for altered mental status.


Causes of hypothermia

Diabetic ketoacidosis


Low ambient temperature

Multisystem trauma

Prolonged cardiac arrest


Severe hypothyroidism

Source: Reference 1

Ms. K had no posturing, rigidity, negativism, or excessive motor activity that would suggest catatonia. Before she became lethargic, her husband had not noted any deterioration of mood, although she did exhibit other behavioral changes that prompted her outpatient psychiatrist to increase the dosage of paliperidone. Although Ms. K began experiencing persecutory delusions--she believed that her caregivers were trying to harm her--she and her family denied perceptual disturbances. On examination, she did not appear responsive to auditory or visual hallucinations.

Frontal lobe syndrome is defined as a set of changes in the cognitive, behavioral, or emotional domains, often leading to disturbed affect, alteration of attention, aphasia, perseveration, disinhibition, and personality changes. (2) These symptoms are not specific to lesions in the frontal lobes but can arise from lesions anywhere in the frontal-striatal-thalamic circuit. (3) Causes include traumatic brain injury, neurodegenerative disorders, cerebrovascular disease, tumors, and aging. (2) Recommended treatment incorporates psychosocial interventions with drug treatment to target specific symptoms. Medications reported to be effective include typical and atypical antipsychotics to target aggression and agitation; benzodiazepines to reduce arousal.; antidepressants for mood symptoms, dopamine agonists (eg, bromocriptine) to decrease apathy, and mood stabilizers to target mood lability. (4)

Before her AVM rupture, review of Ms. K's psychiatric history revealed no psychiatric symptoms or impaired functioning. When hospitalized for the AVM repair, she was started on sertraline. She began seeing a psychiatrist 2 years later because of increased agitation and behavioral disturbances, and aripiprazole was added. Persistent agitation prompted a trial of di-valproex sodium, which was discontinued because of slurred speech and increased distractibility. Aripiprazole was tapered and replaced with paliperidone because of poor response. Citalopram was initiated 1 year before she presented to the ED.

Which tests would you order?

a) brain MRI

b) infectious evaluation (lumbar puncture with analysis of cerebrospinal fluid, complete blood count, blood cultures, chest radiographs)

c) endocrine panel

d) urine toxicology screen

EVALUATION Hypothermia

Laboratory tests reveal multiple abnormalities, including thrombocytopenia (platelet level, 53 x[10.sup.3]/[micro]L), altered coagulation (partial thromboplastin time, 55.6 s), elevated levels of hepatic transaminases (aspartate aminotransferase, 168 U/L; alanine aminotransferase, 357 U/L), and increased alkaline phosphatase (206 U/L). Other mild metabolic disturbances include: sodium, 149 mEq/L; C[O.sub.2], 33 mEq/L; and blood urea nitrogen, 24 mg/dL.

These laboratory values are consistent with complications of hypothermia. (1)

ECG reveals sinus bradycardia (40 bpm) and Osborn waves (additional deflection at the end of the QRS complex), which are seen often in hypothermia. (1) Head CT and brain MRI show chronic changes after Ms. K's right temporoparietal AVM rupture, but no acute abnormality. Urinalysis, blood cultures, and chest radiographs are negative for infection. Urine toxicology screen is negative. Results of thyroid function tests and pituitary hormones studies are significant only for hyperprolac-tinemia of 155.7 ng/mL, a known adverse effect of antipsychotics. (5)

Ms. K is admitted and rewarmed passively and with warm IV fluids; by day 10 of hospitalization, temperature is stable (>35.1[degrees]C [95.2[degrees]H). 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, 34.4[degrees]C (93.9[degrees]F) via bladder probe (Figure, page 75). 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," 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, induding 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-rechallertge, and the resulting hypothermia, are, we concluded, evidence of an adverse drug reaction.

Table 2

Naranjo Causality Scale: Connecting adverse events to a drug

                                         Do not know/
Question                       Yes   No      Not done
Are there previous conclusive   +1    0             0
reports on this reaction?

Did the adverse event appear    +2   -1             0
after the suspected drug was

Did the adverse reaction        +1   0              0
improve when the drug was
discontinued or a specific
antagonist was given?

