* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Fever development in neuroleptic malignant syndrome during
Prescription costs wikipedia , lookup
Adherence (medicine) wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Serotonin syndrome wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Neuropharmacology wikipedia , lookup
Atypical antipsychotic wikipedia , lookup
Pharmacological Reports Copyright © 2013 2013, 65, 279287 by Institute of Pharmacology ISSN 1734-1140 Polish Academy of Sciences Review Fever development in neuroleptic malignant syndrome during treatment with olanzapine and clozapine Anna Szota1, Ewa Og³odek2, Aleksander Araszkiewicz2 1 Department of Psychiatry, University Hospital, Kurpiñskiego 19, PL 85-096 Bydgoszcz, Poland 2 Department of Psychiatry, Collegium Medicum, Nicolaus Copernicus University in Toruñ, Kurpiñskiego 19, PL 85-096 Bydgoszcz, Poland Correspondence: Anna Szota, e-mail: [email protected] Abstract: Neuroleptic malignant syndrome (NMS) is the most dangerous life-threatening complication of antipsychotic medication. It’s development is connected with the blockade of dopaminergic transmission (D2 receptors) in the nigrostriatal system of the brain. Fever is one of the main symptoms of this syndrome and it’s elevation is due to the activation of the immune system. Numerous studies report that treatment with clozapine (doses 37.5–600 mg) or olanzapine (doses 10–25 mg) or the use of these drugs in polytherapy cause pyrexia between 37.8–40.6°C. Additionally, levels of proinflammatory interleukins such as IL-6, IL-1,TNF-a were increased. The aim of this article is to describe how olanzapine and clozapine influence fever development in NMS, in relation to the dose of the drug taken by schizophrenic patients including changes in immunological system. Key words: clozapine, fever, interleukins, neuroleptic malignant syndrome, olanzapine Introduction Neuroleptic malignant syndrome (NMS) is a dangerous and life-threatening complication, mainly occurring in cases of individuals treated with strong neuroleptic drugs (haloperidol and fluphenazine being the most common) [43]. The frequency of cases is between 0.5–1%, of which, young males are twice as likely to develop the disorder as young females. If left untreated, the mortality rate can range between 5–20%. NMS may be linked to other drugs which block dopaminergic transmission such as antidepressant drugs (clomipramine and desipramine), and lithium, amantadine, carbamazepine, L-dopa anti-cholinergic medication and metoclopramide. It may also occur with the use of second generation atypical antipsychotic (AAP) medication such as clozapine and olanzapine, regarded as potentially safe in antipsychotic treatment. The cause of NMS is the blockade of dopaminergic transmission (mainly in case of receptors D2) in the nigrostriatal system [68, 70]. NMS can develop irrespective of which particular drug is used and the duration of the therapy. It usually Pharmacological Reports, 2013, 65, 279287 279 appears a short time after the onset of treatment, however, it may also occur later on in the further course of treatment, and even after the withdrawal of the medication. Risk factors include having a past medical history of NMS, being of a young age, being male, dehydration, excitement, being exposed to a rapid increase in the dose of a drug, receiving the drug intramuscularly, taking other drugs such as lithium, or there being the co-existence of neurological disorders, or affective disorders and organic changes in the central nervous system. The characteristic symptoms of NMS include fever, increased extrapyramidal symptoms (the occurrence of at least two of the following symptoms: an increase in the tonicity of lead-pipe rigidity, ptyalism, external eye muscle contraction, hyperextension of the neck, opisthotonus, tonic facial spasm, dysphagia, dysarthria, choreatic movements and problems affecting the posture or gait), problems with vegetative functions (the occurrence of at least two of the following symptoms: an increase in arterial pressure by at least 20 mmHg in comparison to the baseline recording, tachycardia – an increase in heart rate by 30 bpm, excessive sweating and urinary and fecal incontinence) [67]. The diagnosis is still likely if less than two of the aforementioned symptoms occur, particularly if any of the following present themselves into the clinical picture: obnubilation or delirium, mutism, stupor or coma, leucocytosis in excess of 15,000/mm3 and increased creatine phosphokinase (CPK) in excess of 1,000 IU/ml. An increase in the activity of aminotransferases and mioglobinuria connected with impaired kidney function may also appear [12]. Fever and neuroleptic malignant syndrome Fever is one of the main symptoms of NMS caused by antipsychotic drugs. An elevation in body temperature can vary from low-grade (above 37°C) to