Skip to main content

A case report of acute hypothermia during initial inpatient clozapine titration with review of current literature on clozapine-induced temperature dysregulations



Here we describe a unique case of clozapine-associated hypothermia during initial titration of this medication in an acute inpatient psychiatry setting. Only a handful of cases on this topic have been published. We discuss possible pharmacologic mechanisms supporting or refuting the propensity of clozapine to induce hypothermia, as well as risk factors for clozapine-induced hypothermia, and a comparison to clozapine-induced hyperthermia.

Case presentation

A 70 year-old African American female with treatment-refractory schizoaffective disorder developed hypothermia with a nadir temperature of 89 °F (31.7 °C) after 7 days on clozapine, on a total dose of 50 mg twice daily. Accompanying symptoms included bradycardia, hypotension, QTc prolongation, tachypnea, hypoxemia, and an absence of shivering. The patient was transferred to the ICU, and rewarmed within 10 h with the discontinuation of her clozapine, ziprasidone, and carvedilol. Broad spectrum antibiotics were initiated, but discontinued shortly after, as the patient had no leukocytosis, and blood cultures were negative.


While hypoglycemia, hypothyroidism, sepsis, and stroke were effectively ruled out, alternative drug-disease (including chronic kidney disease), and drug-drug interactions were considered possible contributing features. Benzodiazepines, valproic acid, ziprasidone, and the numerous antihypertensive agents the patient was taking were considered as either primary or compounding factors for hypothermia. After exclusion or inclusion of these alternative causes, we calculated a score of 4 (possible) for clozapine-induced hypothermia on the Naranjo Scale.


Clozapine-induced hypothermia may occur more commonly than clinicians believe. Practitioners should be cognizant of this potentially fatal phenomenon, and monitor for temperature dysregulations while on clozapine, especially during initial titration, in those with multiple comorbid factors, and on additional medications that may contribute to hypothermia.

Peer Review reports


While it is well established that antipsychotics may induce hyperthermia (an often-recognized part of neuroleptic malignant syndrome), hypothermia from these agents may be vastly under-recognized and under-represented within medical literature [1]. It was with the advent of chlorpromazine in the 1950s that the first case report of phenothiazine-induced hypothermia was published [2]. In an older review of neuroleptic-induced temperature dysregulations using primarily first-generation agents in various species, the authors found these agents decreased body temperature in 321 of 651 studies, and increased it in 183 cases [3]. However, of the studies specifically in humans, temperature decreased in only 26 of 153 cases, and increased in 127 cases [3]. A lack of systematic reviews with newer antipsychotics has left a gap in knowledge.

A publication from 2017 examined original case reports of possible antipsychotic-induced hypothermia [4]. The risk of hypothermia appears to be highest during the first 7 days of therapy, but may occur after the first dose [1, 4, 5]. Additional factors, such as advanced age, cold exposure, use of benzodiazepines, and hypothyroidism (subclinical), were also noted to predispose a patient on antipsychotics to hypothermia [1, 6]. Of the 57 case reports analyzed, 52% were with second-generation antipsychotics [4]. These second-generation antipsychotic-induced hypothermia cases were further investigated in a more recent review, which found olanzapine and risperidone to be the most common causes of hypothermia [7]. Based on the comparatively larger number of hypothermia reports to drug-monitoring agencies such as Food and Drug Administration (FDA) Medwatch and World Health Organization (WHO), these authors also concluded that the incidence of hypothermia is at least 10 times higher than is indicated by published literature [4, 6, 7]. Indeed, if one were to compare the 591 cases of hypothermia with second-generation antipsychotics reported to the FDA to the 34 published case reports, this estimate seems highly conceivable [7].

Although one report speculated clozapine may be safely utilized in those with a history of hypothermia from alternative antipsychotics, newer reports suggests this may not be the case [8, 9]. Here we present a unique case of hypothermia occurring on initial titration of clozapine during an inpatient psychiatry admission. We also aim to provide clinicians with greater insight into clozapine-induced temperature dysregulations.

