Confused, Cold, and Lethargic Caridad Ponce Martinez, MD, Christopher P

Cases That Test Your Skills

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

Ms. K, age 48, presents with new-onset altered mental status, How would you hypotension, bradycardia, and severe hypothermia. How would handle this case? Visit CurrentPsychiatry.com you manage her? to input your answers and see how your colleagues responded

CASE Confused and cold 12/min; and temperature, 29.9ºC (85.8ºF) via Ms. K, age 48, is brought to the emergency bladder probe. department (ED) by her husband because she has become increasingly lethargic over the What is your differential diagnosis? past 2 weeks and cannot attend to activities a) major depressive disorder, severe, with of daily living. She is incontinent of stool and catatonic features poorly responsive. b) exposure to cold Ms. K’s husband reports that lethargy cul- c) hypothyroidism minated in his wife sleeping 30 continuous d) drug-induced hypothermia hours. She has a history of a ruptured cerebral e) stroke arteriovenous malformation (AVM) compli- f) sepsis cated by a secondary infarct 7 years ago, with g) delirium residual symptoms of frontal lobe syndrome. Until 2 weeks ago, however, she was in her The authors’ observations usual state of health. Hypothermia is core body temperature Symptoms have included depression, <35ºC (95ºF).1 It often is caused by exposure mood lability, impulsivity, disinhibition, poor to low ambient temperature (Table 1, page focus, and apathy. An outpatient psychiatrist 72),1 but Ms. K’s husband denied that she has managed these symptoms with antide- had been exposed to cold. Because of Ms. pressants and atypical antipsychotics. K’s neurologic history, stroke was high on When Ms. K arrives in the ED, she is tak- the differential diagnosis, but physical ex- ing citalopram, 30 mg/d, and paliperidone, amination did not reveal evidence of focal 6 mg/d. Her psychiatrist started paliperi- dysfunction and was significant only for done 2 months ago, increasing the dosage to altered mental status. 6 mg/d 6 weeks before presentation because Dr. Ponce is a Resident Physician, Department of Psychiatry and of worsening mood lability, disinhibition, and Neurobehavioral Sciences, Dr. Holstege is Associate Professor, paranoia regarding her caregivers. Her hus- Department of Emergency Medicine, Division of Toxicology, and Dr. Ait-Daoud is Associate Professor, Department of Psychiatry and band denies any other medication changes or Neurobehavioral Sciences, University of Virginia, Charlottesville, exposure to environmental toxins. Virginia. In the ED, Ms. K is confused and oriented Disclosure only to person. Vital signs are: pulse 46 bpm; The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers Current Psychiatry blood pressure, 66/51 mm Hg; respirations, of competing products. Vol. 13, No. 2 71 continued Cases That Test Your Skills

Table 1 decrease apathy, and mood stabilizers to target mood lability.4 Causes of hypothermia Before her AVM rupture, review of Ms. Diabetic ketoacidosis K’s psychiatric history revealed no psychi- Drugs atric symptoms or impaired functioning. Low ambient temperature When hospitalized for the AVM repair, Multisystem trauma she was started on sertraline. She began Prolonged cardiac arrest seeing a psychiatrist 2 years later because Sepsis of increased agitation and behavioral dis- Severe hypothyroidism turbances, and aripiprazole was added. Source: Reference 1 Persistent agitation prompted a trial of divalproex sodium, which was discontinued Clinical Point because of slurred speech and increased distractibility. Aripiprazole was tapered Medications Ms. K had no posturing, rigidity, negativ- and replaced with paliperidone because for frontal lobe ism, or excessive motor activity that would of poor response. Citalopram was initiated syndrome include suggest catatonia. Before she became lethar- 1 year before she presented to the ED. typical and atypical gic, her husband had not noted any dete- antipsychotics, rioration of mood, although she did exhibit Which tests would you order? other behavioral changes that prompted her a) brain MRI dopamine agonists, outpatient psychiatrist to increase the dos- b) infectious evaluation (lumbar puncture and mood stabilizers age of paliperidone. Although Ms. K began with analysis of cerebrospinal fluid, experiencing persecutory delusions—she complete blood count, blood cultures, believed that her caregivers were trying to chest radiographs) harm her—she and her family denied per- c) endocrine panel ceptual disturbances. On examination, she d) urine toxicology screen did not appear responsive to auditory or vi- sual hallucinations. Frontal lobe syndrome is defined as a EVALUATION Hypothermia set of changes in the cognitive, behavioral, Laboratory tests reveal multiple abnormali- or emotional domains, often leading to ties, including thrombocytopenia (platelet disturbed affect, alteration of attention, level, 53 ×103/μL), altered coagulation (partial aphasia, perseveration, disinhibition, and thromboplastin time, 55.6 s), elevated levels of personality changes.2 These symptoms are hepatic transaminases (aspartate aminotrans- not specific to lesions in the frontal lobes ferase, 168 U/L; alanine aminotransferase, but can arise from lesions anywhere in the 357 U/L), and increased alkaline phosphatase frontal-striatal-thalamic circuit.3 Causes (206 U/L). Other mild metabolic disturbances