Did the adverse reaction        +2  -1              0
appear when the drug was

Are there alternative causes     1  +2              0
that could have caused the

Did the reaction reappear       -1  +1              0
when a placebo was given?

Was the drug detected in any    +1   0              0
body fluid in toxic

Was the reaction more severe    +1   0              0
when the dose was increased,
or less severe when the dose
was decreased?

Did the patient have a similar  +1   0              0
reaction to the same or
similar drugs in any previous

* >9 = definitive adverse drug reaction
* 5 to 8 = probable adverse drug reaction
* 1 to 4 = possible adverse drug reaction
* 0 = doubtful adverse drug reaction
Source: Reference 6

Using the World Health Organization database for adverse drug reactions, van Marum et al (7) 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 a17 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 indudes 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 a2-adrenergic blockade, which might increase the hypothermic effect by inhibiting peripheral responses to cooling, such as vasoconstriction and shivering. (7), (8) Boschi et a1 (13) 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 paliperi-done is mediated though a D2, 5-HT2A, and a2-receptor antagonism (5); 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 thermoregula tory 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)

Additionally, persons with schizophrenia might be at increased risk of developing hypothermia when exposed to a low environmental temperature. (7), (8) Kudoh et al (19) investigated temperature regulation during anesthesia in patients with chronic ([great than or equal to]7 years) schizophrenia receiving antipsychotics, and compared findings against what was seen in controls. The team reported that patients with schizophrenia had significantly lower intraoperative temperatures.

A published analysis of cases and studies of antipsychotic-induced hypothermia describes the combination of drug variables, patient variables, and environmental variables that contribute to thermal dysregulation (Table 3). (7-12), (15) The recommendation for practitioners is that, when considering an antipsychotic for a patient at high risk of thermal dysregulation, your choice of an agent should take that risk into account, especially when that drug is one that has comparatively stronger serotonergic and peripheral a-adrenergic effects. You should monitor patients closely for hypothermia after starting and when increasing the dosage of the drug. In patients with schizophrenia who might have a problem with baseline thermoregulation, advise them to take measures to counteract their increased susceptibility to low ambient temperatures.

Table 3

Risk factors for hypothermia

Drug         * 5-HT2A receptor antagonism > dopamine receptor
             antagonism (eg, atypical antipsychotics)
             * Peripheral u2-adrenergic blockage (eg,
             chlorpromazine, risperidone, clozapine,

Patient      * Schizophrenia diagnosis
             * Preexisting brain damage

Environment  * Low ambient temperature

Source: References 7-12,15

OUTCOME Readmission

Ms. K was readmitted, rewarmed, and discharged to a skilled nursing facility 4 days later, after baseline function returned to normal and temperature stabilized. Paliperidone is now listed in her electronic medical record as "drug intolerance."

This case also highlights the importance of adequate medication reconciliation at admission and discharge, especially when using an electronic medical record system, because what might otherwise be considered a minor mistake can have devastating consequences.


The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

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Clinical Point

Medications for frontal lobe syndrome include typical and atypical antipsychotics, dopamine agonists, and mood stabilizers

Discuss this article at

Clinical Point

The Naranjo Causality Scale often is used to evaluate whether an adverse clinical event has been caused by a drug

Clinical Point

Patients with preexisting brain damage--such as Ms. K--might be at increased risk of antipsychotic-induced hypothermia

Clinical Point

Persons with schizophrenia might be at increased risk of developing hypothermia when exposed to low temperatures

Clinical Point

Monitor patients at risk of thermal dysregulation for hypothermia after starting and when increasing the dosage of an antipsychotic

RELATED ARTICLE: Related Resource

* Espay AJ, et al. Frontal lobe syndromes. Updated September 17, 2012. Accessed November 3, 2012.

Drug Brand Names

Lamotrigine * Lamictal

Lorazepam *Ativan

Paliperidone * lnvega

Risperidone * Risperdal

Sertraline *Zoloft

Thioridazine * Mellaril


Thermal dysregulation--hyperthermia and hypothermia--can occur secondary to an antipsychotic. Determining whether a patient is at increased risk of either of these adverse effects is important when deciding to use antipsychotics. Recognizing agents that can cause hypothermia is essential, because management requires prompt discontinuation of the offending drug.