Case presentation

Ms. P is a 70-year-old African-American female with a history of schizoaffective disorder (bipolar type), vascular dementia, hypertension, coronary artery disease, chronic heart failure, dissected ascending aortic aneurysm, and chronic kidney disease (CKD) admitted to inpatient psychiatry for symptoms of mania and delusions. Her hospital admission was complicated by profound hypertension, acute kidney injury, and an acute on chronic heart failure exacerbation.

Records indicated Ms. P was prescribed risperidone prior to her hospitalization, which was restarted upon admission at a dose of 1.5 mg daily, titrated to 4 mg daily and continued for 3 weeks. Her risperidone was subsequently switched to olanzapine 5 mg daily, which was titrated to dose of 20 mg daily and continued for 2 weeks, then later changed to ziprasidone 40 mg twice daily. Due to inadequate response to all of these agents, she was ultimately placed on clozapine for her refractory schizoaffective symptoms. At this time, she was kept on ziprasidone with anticipation of tapering off after titrating clozapine to an adequate dose. The clozapine was started at a dose of 12.5 mg twice daily, titrated up to 25 mg twice daily after six doses, then up to 50 mg twice daily after three doses. The patient’s medication list during hospitalization is located in Table 1.

Table 1 Prescribed medications and corresponding doses Ms. P was taking at the time of hypothermia onset

On day 50 of admission, Ms. P developed hypothermia, with a temperature of 90.8 °F (32.7 °C). By the next morning (day 7 of clozapine trial), she displayed hypoxemia (O2 saturation 88%), tachypnea, and worsening hypothermia (Fig. 1). While the patient had been intermittently bradycardic prior to this, her heart rate was lower during this event, ranging between 40 and 50 beats per minute. The patient displayed both hypotension as well as hypertension during this event, with blood pressure readings between 96 and 153 mmHg systolic and 39–75 mmHg diastolic. She appeared somnolent and confused at this time, and remarked that she was cold (and had cold extremities to touch); however, no shivering was noted on exam.

Fig. 1
figure 1

Temperature (°F) log prior to and during hypothermic event

Due to concerns for sepsis, Ms. P was transferred to the intensive care unit, where she became normothermic within approximately 10 h with the use of warming blankets, and the discontinuation of her clozapine, ziprasidone, and carvedilol. Laboratory values were remarkable for elevated procalcitonin (0.61 ng/mL), hypoxemia, and hypercapnia, while other values were within normal limits (Table 2). Broad-spectrum antibiotics were initiated, but were discontinued after 3 days as the patient had no leukocytosis, and blood cultures were negative. Her electrocardiogram was significant for bradycardia with vagally mediated pauses, and a prolonged QTc (505 milliseconds), but no Osborn J-waves were apparent. An echocardiogram conducted did not find any valvular vegetation, but noted a reduced ejection fraction of 49% (baseline 55%). A prior CT of the head within the previous 4 months displayed chronic lacunar infarcts within the left thalamus and right centrum semiovale, but no acute abnormalities or changes. A repeat CT scan was not performed during her hypothermic episode.

Table 2 Laboratory test results performed at time of hypothermia onset


Other considerations of secondary hypothermia included hypothyroidism, hypoglycemia, stroke, and sepsis. However, as indicated in Table 2, the patient’s thyroid stimulating hormone (TSH) and blood glucose drawn at the time of the hypothermic episode were within normal limits. As the patient did not present with leukocytosis and all blood cultures and viral panels returned negative, sepsis was ruled out as a likely cause of the hypothermia. Although altered mental status was noted, stroke was excluded, as neurologic exam was grossly normal. In addition, while we recognize antihypertensives as a potential cause, secondary to their ability to inhibit vasoconstriction and shivering, we do not believe these were the sole reason behind her hypothermia. Rather, these agents might have compounded the effects brought on by clozapine. Our rationale may be supported by the fact that the patient had not received two of her carvedilol doses before the hypothermic episode secondary to bradycardia, and because Ms. P had been on the majority of these antihypertensives (save isosorbide dinitrate) for a prolonged period prior to this hypothermia episode.