include traumatic brain injury, neurode- include: sodium, 149 mEq/L; CO2, 33 mEq/L; generative disorders, cerebrovascular dis- and blood urea nitrogen, 24 mg/dL. ease, tumors, and aging.2 Recommended These laboratory values are consistent with 1 Discuss this article at treatment incorporates psychosocial in- complications of hypothermia. www.facebook.com/ terventions with drug treatment to target ECG reveals sinus bradycardia (40 bpm) CurrentPsychiatry specific symptoms. Medications reported and Osborn waves (additional deflection at to be effective include typical and atypical the end of the QRS complex), which are seen antipsychotics to target aggression and ag- often in hypothermia.1 Head CT and brain itation; benzodiazepines to reduce arousal; MRI show chronic changes after Ms. K’s right antidepressants for mood symptoms, do- temporoparietal AVM rupture, but no acute Current Psychiatry 72 February 2014 pamine agonists (eg, bromocriptine) to abnormality. Urinalysis, blood cultures, and Cases That Test Your Skills

Table 2 Naranjo Causality Scale: Connecting adverse events to a drug Do not know/ Question Yes No Not done Are there previous conclusive reports on this reaction? +1 0 0 Did the adverse event appear after the suspected drug was +2 –1 0 given? Did the adverse reaction improve when the drug was +1 0 0 discontinued or a specific antagonist was given? Did the adverse reaction appear when the drug was +2 –1 0 readministered? Are there alternative causes that could have caused the –1 +2 0 reaction? Did the reaction reappear when a placebo was given? –1 +1 0 Clinical Point Was the drug detected in any body fluid in toxic +1 0 0 The Naranjo concentrations? Causality Scale often Was the reaction more severe when the dose was increased, +1 0 0 or less severe when the dose was decreased? is used to evaluate Did the patient have a similar reaction to the same or similar +1 0 0 whether an adverse drugs in any previous exposure? clinical event has Scoring: • >9 = definitive adverse drug reaction been caused by a • 5 to 8 = probable adverse drug reaction • 1 to 4 = possible adverse drug reaction drug • 0 = doubtful adverse drug reaction Source: Reference 6

chest radiographs are negative for infection. as needed), and discontinuing antipsychotics Urine toxicology screen is negative. Results of are recommended. After she returns to her thyroid function tests and pituitary hormones baseline functioning, Ms. K is discharged to a studies are significant only for hyperprolac- skilled nursing facility. tinemia of 155.7 ng/mL, a known adverse ef- Ms. K presents to the ED 2 days after dis- fect of antipsychotics.5 charge with altered mental status. Vital signs Ms. K is admitted and rewarmed passively are: blood pressure, 90/55 mm Hg; pulse, 59 and with warm IV fluids; by day 10 of hos- bpm; respiratory rate, 14/min; and temperature, pitalization, temperature is stable (>35.1ºC 34.4ºC (93.9ºF) via bladder probe (Figure, page [95.2ºF]). Thrombocytopenia, transaminitis, 75). Laboratory tests were significant for hepatic and altered mental status resolve. transaminitis (aspartate aminotransferase, 75 Ms. K’s oral medications, including citalo- U/L; alanine aminotransferase, 122 U/L) and el- pram and paliperidone, have been held since evated alkaline phosphatase (226 U/L). A review admission because of her altered mental of records from the nursing facility revealed that status. The psychiatry service is consulted to Ms. K was receiving paliperidone because of an evaluate whether her presentation could be error in the discharge summary, which recom- related to her change of medication. mended restarting all prior medications. A literature search reveals no report of paliperidone-induced hypothermia, but The authors’ observations we consider it a possible explanation for The Naranjo Causality Scale,6 which cat- Ms. K’s presentation. Lamotrigine (titrated to egorizes the probability that an adverse Current Psychiatry 50 mg/d), a benzodiazepine (oral lorazepam event is related to a drug (based on several Vol. 13, No. 2 73 Cases That Test Your Skills

Table 3 Risk factors for hypothermia Drug • 5-HT2A receptor antagonism > dopamine receptor antagonism (eg, atypical antipsychotics) • Peripheral α2-adrenergic blockage (eg, chlorpromazine, risperidone, clozapine, thioridazine) Patient • Schizophrenia diagnosis • Preexisting brain damage Environment • Low ambient temperature Source: References 7-12,15