hyperpyrexial (above 41°C) and can vary depending on the type of drug used and the dosage administered. Fever is a rise in body temperature to a level which exceeds it’s normal circadian changes, but with a normal functional thermoregulatory system. Fever is an important part of the nonspecific host defense response to infection or inflammation [41]. Fever is also 280 Pharmacological Reports, 2013, 65, 279287 defined as a strictly controlled, well-regulated pathophysiological reaction, which is responsible for the restoration of homeostasis disturbed by inflammatory factors [41]. Thermoregulatory conception of fever The control centre of the thermoregulatory system is located in the anterior hypothalamus, which is responsible for the maintenance of the body’s thermal homeostasis [42]. Sensory signals from thermoreceptors are sent to the anterior hypothalamus where they are compared with the ‘set-point’. Effector mechanisms of thermoregulation (behavioral and physical) are activated accordingly and body temperature is compensated in line with the thermoregulatory ‘set-point’, by means of heat-production and heat-dispersion. Fever is therefore defined as a rise in body temperature when the regulatory ‘set-point’ has been elevated [39]. An elevation in core temperature is triggered by substances known as pyrogens. Pyrogens can be either endogenous and exogenous. It is currently thought that the factors which activate the synthesis of endogenous pyrogens in immunocompetent cells of the body are exogenous pyrogens [64]. Several studies looking at fever mechanisms show that exogenous pyrogens include bacteria, viruses, protozoans, fungi, alkaloids or lectins [17, 72]. Taking into consideration the above facts, we suggest that AAPs which activate the release of endogenous pyrogens also act as exogenous pyrogens and can therefore cause fever in NMS. Exogenous pyrogens activate immune system cells to produce endogenous pyrogens such as: • interleukins: IL-1, IL-6, IL-8, IL-11, IL-12, IL-18 • interferons: INF-g, INF-b, INF-a • tumor necrosis factor: TNF-a, TNF-b • other cytokines: MIP-1, AFGF [40]. These proteins are produced by monocytes, granulocytes, macrophages and T lymphocytes. As well as increasing body temperature, pyrogens can also induce anorexia, somnolence, stimulate the production of acute-phase proteins, activate the neurohumoral axis or have a sedative effect [6, 10, 40]. Endogenous pyrogens produced peripherally are released into the blood. Their main role is to activate mechanisms in the central nervous system, responsible for altering the ‘set-point’ to a higher level, consequently causing fever [8]. Neuroleptic malignant syndrome Anna Szota et al. Clozapine and olanzapine and fever development in NMS According to current available studies regarding the occurrence of NMS with associated fever in patients treated with AAPs, it is clear that fever can be induced by clozapine and olanzapine. Clozapine (dibenzodiazepine derivative) is an AAP which can give substantial improvement in the treatment of schizophrenia [48], especially in patients refractory to the classic neuroleptic drugs or in those experiencing intense extrapyramidal symptoms. Moreover, this drug reduces suicide in high risk schizophrenic patients [48]. However, clozapine is also known for its toxic effects, which can cause acute agranulocytosis and leucopenia [49]. This drug has low affinity for D2 receptors, relatively high affinity for D4 receptors and a high affinity for serotonin receptor subtypes (5HT2A, 5HT2c, 5HT6, 5HT7), histamine H1 receptors and muscarinic acetylcholine receptors [34]. Clozapine is metabolized in the liver by the cytochrome (CYP) 450 enzymes mainly into four metabolites. It is a very efficacious drug, however, it can cause NMS with fever. For the first time, NMS with fever caused by clozapine was noticed by Blum and Mauruschat [9]. Further publications of cases of NMS development with fever in clozapine therapy support the earlier findings of Blum and Mauruschat [9]. It was reported that clozapine doses of 37.5–600 mg/d (mean 153 mg/d) caused NMS with fever in 13 of 52 patients after 14 days of treatment [53]. Temperatures of 38°C were recorded and lasted 2.6 days. Hinze-Selch et al. [31] noticed that clozapine at doses of 250 mg/d induced fever up to 39°C 14 days after treatment. However, in this case the onset of the fever was not connected with NMS and extrapyramidal symptoms, but it was due to systemic host response [31]. Lower levels of fever were found by Kluge et al. [38], and Yacoub and Francist [71]. NMS with fever developed in 5 of 15 patients and temperatures were recorded above 38°C [38], in relation to the dosage of 25–200 mg/d [38]. Also in 2 patients described by Yacoub and Francist [71] NMS with fever appeared. Temperatures were recorded at 38.1°C and 38.3°C in relations to the dose of the drug 100 mg/d and 175 