Alternative drug-disease interactions must also be considered a risk factor for hypothermia in this patient. Clozapine (along with all other antipsychotics) possesses a black box warning for all-cause mortality in those with dementia. This risk appears to be consistent even for those specifically with vascular dementia [10]. It is evident based on the current data that those with dementia are more highly susceptible to the adverse effects (possibly including hypothermia) of antipsychotics. Acute heart failure exacerbations may also precipitate hypothermic events, secondary to inadequate oxygen delivery in the body, and may have been a causative factor in our patient [11]. However, the inverse of this might also be true, as hypothermia may induce or exacerbate heart failure [12]. The patient’s history of CKD should also be taken into account. While the manufacturer lists no specific dose adjustments for clozapine in those with renal dysfunction, only 0.55% is recovered within the urine unchanged, with 48.5% excreted as non-pharmacologically active metabolites [13]. Dose reductions of clozapine may be a necessity in those with renal dysfunction.

Ms. P was taking additional psychotropics aside from clozapine, all of which have case reports of hypothermia, or are thought to magnify the risk of hypothermia (Table 1). Although the literature appears varied, divalproex may significantly increase the levels of clozapine [14, 15]. While divalproex was the primary agent considered to have caused hypothermia in some of the available reports, it should be noted that data exists on hypothermic resolution after antipsychotic cessation in the presence of continued divalproex use [16]. As previously stated, our patient was kept on divalproex, with no further episodes of hypothermia during her stay, leading us to rule out divalproex as the sole cause of her hypothermia. Although cases of using ziprasidone safely in those with a history of hypothermia exist, other cases portray ziprasidone-induced hypothermia occurring even after 3 years on this medication [17]. Thus, we cannot fully rule out ziprasidone as a potential cause of hypothermia in our patient. Benzodiazepines, such as the lorazepam prescribed to our patient, are thought to inhibit the preoptic nucleus, preventing vasoconstriction and shivering [18]. Because nearly 80% of case reports denote hypothermia generally occurs after drug initiation or dose increases, we considered clozapine as the most likely cause in our patient [1, 7]. After exclusion or inclusion of these alternative causes, we calculated a score of 4 (possible) for clozapine-induced hypothermia on the Naranjo Scale for determining the probability of an adverse drug reaction (scoring “yes” on questions 1, 2, 3, 5, and 10) [19].

It should be acknowledged that Ms. P has never had pharmacogenomic testing performed. Owing to the fact that clozapine is highly metabolized by cytochrome P450 (CYP) 1A2 and CYP2D6, we cannot discount that a genetic polymorphism placed this patient at increased risk for hypothermia secondary to higher than intended levels. As depicted in Table 1, the patient was not on any medications known to inhibit CYP1A2 or CYP2D6. A clozapine level was not performed at the time of hypothermia to determine if the level was supratherapeutic. Also of interest, pharmacokinetic and pharmacodynamic processes are altered in hypothermia. CYP450 metabolizing enzymes (including CYP3A4 and CYP2D6) are noted to be less active during hypothermia, leading to decreased clearance of the medications they metabolize [20]. Though unclear, it is possible the effects of a medication leading to hypothermia may be amplified in such an environment, if that particular medication is metabolized through a CYP450 pathway.

Literature review

Only a handful of case reports on clozapine-induced hypothermia exist, with varying onset and doses depicted. Papazisis et al. described a 71-year old male individual with hypothermia and accompanying Osborn J-waves after a year on 300 mg/day of clozapine [21]. This patient was switched to quetiapine with no further incidence of hypothermia [21]. Pelechas et al. described a 61-year old male taking clozapine, diazepam, and haloperidol who developed hypothermia after an unknown period [22]. A more recently published case series reported a 65-year old male who developed mild hypothermia after 5 days of clozapine use, on a total dose of 50 mg/day, which subsided after discontinuing clozapine and switching to olanzapine [4]. These authors also reported a 59-year old female with hypothermia lasting more than 6 days while on clozapine, risperidone, and olanzapine [4]. The authors appear to attribute this case primarily to risperidone, as this agent was recently titrated, and because hypothermia persisted even after discontinuing the olanzapine and clozapine [4]. In a case of intentional overdose on 3.5 g of clozapine (concentration 2183 ng/mL), the patient was noted to have a temperature of 91.6 °F (33.1 °C) upon admission [23].