Clinical Point variables, including timing of the drug ad- or dosage increase of the antipsychotic. ministration with the onset of event, drug These observations have been noted in Patients with dosage and levels, response relationships case reports and case series of hypother- preexisting brain to a drug, including re-challenge when pos- mia associated with antipsychotic use.8-12 damage—such as sible, and previous patient experience with Ms. K—might be the medication), often is used to evaluate at increased risk whether an adverse clinical event has been Mechanism of action caused by a drug (Table 2). We applied the One proposed mechanism for antipsychot- of antipsychotic- Scale to Ms. K’s case, which revealed a score ic-induced hypothermia includes prefer- induced hypothermia of 7—indicating a probable adverse drug re- ential 5-HT2A receptor antagonism over action. The sequence of events in Ms. K’s D2 receptor antagonism.7,12 It has been be- case that led to a paliperidone challenge- lieved that, under normal conditions, the dechallenge-rechallenge, and the resulting action of dopamine to reduce body temper- hypothermia, are, we concluded, evidence ature and the action of serotonin to elevate of an adverse drug reaction. it are in balance.9 Using the World Health Organization Another possible mechanism is periph- database for adverse drug reactions, van eral α2-adrenergic blockade, which might Marum et al7 found 480 reports hypother- increase the hypothermic effect by inhibiting mia with antipsychotics as of 2007 (com- peripheral responses to cooling, such as va- pared with 524 reports of hyperthermia soconstriction and shivering.7,8 Boschi et al13 in the same period); 55% involved atypi- found that antipsychotics cause hypother- cal antipsychotics, mainly risperidone. mia in rats when the drug is administered There are no case reports of paliperidone- intraperitoneally but not when given intra- induced hypothermia; however, several thecally. Perhaps for these reasons, in the reports of hypothermia have been attribut- early 1950s, before its psychotropic proper- ed to risperidone, and paliperidone is the ties were known, chlorpromazine was used primary active metabolite of risperidone.5 during surgery to induce artificial hiberna- To identify risk factors for hypothermia tion and suppress the body’s response to with antipsychotic use, van Marum et al7 cooling.7 The therapeutic activity of paliperi- performed a literature search for case re- done is mediated though a D2, 5-HT2A, and ports of antipsychotic-induced hypother- α2-receptor antagonism5; these mechanisms mia, which revealed no association with could, therefore, be contributing to Ms. K’s age or sex. The most common diagnosis in hypothermia. cases of antipsychotic-induced hypother- Patients with preexisting brain damage— mia was schizophrenia (51%). In 73% of such as Ms. K—might be at increased risk Current Psychiatry 74 February 2014 the cases, hypothermia followed the start of antipsychotic-induced hypothermia.7,8 Cases That Test Your Skills

Figure Ms. K’s temperature during hospitalization

33 Temperature

e (°C) Source Bladder 31 Oral Clinical Point

emperatur Rectal T 29 Axillary Persons with schizophrenia might Re-admission 27 be at increased risk of developing 25 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 hypothermia when Hospitalization day exposed to low temperatures

This includes focal damage to central ther- nia might be at increased risk of develop- moregulatory centers, such as the pre-optic ing hypothermia when exposed to a low anterior hypothalamic region,14 and more environmental temperature.7,8 Kudoh et al19 diffuse damage seen in patients with cogni- investigated temperature regulation during tive impairment or a seizure disorder.8 anesthesia in patients with chronic (≥7 years) Studies of people with schizophrenia schizophrenia receiving antipsychotics, and show a decrease in core temperature after compared findings against what was seen administration of an antipsychotic,15 rais- in controls. The team reported that patients ing the possibility of an impairment of with schizophrenia had significantly lower baseline thermoregulatory control. Such intraoperative temperatures. thermal dysregulation in patients with A published analysis of cases and studies schizophrenia might be explained by of antipsychotic-induced hypothermia de- changes in neurotensin levels.7 scribes the combination of drug variables, The neuropeptide neurotensin has been patient variables, and environmental vari- implicated in the regulation of prolactin re- ables that contribute to thermal dysregula- lease and interacts to a significant degree tion (Table 3).7-12,15 The recommendation for with the dopaminergic system.16 When ad- practitioners is that, when considering an ministered to animals, neurotensin suppress- antipsychotic for a patient at high risk of es heat production and increases heat loss.17 thermal dysregulation, your choice of an The neurotensin level in CSF was found to agent should take that risk into account, be lower in non-medicated patients with especially when that drug is one that has schizophrenia than in healthy controls, with comparatively stronger serotonergic and an inverse correlation between the severity peripheral α-adrenergic effects. You should of symptoms and the neurotensin level.18 monitor patients closely for hypothermia Current Psychiatry Additionally, persons with schizophre- after starting and when increasing the dos- Vol. 13, No. 2 75 Cases That Test Your Skills