mg/d [71], respectively. Interesting results connected with clozapine treatment of schizophrenic patients were obtained by Hinze-Selch et al. [30]. Fever developed in 8 of 17 patients, however, the authors did not define precisely that it was NMS with fever despite of the symptoms of NMS. They excluded that infection was a reason of fever. Temperatures ranged from 38°C to 39°C (mean 38.8°C) starting between the 2nd and 25th day (mean 14 days) and the administered dose was 178 ± 57 mg/d (first week of treatment), 281 ± 111 mg/d (second week of treatment) and 325 ± 152 mg/d (sixth week of treatment), respectively [30]. Because clozapine had not reached the therapeutic level (300 mg/d) in the patients’ blood, the question of the origin of fever was raised. Another group of patients took clozapine at therapeutic doses between 300–450 mg/d and up to 600 mg/d. Fever developed after a few months with the higher dose (600 mg/d), not after 2 weeks with the low dose (less than 300 mg/d), however, temperatures did not rise in line with the increase of the dosage. What is more, elevations in body temperature were similar to those measured in patients taking low doses [25]. Haack et al. [26] described cases of 3 patients who developed NMS with fever after a year of clozapine administration. Two patients were taking 600 mg/d and had fever above 38°C. In one of the patients treatment with clozapine was discontinued and replaced with oxazepam (doses ranging from 100–200 mg/d). What is more, the doctors decreased the dose of clozapine (to 500 mg/d) for the second patient, but against expectation the temperature rose to 39.8°C (treatment was discontinued). Additionally, a third patient had a higher fever after changing the dose of clozapine from 300 mg/d to 400 mg/d. Temperature exceeded 40°C and further treatment was discontinued because of a toxic clozapine level (1824 µg/l) in the patients’ blood. The last patient described by Haack et al. [26] was taking clozapine at a dose of 400 mg/d. The drug dose was increased to 500 mg/d after 2.5 months. Clozapine was discontinued because of a toxic plasma level (2349 µg/l) [26]. When considering the influence of clozapine on the development of fever and NMS, it is worth highlighting that temperatures did not increase in line with drug dosage. This was confirmed by the findings of 21 patients who were taking clozapine at a dose of 318 mg/d for 218 days, who experienced NMS with fever of up to 38.7°C [4, 15, 32, 33, 37, 59]. Similar fever was observed when patients were treated with clozapine (600 mg/d). No matter what dose was used the value of the fever was the same. The mechanism responsible for this is unknown, therefore, further research is required. Pharmacological Reports, 2013, 65, 279287 281 Whilst considering how clozapine influences NMS development, we should also take into account its use in polytherapy, such as when it is used with aripiprazole. In contrast to clozapine causing fever, using both of these drugs did not induce fever at all. One exception is the case of a patient who took clozapine (300 mg/d) and aripiprazole (30 mg/d), which increased the temperature to 38.5°C after 12 days [16]. However, after 12 days, the patient suddenly became confused, displayed a moderate degree of fever (38.5°C), and a slight extrapyramidal rigidity [16]. Englisch and Zink [21] described 94 patients treated with clozapine (average dose 476.7 mg/d) and aripiprazole (average dose 20.5 mg/d) for 9 weeks. None of the patients had fever, but 12 of them were diagnosed with NMS. It is possible that the absence of fever my be due to the pharmacodynamic interactions between these two drugs but further research is required. Another AAP similar to clozapine both in structure and in its effects on neurotransmission is olanzapine [66, 70]. Olanzapine (thienobenzodiazapine derivative) has affinity for dopamine receptors (D4, D3, D1, D2), serotonin receptors (5-HT2A, 5-HT2C, 5-HT3, 5-HT6), histamine receptor H1, muscarinic receptor M1 and adrenergic receptor a1. Several clinical studies have revealed that olanzapine causes relatively few extrapyramidal effects in comparison to conventional antipsychotic drugs, but like clozapine can cause NMS [47, 69]. The first such case being recorded in 1998 [22, 28, 36, 50]. Several publications on this topic point to the fact that olanzapine used in mono and polytherapy has both a pyretic and antipyretic influence in NMS. The pyretic influence in patients treated with olanzapine was observed by Burkchard et al. [11] and García López et al. [23]. They reported that olanzapine 10 mg/d caused fever (37.5–38.2°C) after 14 days of treatment [11, 23]. Ananth et al. [3] also observed NMS fever in 19 patients using the same dose of the drug. Fever began after 123 days of treatment. It was also noticed that a higher dose of olanzapine (12.5 mg/d) caused NMS with a higher fever (40.6°C), which is found to be life-threatening for the patient [46]. Olanzapine used in monotherapy rarely causes NMS with fever, than clozapine. Hickney et al. [29] and Hanel et al. [28] noticed that NMS without fever appear in any patients taking olanzapine at doses of 7.5 mg/d and 10 mg/d, respectively. However, the authors did not mention how this drug can influence 282 Pharmacological Reports, 2013, 65, 279287 interleukin levels in the blood. This is important because interleukins are involved in the mechanism of fever pathogenesis. Therefore, the measurement of interleukins levels might be a starting point in explaining the twofold influence of olanzapine on body temperature. As seen with clozapine, when used in polytherapy olanzapine (e.g., with clozapine, levopromazine or nefazodone) caused NMS with fever among large groups of patients after 14 days of treatment. Regardless of the combination of polytherapy, temperatures did not differ that significantly. Olanzapine (10 mg/d) [50] or 25 mg/d [20] taken with clozapine (300 mg/d) induced fevers of 38.6°C and 38.8°C, respectively. Whereas, olanzapine (10 mg/d) taken with levopromazine [35] or haloperidol and nefazodone [54] raised temperatures up to 38.1°C and 38.5°C, respectively. There have been reports about olanzapine (5 mg/d) used in conjunction with lithium or fluoxetine [63] or valproic acid [36]. In all cases patients suffered from NMS and fever and temperatures recorded were above 38°C. Significantly much higher temperatures (39.9°C) were induced by olanzapine (10 mg/d) when taken with valproic acid [65]. Whilst considering the influence of olanzapine in polytherapy, it is worth pointing out that not all patients experienced fever, but they had NMS. Gheorghiu et al. [24] noticed that when olanzapine (10 mg/d) is taken with carbamazepine, there was no significant rise in body temperature above 37°C. Taking olanzapine at the same dose with lithium, also did not increase body temperature [36]. In all cases described in this article so far, curing with clozapine or olanzapine caused typical NMS with fever or without fever. However, it should be noted that atypical antipsychotics may cause atypical NMS with fever as a dominant feature, but without clear extrapyramidal symptoms. Atypical NMS caused by clozapine (550–700 mg/d) was described by Corallo and Ernest [14]. A patient cured with this drug did not reveal extrapyramidal symptoms, but had a very high fever (38.6°C), diaphoresis, tachycardia and altered conscious state. Laboratory test revealed leukocytosis with neutrophilia and increased creatinine kinase CK (63,328 IU/l). Also, Ahmadkhaniha et al. [2] described a patient who was taking clozapine at a dose of 400 mg/d for 3.5 months. After that time, NMS with a very high fever (38.2°C) developed. On the basis of symptoms which were observed in this patient a diagnose of atypical NMS was made. There Neuroleptic malignant syndrome Anna Szota et al. were observed symptoms such as mild muscular rigidity, the rigidity was only in extremities instead of general muscular rigidity and mild extra pyramidal symptoms [2]. Similar to clozapine, olanzapine also may induce atypical NMS. Hall et al. [27] reported that olanzapine 10 mg/d caused atypical neuroleptic malignant syndrome with a very high fever (40.8°C). Additionally, autonomic disturbances and mental status changes arised. The patient did not have muscular rigidity, or tremors, which are usually considered along with fever, to be the cardinal features of NMS. Atypical NMS was also described by Reevers et al. [57]. In this case olanzapine (10 mg/d) induced several symptoms of NMS such as: a very high fever (39.4°C), increased level of CPK (1,388 IU/l) and autonomic dysfunction. However, there was no severe muscular rigidity or increased muscle tone [57]. Clozapine and olanzapine – mechanisms of fever As it was mentioned before, fever is one of the main symptoms of NMS caused by antipsychotic drugs and is connected with the influence of the drugs on dopaminergic transmission in the brain. Both clozapine and olanzapine bind to dopamine receptors (D2, D4) with different affinity and they block these receptors [34, 47]. The dopaminergic receptors antagonism caused by neuroleptics may interfere with dopamine’s normal role in central thermoregulation. The blockade of dopamine receptors within the nigrostratial, hypothalamic and mesolimbic/cortical pathways seems to be responsible for development of some clinical features of NMS including fever, rigidity and altered mental status [1]. This theory is supported by an earlier observation that the primary cause of NMS was the use of antipsychotic drugs that specifically block dopamine D2 receptors and that the syndrome can also be induced by abrupt dopamine withdrawal. Additionally, support comes from another study showing low levels of the dopamine metabolite, homovanillic