We extracted data on clozapine and hypothermia from the FDA Adverse Event Reporting System (Table 3) [24]. Data from 1990 to 2019 demonstrated 109 separate cases of individuals experiencing hypothermia while taking clozapine. Clozapine was the primary suspect in 83 of these cases. The majority of cases were considered serious, and 21 patients died after exposure. Schizophrenia was by in large the most common indication for use of clozapine. Table 3 provides information on the onset of hypothermia after initiation of clozapine. While the single largest percentage of cases occurred within the first month (~ 27%), it is important to note that the majority of cases happened within 1 year of being on this medication, and even after 10 years on clozapine. However, it is unknown as to whether or not cases occurring later in therapy happened after any dose increases. Of those with clozapine-induced hypothermia, 60% were male. Middle to advanced age appeared more highly correlated with clozapine-induced hypothermia (63% for ages 40+, with 25.8% aged 60+), with the average age of 46 years. Haloperidol, antidepressants (any), valproic acid, olanzapine, and benzodiazepines (or any “z” drugs), were among the top co-prescribed medications for those with clozapine-induced hypothermia (9.2, 11, 11, 12, and 17.4% respectively). When co-administered with clozapine, event reporters considered valproic acid a suspect of hypothermia in 4 (15.4%) cases, benzodiazepines were considered suspects in 5 (19.2%) cases, while olanzapine was considered a suspect in 8 (30.7%) cases. Interestingly, the demographics and characteristics within Table 3 fit relatively closely with those depicted in a publication from Windfuhr et al., wherein the incidence of sudden unexplained death (SUD) from antipsychotics was examined [25]. In this paper, the authors found that older male patients were slightly more at risk of SUD (58% vs. 42% female), with other risk factors including clozapine, benzodiazepines, cardiovascular disease, and a diagnosis of dementia [25]. This correlation may point to hypothermia as a potential cause of SUD from antipsychotics.

Table 3 Demographics & Characteristic Features of Clozapine-Induced Hyper- and Hypothermia

In a 2007 review, van Marum et al. found 524 cases of hyperthermia during antipsychotic use reported to the WHO international database for Adverse Drug Reactions [1]. This was surprisingly similar to the number of hypothermia cases reported (n = 480). The incidence of NMS from antipsychotics in recent studies ranges from 0.01–0.02%, while earlier studies reported incidences between 0.2–3.23% [29, 30]. This decline in incidence may represent an increased awareness by practitioners. NMS caused by antipsychotics has been postulated to be secondary to potent D2 antagonism, and thus considered more common with the first-generation antipsychotics; although this remains uncertain, as virtually every antipsychotic has had case reports depicting NMS [30]. Even in the absence of frank NMS, some antipsychotics have been noted to cause fever, with clozapine being the most notable. In reference to clozapine, fever is most commonly seen within the first 3 weeks of therapy, and has a very wide reported incidence (0.5–55%) [26, 30, 31]. While clozapine-induced fevers are generally noted to be transient (lasting between 2 and 4 days on average) and benign, they may necessitate discontinuation, or at the very least further investigation to rule out alternative pathophysiology [26, 27, 32]. In the instance where clozapine is restarted after discontinuation, case reports determine it is well-tolerated with no further episodes of fever; however, Chung et al. found 1 out of 7 patients (14.3%) had fever on rechallenge [28, 33]. It is unclear if fever from clozapine is related to dose or the rate of titration, though it has been noted to occur with titration rates of > 50 mg/week, and when given concomitantly with valproic acid [28, 31]. Studies have demonstrated that the pro-inflammatory cytokine interleukin-6 may have a specific role in mediating clozapine-induced fevers [31].