(1.) Aslam AF, Aslam AK, Vasavada BC, et al. Hypothermia: evaluation, electrocardiographic manifestations, and management. Am J Med. 2006;119(4):297-301.

(2.) Hanna-Pladdy B. Dysexecutive syndromes in neurologic disease. .J Neurol Phys Ther. 2007;31(3)119-127.

(3.) Salloway SP. Diagnosis and treatment of patients with "frontal lobe" syndromes. J Neuropsychiatry Clin Neurosci. 1994;6(4):388-398.

(4.) Campbell JJ, Duffy JD, %noway SP. Treatment strategies for patients with dysexecutive syndromes. In: Salloway SP, Malloy PF, Duffy JD, eds. The frontal lobes and neuropsychiatric illness. Washington, DC: American Psychiatric Press; 2001:153-163.

(5.) Stahl SM. Essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. New York, NY: Cambridge University Press; 2000:336.

(6.) Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 198130(2):239-245.

(7.) van Marum RJ, Wegewijs MA, Loonen AJM, et al. Hypothermia following antipsychotic drug use. Eur J an Pharmacol. 2007;63(6):627-631.

(8.) Kreuzer P, Landgrebe M, Wittmann M, et al. Hypothermia associated with antipsychotic drug use: a clinical case series and review of current literature. J Clin Pharmacol. 2012;52(7)1090-1097.

(9.) Hung CE Huang TY, Lin PY. Hypothermia and rhabdomyolysis following olanzapine injection in an adolescent with schizophreniform disorder. Gen Hasp Psychiatry. 2009;31(4):376-378.

(10.) Rang M, Samma M. A case of risperidone-induced hypothermia. Am J Then 2004;11(3):229-230.

(11.) Schwaninger M, Weisbrod M, Schwab S. etal. Flypothennia induced by atypical neuroleptics. Clin Neuropharmacol. 1998;21(6):344-346.

(12.) Bookstaver PB, Miller AD. Possible long-acting risperidone-induced hypothermia precipitating phenytoin toxicity in an elderly patient. J Clin Pharm Ther. 2011; 36(3):426-429.

(13.) Boschi G, Launay N, Rips R. Neuroleptic-induced hypothermia in mice: lack of evidence for a central mechanism. Br J Pharmacol. 1987;90(4):745-751.

(14.) Sessler DI. Thermoregulatory defense mechanisms. Crit Care Med. 2009;37(suppl 7):S203-S210.

(15.) Shiloh R, Weizman A, Epstein Y, et al. Abnormal thermoregulation in drug-free male schizophrenia patients. Eur Nettropsychopharmacol. 2001;11(4):285-288.

(16.) McCann SM, Vijay-cm E. Control of anterior pituitary hormone secretion by neurotensin. Ann N Y Acad Sci. 1992; 668:287-297.

(17.) Chandra A, Chou HC, Chang C, et al. Effecst of intraventricular administration of neurotensin and sornatostatin on thermoregulation in the rat. Neuropharmacology. 1981;20(7):715-718.

(18.) Sharma RP, Janicak PG, Bissette G, et al. CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorder. Am J Psychiatry. 1997; 154(7):1019-1021.

(19.) Kudoh A, Takase H, Takazawa T. Chronic treatment with antipsychotics enhances intraoperative core hypothermia. Anesth Analg. 2004;98(1):111-115.

Caridad Ponce Martinez, MD, Christopher P. Holstege, MD, and Nassima Ait-Daoud, MD

Dr. Ponce is a Resident Physician, Department of Psychiatry and Neurobehavioral Sciences, Dr. Holstege is Associate Professor, Department of Emergency Medicine, Division of Toxicology, and Dr. Ait-Daoud is Associate Professor, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.
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Title Annotation:Cases That Test Your Skills
Author:Martinez, Caridad Ponce; Holstege, Christopher R; Ait-Daoud, Nassima
Publication:Current Psychiatry
Article Type:Case study
Date:Feb 1, 2014
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