acid, in the cerebro-spinal fluid (CSF) of patients with acute NMS [52]. Therefore, the blockade of dopaminergic receptors in preoptic area (POA), where thermoregulatory center can be found [58] leads to elevation of the thermoregulatory ‘set-point’ to a higher level and as a result initiating fever. Production of the heat is also connected with stimulating effect of serotonin in hypothalamus, dopamine blockades this process [73]. Consequently, dopaminergic blockade leads to less inhibition of serotonin stimulation and contributes to heat production and fever develops [5]. However, development of fever is not only connected with the influence of antipsychotic drugs on dopaminergic and serotonergic receptors. It is also associated with activation of immunologic system and interleukins production. As already outlined, endogenic pyrogens are involved in fever development by crucially elevating the thermoregulatory ‘set-point’ [7]. Studies so far have concentrated on the influence of clozapine or olanzapine and have looked closely at the efficiency of these drugs according to the doses. Nevertheless, the influence of clozapine and olanzapine on interleukins levels in the blood seems to be a very important point. The influence of antipsychotic drugs on inflammatory interleukins levels such as IL-1, IL-6 and TNF-a is particularly important because it would help to explain the origin of fever in NMS. From available studies we can clearly see that levels of fever in NMS were very high (38–41°C) after treatment with AAPs (clozapine, olanzapine both in mono and polytherapy). Such high temperatures may not only damage neurons in brain, but may also be life-threatening if medication is not discontinued. Therefore, understanding how a particular type and dose of AAP can effect interleukin levels seems to be pivotal when choosing a patients drug regime. From previous studies we know that treatment with clozapine, similar to when using typical neuroleptic drugs, may lead to NMS with fever regardless of the dosage. It is worth highlighting that fever was noticed in patients, even when the drug had not reached therapeutic levels in the blood [30, 56]. So, the question naturally rises as to the cause of fever. This is most likely connected to the increase of interleukin levels in the blood of treated patients. Pollmächer et al. [56], Maes et al. [45] and Hinze-Selch et al. [30] established that the level of IL-6 becomes raised after clozapine treatment. It is well documented that IL-6, as well as IL-1 are the major cytokines responsible for the development of fever [8, 18, 40, 72]. IL-6 is lyophobic and quite a large protein which is produced by a variety of immunocompetent cells before being released into the blood. For many years it has been considered that cytokines (IL-6 and IL-1) circumvent the blood-brain barrier, especially in the Pharmacological Reports, 2013, 65, 279287 283 circumventricular organ known as the organum vasculosum of the lamina terminalis (OVLT) where the barrier is incomplete. This area is situated very closely to the POA, where the thermoregulatory center can be found [58]. However, cytokines synthesized peripherally, cross the brain so slowly that this process is not fundamental in the pathogenesis of fever. Nevertheless, this is not equal to the lack of involvement of the OVLT in fever, because this area is sensitive and possesses many receptors for endogenous pyrogens [7]. Nowadays, it is thought that proinflammatory cytokines produced peripherally induce the production of prostaglandin E2 (PGE2 ) in the brain [13]. Prostaglandins produced in the neural or glial cells of the POA and prostaglandins produced in microglial cells in area of the OVLT are extremely influential [62]. These prostaglandins diffuse into the anterior hypothalamus, induce the local production of pyrogenic cytokines, which then act on neurons of the thermoregulatory center to elevate the thermoregulatory ‘set-point’ to a higher level, therefore, initiating fever [18]. Clozapine as an atypical antipsychotic drug, not only stimulates the synthesis of IL-6, but also significantly increases levels of TNF-a and activates receptors for this cytokine (sTNF-Rs) [25, 56]. In contrast to IL-6, TNF-a is a cytokine which has a two-sided influence on the human body, both pyretic and antipyretic. Associated with very high temperatures in patients treated with clozapine, we may assume that TNF-a has a pyretic influence in such cases [51]. On the basis of the above facts we may suggest that the development of fever in patients taking clozapine is strongly connected to the activation of the immune system and the increase in the levels of IL-6 and TNF-a. In view of this fact, it seems vital to measure the levels of these cytokines in the cerebrospinal fluid. It would allow verification and specification of the mechanisms responsible for development of fever in patients treated with clozapine. Whilst considering fever mechanisms we must take into account how peripherally induced fever alerts the central nervous system. It is not only via humoral pathways, but also within neuronal tracts. Pyrogenic cytokines released peripherally activate the subdiaphragmatic vagal afferent fibers, through which information is transferred to the nucleus of the solitary tract (NTS), and then via adrenergic fibres to the hypothalamus. Catecholamines are released in the hypothalamus in turn stimulating the local release of PGE2 and fever develops [61]. 