Less well known, the pathophysiology behind antipsychotic-induced hypothermia appears complex, and multiple mechanisms have been proposed. Clozapine possesses a unique pharmacologic profile that encompasses activity on numerous receptors, including antagonistic effects on D2, D3, alpha-1, 5-HT2A/C, and M3, and partial agonistic effects on 5-HT1A. N-desmethylclozapine (NDMC), unlike its parent compound, possesses D2 and D3 partial agonistic effects, as well as M3 agonism [34, 35]. Table 4 summarizes literature on mice (or rat) studies conducted with various unique compounds possessing similar or opposite effects as clozapine on these receptors. Intrinsic efficacy of clozapine on D1 receptors appears to show it may be an agonist, rather than antagonist, at this receptor [54]. If this were true, it would suggest D1 agonism as a cause of hypothermia. Mitigation of clozapine-induced hypothermia by the D1 antagonist SCH-23390 supports this hypothesis [37]. Antagonistic effects on D2 do not support clozapine-induced hypothermia, but may be supported by the agonistic effects of NDMC on this receptor, as the D2 agonist bromocriptine has been shown to produce hypothermia in mice [34, 38, 39]. Similarly, hypothermic effects by norclozapine have been mimicked by the D2/3 agonist (+)-7-OH-DPAT, and blocked by the D3-selectve antagonist (+/−)-S 11566 in rats [40]. However, studies in D3 knockout mice have indicated that this effect may not be secondary to D3 agonism [41]. 5-HT2A/C antagonism corroborates potential hypothermic effects from clozapine, as agonists of this receptor (MK-212 and DOI) have been shown to reverse the hypothermic effects of chlorpromazine and haloperidol (antagonists of this receptor) [47]. Conversely, because clozapine is thought to possess 5-HT7 inverse agonist properties, the hypothermic effects seen with the selective 5HT7 receptor agonist LP-44 may disprove any implication of this receptor [50]. Minimal data exists on the effects of M3-selective agonists on temperature dysregulation, but if one were to consider the hyperthermic effects of M3 antagonists such as hyoscine, then it may stand to reason that the opposite effects potentially induce hypothermia [52]. Inhibition of compensatory responses to hypothermic reactions, such as shivering and vasoconstriction, through the peripheral alpha-1 antagonistic properties of clozapine should also be considered as an exacerbating, or possibly primary, factor [43]. Lastly, it has been shown that all antipsychotics increase neurotensin levels within the rodent brain [55, 56]. Central agonistic effects of neurotensin induce hypothermia, while peripheral effects may induce hypotension [55, 56]. Given that clozapine and NDMC bind to a multitude of receptors, it is possible that no single mechanism is responsible, but rather may be caused by an interplay of activity tilting the balance in favor of hypothermia. However, because other antipsychotics not possessing the same receptor profile as clozapine or NDMC have been noted to cause hypothermia, a reasonable assumption would be the commonality of 5HT2A antagonism or neurotensin-1 augmentation amongst these agents as the primary pathophysiology.

Table 4 Receptor/Ligand Data Supporting or Refuting Propensity of Clozapine & NDMC to Induce Hypothermia


Clinicians should be cognizant of the risk of hypothermia from clozapine, which can be severe or even fatal. Frequent temperature monitoring should be performed during initiation and titration of an antipsychotic, especially in those with comorbid CKD or dementia, or concomitantly taking benzodiazepines, valproic acid, or additional antipsychotics. This effect requires additional investigation, as multiple pharmacologic mechanisms are proposed.

Availability of data and materials

Data sharing is not applicable to this article, as this is a single-patient case report. No datasets besides those reported in the article were generated during the current study.



Chronic kidney disease


Food and Drug Administration


World Health Organization


Cytochrome P450


Neuroleptic malignant syndrome




Thyroid stimulating hormone


Sudden unexpected death


  1. van Marum RJ, Wegewijs MA, Loonen AJ, et al. Hypothermia following antipsychotic drug use. Eur J Clin Pharmacol. 2007;63(6):627–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Dundee JW, Mesham PR, Scott WE. Chlorpromazine and the production of hypothermia. Anaesthesia. 1954;9(4):296–302.

    Article  CAS  PubMed  Google Scholar 

  3. Clark WG, Lipton JM. Changes in body temperature after administration of amino acids, peptides, dopamine, neuroleptics and related agents: II. Neurosci Biobehav Rev. 1985;9(2):299–371.

    Article  CAS  PubMed  Google Scholar 

  4. Zonnenberg C, Bueno-de-Mesquita JM, Ramlal D, et al. Hypothermia due to antipsychotic medication: a systematic review. Front Psychiatry. 2017;8:165.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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):1090–7.