3. Salloway SP. Diagnosis and treatment of patients with “frontal lobe” syndromes. J Neuropsychiatry Clin Neurosci. Related Resource 1994;6(4):388-398. • Espay AJ, et al. Frontal lobe syndromes. http://emedicine. 4. Campbell JJ, Duffy JD, Salloway SP. Treatment strategies medscape.com/article/1135866-overview. Updated for patients with dysexecutive syndromes. In: Salloway September 17, 2012. Accessed November 3, 2012. SP, Malloy PF, Duffy JD, eds. The frontal lobes and neuropsychiatric illness. Washington, DC: American Drug Brand Names Psychiatric Press; 2001:153-163. Aripiprazole • Abilify Lamotrigine • Lamictal 5. Stahl SM. Essential psychopharmacology: neuroscientific Bromocriptine • Parlodel Lorazepam • Ativan basis and practical applications. 3rd ed. New York, NY: Cambridge University Press; 2000:336. Chlorpromazine • Thorazine Paliperidone • Invega Citalopram • Celexa Risperidone • Risperdal 6. Naranjo CA, Busto U, Sellers EM, et al. A method for Clozapine • Clozaril Sertraline • Zoloft estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239-245. Divalproex sodium • Depakote Thioridazine • Mellaril 7. van Marum RJ, Wegewijs MA, Loonen AJM, et al. Hypothermia following antipsychotic drug use. Eur J Clin Pharmacol. 2007;63(6):627-631. 8. Kreuzer P, Landgrebe M, Wittmann M, et al. Hypothermia associated with antipsychotic drug use: a clinical case Clinical Point age of the drug. In patients with schizo- series and review of current literature. J Clin Pharmacol. phrenia who might have a problem with 2012;52(7)1090-1097. Monitor patients 9. Hung CF, Huang TY, Lin PY. Hypothermia and baseline thermoregulation, advise them to rhabdomyolysis following olanzapine injection in an at risk of thermal adolescent with schizophreniform disorder. Gen Hosp take measures to counteract their increased Psychiatry. 2009;31(4):376-378. dysregulation for susceptibility to low ambient temperatures. 10. Razaq M, Samma M. A case of risperidone-induced hypothermia. Am J Ther. 2004;11(3):229-230. hypothermia after 11. Schwaninger M, Weisbrod M, Schwab S, et al. Hypothermia starting and when induced by atypical neuroleptics. Clin Neuropharmacol. OUTCOME Readmission 1998;21(6):344-346. increasing the dosage 12. Bookstaver PB, Miller AD. Possible long-acting Ms. K was readmitted, rewarmed, and dis- risperidone-induced hypothermia precipitating phenytoin of an antipsychotic toxicity in an elderly patient. J Clin Pharm Ther. 2011; charged to a skilled nursing facility 4 days 36(3):426-429. later, after baseline function returned to nor- 13. Boschi G, Launay N, Rips R. Neuroleptic-induced hypothermia in mice: lack of evidence for a central mal and temperature stabilized. Paliperidone mechanism. Br J Pharmacol. 1987;90(4):745-751. is now listed in her electronic medical record 14. Sessler DI. Thermoregulatory defense mechanisms. Crit as “drug intolerance.” Care Med. 2009;37(suppl 7):S203-S210. 15. Shiloh R, Weizman A, Epstein Y, et al. Abnormal This case also highlights the importance thermoregulation in drug-free male schizophrenia patients. of adequate medication reconciliation at Eur Neuropsychopharmacol. 2001;11(4):285-288. 16. McCann SM, Vijayan E. Control of anterior pituitary admission and discharge, especially when using hormone secretion by neurotensin. Ann N Y Acad Sci. 1992; an electronic medical record system, because 668:287-297. 17. Chandra A, Chou HC, Chang C, et al. Effecst what might otherwise be considered a minor of intraventricular administration of neurotensin and somatostatin on thermoregulation in the rat. mistake can have devastating consequences. Neuropharmacology. 1981;20(7):715-718. 18. Sharma RP, Janicak PG, Bissette G, et al. CSF neurotensin References concentrations and antipsychotic treatment in schizophrenia 1. Aslam AF, Aslam AK, Vasavada BC, et al. Hypothermia: and schizoaffective disorder. Am J Psychiatry. 1997; evaluation, electrocardiographic manifestations, and 154(7):1019-1021. management. Am J Med. 2006;119(4):297-301. 19. Kudoh A, Takase H, Takazawa T. Chronic treatment with 2. Hanna-Pladdy B. Dysexecutive syndromes in neurologic antipsychotics enhances intraoperative core hypothermia. disease. J Neurol Phys Ther. 2007;31(3):119-127. Anesth Analg. 2004;98(1):111-115.

Bottom Line 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 Current Psychiatry 76 February 2014 requires prompt discontinuation of the offending drug.