284 Pharmacological Reports, 2013, 65, 279287 In contrast to clozapine, olanzapine may reveal both pyretic and antipyretic effects in mono and polytherapy. It has been reported that olanzapine used in monotherapy does not increase the level of IL-6 [55] and TNF-a [19]. Moreover, Lü et al. [44] and Schuld et al. [60] found that cytokine levels were actually decreased. These findings allow us to formulate the hypothesis that the lack of pyrogenic influence of olanzapine is directly connected to suppression of the immune system. Nevertheless, the mechanism of fever induced by olanzapine is still unclear because the levels of the proinflammatory cytokines (IL-6 and TNF-a) are not increased [19]. Olanzapine used in polytherapy causes fever above 38°C regardless of the dose. Using olanzapine with clozapine or olanzapine with valproic acid trigger fever as high as 38.8°C and 39.9°C, respectively. Taking into account that clozapine in contrast to olanzapine stimulates the production of proinflammatory interleukins, we may suggest that clozapine used in polytherapy is responsible for the development of fever. Conclusions The scientific reports presented in this article make it possible to arrive at the conclusion that olanzapine, when used in mono or polytherapy, is a drug with a safer pharmacological profile than clozapine. Treatment with olanzapine, similar to that with clozapine, is connected with the risk of developing neuroleptic malignant syndrome. Nevertheless, the development of this syndrome is seen less with olanzapine, which does not induce fever that can become severe enough to threaten the lives of many patients. When choosing medication-based therapy, one should pay particular attention to the risk of such life-threatening side effects, the pharmacological reactions that can take place, and consider monitoring drug (serum) levels as a matter of routine. Acknowledgment: The authors would like to thank Peter Koœmider-Jones for checking an English version of the article. Disclosure of conflict of interest: The authors have no conflicts interest that are directly relevant to the content of this review. Neuroleptic malignant syndrome Anna Szota et al. References: 1. Adnet P, Lestavel P, Krivosic-Horber R: Neuroleptic malignant syndrome. Br J Anaesth, 2000, 85, 129–135. 2. Ahmadkhaniha H, Tayebi A: A case report of neuroleptic malignant syndrome induced by clozapine. Is neuroleptic malignant syndrome diagnostic criteria adequately sensitive to identify diverse features of the syndrome? Iran J Psychiatry Behav Sci, 2008, 2, 50–54. 3. Ananth J, Parameswaran S, Gunatilake S, Burgoyne K, Sidhom T: Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry, 2004, 65, 464–470. 4. Bacewicz AM, Chandra R, Whelan P: Clozapineassociated neuroleptic malignant syndrome. Ann Intern Med, 2002, 137, 374. 5. Berman BD: Neuroleptic malignant syndrome: A review of neurohospitalists. The Neurohospitalist, 2011, 1, 41–47. 6. Besedovsky H, del Rey A: Neuroendocrine and metabolic responses induced by interleukin-1. J Neurosci Res, 1987, 18, 172–178. 7. Blatteis CM: Role of the OVLT in the febrile response to circulating pyrogens. Prog Brain Res, 1992, 91, 409–412. 8. Blatteis CM, Sehic E, Li S: Complement and the pathogenesis of endotoxic fever. Int J Biometeorol, 2000, 43, 176–183. 9. Blum A, Mauruschat W: Rises in temperature and changes of blood protein fractions under therapy with neuroleptics – with special regard to the new dibenzodiazepine derivative clozapine (German). Pharmacopsychiatry, 1972, 5, 155–169. 10. Bluthé RM, Dantzer R, Kelley KW: Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Res, 1992, 573, 318–320. 11. Burkhard PR, Vingerhoets FJ, Alberque C Landis T: Olanzapine-induced neuroleptic malignant syndrome. Arch Gen Psychiatry, 1999, 56, 101–102. 12. Casamassima F, Lattanzi L, Perlis RH, Litta A, Fui E, Bonuccelli U, Fricchione G et al.: Neuroleptic malignant syndrome: further lessons from a case report. Psychosomatics, 2010, 51, 349–354. 13. Coceani F, Bishai I, Lees J, Sirko S: Prostaglandin E2 and fever: a continuing debate. Yale J Biol Med, 1986, 59, 169–174. 14. Corallo CE, Ernest D: Atypical neuroleptic malignant syndrome with long-term clozapine. Crit Care Resusc, 2007, 9, 338–340. 15. Dalkilic A, Grosch WN: Neuroleptic malignant syndrome following initiation of clozapine therapy. Am J Psychiatry, 1997, 154, 881–882. 16. Dassa D, Drai-Moog D, Samuelian JC: Neuroleptic malignant syndrome with the addition of aripiprazole to clozapine. Prog Neuropsychopharmacol Biol Psychiatry, 2010, 34, 427–428. 17. Dinarello CA, Wolff SM: Exogenous pyrogens. In: Pyretics and Antypyretics. Handbook of Experimental Pharmacology. Ed. Milton AS, Springer-Verlag, BerlinHeidelberg, 1982, 73–112. 18. Dinarello CA: Infection, fever, and exogenous and endogenous pyrogens: some concepts have changed. J Endotoxin Res, 2004, 10, 201–222. 19. Drzyzga L, Obuchowicz E, Marcinowska A, Herman ZS: Cytokines in schizophrenia and the effects of antipsychotic drugs. Brain Behav Immun, 2006, 20, 532–545. 20. Emborg C: Neuroleptic malignant syndrome after treatment with olanzapine (Danish). Ugeskr Laeger, 1999, 161, 1424–1425. 21. Englisch S, Zink M: Combined antipsychotic treatment involving clozapine and aripiprazole. Prog Neuropsychopharmacol Biol Psychiatry, 2008, 32, 1386–1392. 22. Filice GA, McDougall BC, Ercan-Fang N, Billington CJ: Neuroleptic malignant syndromeassociated with olanzapine. Ann Pharmacother, 1998, 32, 1158–1159. 23. García López MM, Ciprés L, de Cendra E, Vilalta Franch J: Neuroleptic malignant syndrome associated with olanzapine (Spanish). Med Clin (Barc), 1999, 113, 239. 24. Gheorghiu S, Knobler HY, Drumer D: Recurrence of neuroleptic malignant syndrome with olanzapine treatment. Am J Psychiatry, 1999, 156, 1836. 25. Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kühn M, Schuld A, Pollmächer T: Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res, 1999, 33, 407–418. 26. Haack MJ, Bak ML, Beurskens R, Maes M, Stolk LM, Delespaul PA: Toxic rise of clozapine plasma concentrations in relation to inflammation. Eur Neuropsychopharmacol, 2003, 13, 381–385. 27. Hall RC, Appleby B, Hall RC: Atypical neuroleptic malignant syndrome presenting as fever of unknown origin in the elderly. South Med J, 2005, 98, 114–117. 28. Hanel RA, Sandmann MC, Kranich M, De Bittencourt PR: Neuroleptic malignant syndrome: case report with recurrence associated with the use of olanzapine (Portuguese). Arq Neuropsiquiatr, 1998, 56, 833–837. 29. Hickey C, Stewart C, Lippmann S: Olanzapine and NMS. Psychiatr Serv, 1999, 50, 836–837. 30. Hinze-Selch D, Becker EW, Stein GM, Berg PA, Mullington J, Holsboer F, Pollmächer T: Effects of clozapine on in vitro immune parameters: a longitudinal study in clozapine-treated schizophrenic patients. Neuropsychopharmacology, 1998, 19, 114–122. 31. Hinze-Selch D, Mullington J, Pollmächer T: Sleep during clozapine-induced fever in schizophrenic patient. Biol Psychiatry, 1995, 38, 690–693. 32. Huang TL: Neuroleptic malignant syndrome associated with long-term clozapine treatment: report of a case and results of a clozapine rechallenge. Chang Gung Med J, 2001, 24, 522–525. 33. Illing M, Ancill R: Clozapine-induced neuroleptic malignant syndrome: clozapine monotherapy rechallenge in a case of previous NMS. Can J Psychiatry, 1996, 41, 258. 34. Jann MW, Grimsley SR, Gray EC, Chang WH: Pharmacokinetics and pharmacodynamics of clozapine. Clin Pharmacokinet,1993, 24, 161–176. Pharmacological Reports, 2013, 65, 279287 285 35. Järventausta K, Leinonen E: Neuroleptic malignant syndrome during olanzapine and levomepromazine treatment. Acta Psychiatr Scand, 2000, 102, 231–233. 36. Johnson V, Bruxner G: Neuroleptic malignant syndrome associated with olanzapine. Aust N Z J Psychiatry, 1998, 32, 884–886. 37. Karagianis JL, Phillips LC, Hogan KP, LeDrew KK: Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother, 1999, 33, 623–630. 38. Kluge M, Schuld A, Schacht A, Himmerich H, Dalal MA, Wehmeier PM, Hinze-Selch D et al.: Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever. Psychoneuroendocrinology, 2009, 34, 118–128. 39. Kluger MJ: Fever: Its biology, evolution and function, Princeton University Press, Princeton, New York, 1979. 40. Kluger MJ: Fever: role of pyrogens and cryogens. Physiol Rev, 1991, 71, 93–127. 41. Kluger MJ, Kozak W, Conn CA, Leon LR, Soszynski D: The adaptive value of fever. Infect Dis Clin North Am, 1996, 10, 1–20. 42. Kozak W: Fever: a possible strategy for membrane homeostasis during infection. Perspect Biol Med, 1993, 37, 14–34. 43. Liu PY, Wu PC, Chen CY Chen YC: Potentiating effect of fluphenazine decanoate and risperidone on development of neuroleptic malignant syndrome. Gen Hosp Psychiatry, 2011, 33, 84.e5–84e7. 44. Lü LX, Guo SQ, Chen WLi Q, Cheng J, Guo JH: Effect of clozapine and risperidone on serum cytokine levels in patients with first-episode paranoid schizophrenia (Chinese). Di Yi Jun Yi Da Xue Xue Bao, 2004, 24, 1251–1254. 45. Maes M, Bosmans E, Calabrese J Smith R, Meltzer HY: Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res, 1995, 29, 141–152. 46. Margolese HC, Chouinard G: Olanzapine-induced neuroleptic malignant syndrome with mental retardation. Am J Psychiatry, 1999, 156, 1115–1116. 47. Martín J, Gómez JC, García-Bernardo E, Cuesta M, Alvarez E, Gurpegui M: Olanzapine in treatment-refractory schizophrenia: results of an open-label study. The Spanish Group for the Study of Olanzapine in TreatmentRefractory Schizophrenia. J Clin Psychiatry, 1997, 58, 479–483. 48. Meltzer HY: Outcome in schizophrenia: beyond symptom reduction. J Clin Psychiatry, 1999, 60, Suppl 3, 3–7, discussion 8. 49. Miller DD: Review and management of clozapine side effects. J Clin Psychiatry, 2000, 61, Suppl 8, 14-17, discussion 18–19. 50. Moltz DA, Coeytaux RR: Case report: possible neuroleptic malignant syndrome associated with olanzapine. J Clin Psychopharmacol, 1998, 18, 485–486. 51. Monteleone P, Fabrazzo M, Tortorella A, Maj M: Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment. Psychiatry Res, 1997, 71, 11–17. 52. Nisijima K, Ishiguro T: Cerebrospinal-fluid levels of monoamine metabolites and gamma-aminobutyric-acid 286 Pharmacological Reports, 2013, 65, 279287 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. in neuroleptic malignant syndrome. J Psychiatr Res, 1995, 29, 233–244. Nitenson NC, Kando JC, Frankenburg FR, Zanarini MC: Fever associated with clozapine administration. Am J Psychiatry, 1995, 152, 1102. Nyfort-Hansen K, Alderman CP: Possible neuroleptic malignant syndrome associated with olanzapine. Ann Pharmacother, 2000, 34, 667. Pollmächer T, Haack M, Schuld A, Kraus T, Hinze-Selch D: Effects of antipsychotic drugs on cytokine networks. J Psychiatr Res, 2000, 34, 369–382. Pollmächer T, Hinze-Selch D, Mullington J: Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J Clin Psychopharmacol, 1996, 16, 403–409. Reeves RR, Torres RA, Liberto V, Hart RH: Atypical neuroleptic malignant syndrome associated with olanzapine. Pharmacotherapy, 2002, 22, 641–644. Romanovsky AA, Sugimoto N, Simons CT, Hunter WS: The organum vasculosum laminae terminalis in immune-to-brain febrigenic signaling: a reappraisal of lesion experiments. Am J Physiol Regul Integr Comp Physiol, 2003, 285, 420–428. Sachdev P, Kruk J, Kneebone M, Kissane D: Clozapineinduced neuroleptic malignant syndrome: review and report of new cases. J Clin Psychopharmacol, 1995, 15, 365–371. Schuld A, Kraus T, Haack M, Hinze-Selch D, Kühn M, Pollmächer T: Plasma levels of cytokines and soluble cytokine receptors during treatment with olanzapine. Schizophr Res, 2000, 43, 164–166. Sehic E, Székely M, Ungar AL, Oladehin A, Blatteis CM: Hypothalamic prostaglandin E2 during lipopolysaccharide-induced fever in guinea pigs. Brain Res Bull, 1996, 39, 391–399. Sehic E, Ungar AL, Blatteis CM: Interaction between norepinephrine and prostaglandin E2 in the preoptic area of guinea pigs. Am J Physiol, 1996, 271, 528–536. Sierra-Biddle D, Herran A, Diez-Aja S, Gonzalez-Mata JM, Vidal E, Diez-Manrique F, Vazquez-Barquero JL: Neuropletic malignant syndrome and olanzapine. J Clin Psychopharmacol, 2000, 20, 704–705. Soszyñski D: The pathogenesis and the adaptive value of fever (Polish). Postepy Hig Med Dosw, 2003, 57, 531–554. Stanfield SC, Privette T: Neuroleptic malignant syndrome associated with olanzapine therapy: a case report. J Emerg Med, 2000, 19, 355–357. Stephenson CM, Pilowsky LS: Psychopharmacology of olanzapine. A review. Br J Psychiatry, 1999, 174, Suppl 38, 52–58. Storm C, Gebker R, Krüger A, Nibbe L, Schefold JC, Martens F, Hasper D: A rare case of neuroleptic malignant syndrome presenting with serious hyperthermia treated with a non-invasive cooling device: a case report. J Med Case Reports, 2009, 19, 6170. Strawn JR, Keck Jr PE, Caroff SN: Neuroleptic malignant syndrome. Am J Psychiatry, 2007, 164, 870–876. Tran PV, Dellva MA, Tollefson GD, Beasley Jr CM, Potvin JH, Kiesler GM: Extrapyramidal symptoms and tolerability of olanzapine versus haloperidol in the acute treatment of schizophrenia. J Clin Psychiatry, 1997, 58, 205–211. Neuroleptic malignant syndrome Anna Szota et al. 70. Tybura P, Samochowiec A, Beszlej A, Grzywacz A, Mak M, Frydecka D, Bieñkowski P et al.: Some dopaminergic genes polymorphism are not associated with response to antipsychotic drugs in schizophrenic patients. Pharmacol Rep, 2012, 64, 528–535. 71. Yacoub A, Francis A: Neuroleptic malignant syndrome induced by atypical neuroleptics and responsive to lorazepam. Neuropsychiatr Dis Treat, 2006, 2, 235–240. 72. Zeisberger E: From humoral fever to neuroimmunological control of fever. J Thermal Biol, 1999, 24, 287–326. 73. Ziomber A, Thor P, Krygowska-Wajs A, Za³êcki T, Moska³a M, Romañska I, Michaluk J et al.: Chronic impairment of the vagus nerve function lead to inhibition of dopamine but not serotonin neurons in rat brain structures. Pharmacol Rep, 2012, 64, 1359–1367. Received: April 26, 2012; in the revised form: November 17, 2012; accepted: November 26, 2012. Pharmacological Reports, 2013, 65, 279287 287