    Article  CAS  PubMed  Google Scholar 

  6. Scherl TA, Langguth B, Kreuzer PM. Hypothermia associated with antipsychotic medication: a clinical surveillance study. J Clin Psychopharmacol. 2017;37(6):751–3.

    Article  PubMed  Google Scholar 

  7. Szota AM, Araszkiewicz AS. The risk factors, frequency and diagnosis of atypical antipsychotic drug-induced hypothermia: practical advice for doctors. Int Clin Psychopharmacol. 2019;34(1):1–8.

    Article  PubMed  Google Scholar 

  8. Löffler S, Danos P, Schillen TB, et al. Recurrent dysregulation of body temperature during antipsychotic pharmacotherapy. Psychiatr Prax. 2008;35(2):91–3.

    Article  PubMed  Google Scholar 

  9. Zonnenberg C, Bueno-de-Mesquita JM, Ramlal D, et al. Antipsychotic-related hypothermia: five new cases. Front Psychiatry. 2019;10:543.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Schwertner E, Secnik J, Garcia-Ptacek S, et al. Antipsychotic treatment associated with increased mortality risk in patients with dementia. A registry-based observational cohort study. J Am Med Dir Assoc. 2019;20(3):323–9.

    Article  PubMed  Google Scholar 

  11. Omar HR, Guglin M. Hypothermia is an independent predictor of short and intermediate term mortality in acute systolic heart failure: insights from the ESCAPE trial. Int J Cardiol. 2016;220:729–33.

    Article  PubMed  Google Scholar 

  12. Danzl DF, Pozos RS. Accidental hypothermia. N Engl J Med. 1994;331(26):1756–60.

    Article  CAS  PubMed  Google Scholar 

  13. Sheehan JJ, Sliwa JK, Amatniek JC, et al. Atypical antipsychotic metabolism and excretion. Curr Drug Metab. 2010;11(6):516–25.

    Article  CAS  PubMed  Google Scholar 

  14. Hommers L, Scharl M, Hefner G, et al. Comedication of Valproic acid is associated with increased metabolism of clozapine. J Clin Psychopharmacol. 2018;38(3):188–92.

    Article  CAS  PubMed  Google Scholar 

  15. Rajkumar AP, Poonkuzhali B, Kuruvilla A, et al. Clinical predictors of serum clozapine levels in patients with treatment-resistant schizophrenia. Int Clin Psychopharmacol. 2013;28(1):50–6.

    Article  PubMed  Google Scholar 

  16. Ajayi OO, Holroyd S. Severe recurrent hypothermia in an elderly patient with refractory mania associated with atypical antipsychotic, valproic acid and oxcarbazepine therapy. BMJ Case Rep. 2017;2:2017.

    Google Scholar 

  17. Sethi R, Kavuru B. Hypothermia secondary to ziprasidone use in a man with schizophrenia. Prim Care Companion CNS Disord. 2012;14(4).

  18. Mallet ML. Pathophysiology of accidental hypothermia. QJM. 2002;95(12):775–85.

    Article  CAS  PubMed  Google Scholar 

  19. Naranjo CA, Busto U, Sellers EM, et al. A method of estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–45.

    Article  CAS  PubMed  Google Scholar 

  20. Wood T, Thoresen M. Physiological responses to hypothermia. Semin Fetal Neonatal Med. 2015;20(2):87–96.

    Article  PubMed  Google Scholar 

  21. Papazisis G, Tzellos T, Tahmatzidis D, et al. Late-onset clozapine-induced hypothermia accompanied by electrocardiogram Osborn waves. J Clin Psychopharmacol. 2009;29(2):183–5.

    Article  PubMed  Google Scholar 

  22. Pelechas E, Tsigaridas N, Kyrama S, et al. Electrocardiographic manifestations in three psychiatric patients with hypothermia - case report. Hell J Cardiol. 2016;8:267–70.

  23. Thomas L, Pollak PT. Delayed recovery associated with persistent serum concentrations after clozapine overdose. J Emerg Med. 2003;25(1):61–6.

    Article  PubMed  Google Scholar 

  24. FDA Adverse Event Reporting System (FAERS) Public Dashboard. Accessed 11/10/19.

  25. Windfuhr K, Turnbull P, While D, et al. The incidence and associated risk factors for sudden unexplained death in psychiatric in-patients in England and Wales. J Psychopharmacol. 2011;25(11):1533–42.

    Article  PubMed  Google Scholar 

  26. Novartis Pharmaceuticals. Clozaril (clozapine) package insert. Accessed 12/2/19.

  27. Lowe CM, Grube RR, Scates AC. Characterization and clinical management of clozapine-induced fever. Ann Pharmacother. 2007;41(10):1700–4.

    Article  CAS  PubMed  Google Scholar 

  28. Pui-yin Chung J, Shiu-yin Chong C, Chung KF, et al. The incidence and characteristics of clozapine- induced fever in a local psychiatric unit in Hong Kong. Can J Psychiatr. 2008;53(12):857–62.

    Article  Google Scholar 

  29. Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011;1(1):41–7.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ware MR, Feller DB, Hall KL. Neuroleptic malignant syndrome: diagnosis and management. Prim Care Companion CNS Disord. 2018;20(1).

  31. Hung YP, Wang CS, Yen CN, et al. Role of cytokine changes in clozapine-induced fever: a cohort prospective study. Psychiatry Clin Neurosci. 2017;71(6):395–402.

    Article  CAS  PubMed  Google Scholar 

  32. Kohen I, Afzal N, Hussain S, Manu P. Increases in C-reactive protein may predict recurrence of clozapine-induced fever. Ann Pharmacother. 2009;43(1):143–6.

    Article  PubMed  Google Scholar 

  33. Bruno V, Valiente-Gómez A, Alcoverro O. Clozapine and fever: a case of continued therapy with clozapine. Clin Neuropharmacol. 2015;38(4):151–3.

    Article  PubMed  Google Scholar 

  34. Burstein ES, Ma J, Wong S, et al. Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist. J Pharmacol Exp Ther. 2005;315(3):1278–87.

    Article  CAS  PubMed  Google Scholar 

  35. Weiner DM, Meltzer HY, Veinbergs I, et al. The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology. 2004;177(1–2):207–16.

    Article  CAS  PubMed  Google Scholar 

  36. Ogren SO, Fuxe K. Apomorphine & pergolide induce hypothermia by stimulation of dopamine D-2 receptors. Acta Physiol Scand. 1988;133(1):91–5.

    Article  CAS  PubMed  Google Scholar 

  37. Salmi P, Karlsson T, et al. Antagonism by SCH 23390 of clozapine-induced hypothermia in the rat. Eur J Pharmacol. 1994;253(1–2):67–73.

    Article  CAS  PubMed  Google Scholar 

  38. Zarrindast MR. Bromocriptine-induced hypothermia: D-2 receptor involvement. Arch Int Pharmacodyn Ther. 1989;298:38–49.

    CAS  PubMed  Google Scholar 

  39. Boulay D, Depoortere R, Perrault G, et al. Dopamine D2 receptor Knock-out mice are insensitive to the Hypolocomotor and hypothermic effects of dopamine D2/D3 receptor agonists. Neuropharmacology. 1999;38(9):1389–96.

    Article  CAS  PubMed  Google Scholar 

  40. Millan MJ, Audinot V, Melon C, et al. Evidence that dopamine D3 receptors participate in clozapine-induced hypothermia. Eur J Pharmacol. 1995;280(2):225–9.

    Article  CAS  PubMed  Google Scholar 

  41. Perachon S, Betancur C, Pilon C, et al. Role of dopamine D3 receptors in thermoregulation: a reappraisal. Neuroreport. 2000;11(1):221–5.

    Article  CAS  PubMed  Google Scholar 

  42. Varty GB. Dopamine agonist-induced hypothermia and disruption of prepulse inhibition: evidence for a role of D3 receptors? Behav Pharmacol. 1998;9(5–6):445–55.

    Article  CAS  PubMed  Google Scholar 

  43. Boschi G, Launay N, Rips R. Neuroleptic-induced hypothermia in mice: lack of evidence for a central mechanism. Br J Pharmacol. 1987;90(4):745–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gudelsky GA, Koenig JI, Meltzer HY. Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat. Evidence for opposing roles of 5-HT2 and 5-HT1A receptors. Neuropharmacology. 1986;25(12):1307–13.

    Article  CAS  PubMed  Google Scholar 

  45. Abdel-Fattah AF, Matsumoto K, El-Hady KA, et al. 5-HT1A and 5-HT2 receptors mediate hypo- and hyperthermic effects of tryptophan in pargyline-pretreated rats. Pharmacol Biochem Behav. 1995;52(2):379–84.

    Article  CAS  PubMed  Google Scholar 

  46. Neves G, Kliemann M, Betti AH, et al. Serotonergic neurotransmission mediates hypothermia induced by the N-phenylpiperazine antipsychotic prototypes LASSBio-579 and LASSBio-581. Pharmacol Biochem Behav. 2008;89(1):23–30.

    Article  CAS  PubMed  Google Scholar 

  47. Yamada J, Sugimoto Y, Horisaka K. Serotonin2 (5-HT2) receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) inhibits chlorpromazine- and haloperidol-induced hypothermia in mice. Biol Pharm Bull. 1995;18(11):1580–3.

    Article  CAS  PubMed  Google Scholar 

  48. Murphy TJ, Murnane KS. The serotonin 2C receptor agonist WAY-163909 attenuates ketamine-induced hypothermia in mice. Eur J Pharmacol. 2019;842:255–61.

    Article  CAS  PubMed  Google Scholar 

  49. Hedlund PB, Leopoldo M, Caccia S, et al. LP-211 is a brain penetrant selective agonist for the serotonin 5-HT(7) receptor. Neurosci Lett. 2010;481(1):12–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Naumenko VS, Kondaurova EM, Popova NK. On the role of brain 5-HT7 receptor in the mechanism of hypothermia: comparison with hypothermia mediated via 5-HT1A and 5-HT3 receptor. Neuropharmacology. 2011;61(8):1360–5.

    Article  CAS  PubMed  Google Scholar 

  51. Black CE, Huang N, Neligan PC, et al. Effect of nicotine on vasoconstrictor and vasodilator responses in human skin vasculature. Am J Physiol Regul Integr Comp Physiol. 2001;281(4):R1097–104.

    Article  CAS  PubMed  Google Scholar 

  52. Golding JF, Wesnes KA, Leaker BR. The effects of the selective muscarinic M3 receptor antagonist darifenacin, and of hyoscine (scopolamine), on motion sickness, skin conductance & cognitive function. Br J Clin Pharmacol. 2018;84(7):1535–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Feifel D, Goldenberg J, Melendez G, et al. The acute and subchronic effects of a brain-penetrating, neurotensin1 receptor agonist on feeding, body weight and temperature. Neuropharmacology. 2010;58(1):195–8.

    Article  CAS  PubMed  Google Scholar 

  54. Ahlenius S. Clozapine: dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a Rosetta stone of antipsychotic drugs. Pharmacol Toxicol. 1999;84(5):193–6.

    Article  CAS  PubMed  Google Scholar 

  55. Vadnie CA, Ayers-Ringler J, Oliveros A, et al. Antipsychotic-like effects of a neurotensin receptor type 1 agonist. Behav Brain Res. 2016;305:8–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Prange AJ Jr, Nemeroff CB. The manifold actions of neurotensin: a first synthesis. Ann N Y Acad Sci. 1982;400:368–75.

    Article  CAS  PubMed  Google Scholar 

Download references


We express gratitude to the presented patient and their family.


There was no source of funding.

Author information

Authors and Affiliations



BB and AW were all involved in the medication therapy management and assessment of the patient. BB wrote the first draft of the manuscript. BB, AW, and BC contributed in the preparation of the manuscript and have approved the final version of the manuscript.

Corresponding author

Correspondence to Bradley G. Burk.

Ethics declarations

Ethics approval and consent to participate

Our institutional review board granted consent for publication of encrypted information in this case.

Consent for publication

Written informed consent for publication of this case report was obtained from the deceased patient’s family. A copy of the signed written consent to publish is available for review by the editor of this journal.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Burk, B.G., Ward, A.H. & Clark, B. A case report of acute hypothermia during initial inpatient clozapine titration with review of current literature on clozapine-induced temperature dysregulations. BMC Psychiatry 20, 290 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: