Clozapine-Associated Neuroleptic Malignant Syndrome: Two New Cases and a Review of the Literature

Karagianis, Jamie; Phillips, Leslie; Hogan, Kevin; LeDrew, Kellie

doi:10.1345/aph.18286

Cited by 127 publications

(62 citation statements)

References 25 publications

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“…Many antipsychotics, in particular CPZ, HAL, RIS and CLZ, have been demonstrated to directly damage mitochondria [18,21]. Indeed, the toxicological effects of these drugs on mitochondria are thought to underlie some of their central nervous system (CNS) associated neurological side effects [4,22] that are associated with antipsychotic overuse and misuse, such as tardive dyskinesia [23], neuroleptic associated cerebral oedema [24] and neuroleptic malignant syndrome [25]. …”

Section: Clinical Significancementioning

confidence: 99%

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Elmorsy

Smith

2015

Biochemical and Biophysical Research Communications

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Antipsychotics (APs) are widely used medications, however these are not without side effects such as disruption of blood brain barrier function (BBB). To investigate this further we have studied the chronic effects of the typical APs, chlorpromazine (CPZ) and haloperidol (HAL) and the atypical APs, risperidone (RIS) and clozapine (CLZ), on the bioenergetics of human micro-vascular endothelial cells (HBVECs) of the BBB. Alamar blue (AB) and ATP assays showed that these APs impair bioenergenesis in HBVECs in a concentration and time dependent manner. However since these effects were incomplete they suggest a population of cell bioenergetically heterogeneous, an idea supported by the bistable nature by which APs affected the mitochondrial transmembrane potential. CPZ, HAL and CLZ inhibited the activity of mitochondrial complexes I and III.Our data demonstrates that at therapeutic concentrations, APs can impair the bioenergetic status of HBVECs, an action that help explains the adverse side effects of these drugs when used clinically.

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Section: Clinical Significancementioning

confidence: 99%

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Elmorsy

Smith

2015

Biochemical and Biophysical Research Communications

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“…91 In addition, clozapine has a dose-dependent risk of epileptic seizures (about 5% at a daily dose of 600 mg or more); 91 potentially massive weight gain; 92 possible cardiac damage, including early myocarditis (≤ 19 per 10 000) or late cardiomyopathy (≤ 10 per 10 000); 93,94 cerebral intoxication such as that seen with neuroleptic malignant syndrome, with delirium and fever but not muscle rigidity or elevated creatine kinase levels; 60 and severe depression of intestinal motility.…”

Section: Clozapinementioning

confidence: 99%

Modern antipsychotic drugs: a critical overview

Gardner

Baldessarini²,

Waraich³

2005

Canadian Medical Association Journal

353

250

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SynthèseA ntipsychotic drugs are useful for treating a range of severe psychiatric disorders. Applications include the short-term treatment of acute psychotic, manic and psychotic-depressive disorders as well as agitated states in delirium and dementia and the long-term treatment of chronic psychotic disorders including schizophrenia, schizoaffective disorder and delusional disorders. Newer, "second-generation" antipsychotic drugs have largely replaced older phenothiazine, thioxanthene and butyrophenone neuroleptics in clinical practice (Table 1).1,2 The development of modern antipsychotic drugs was stimulated by a landmark 1988 study that showed clozapine to be superior in efficacy to chlorpromazine in schizophrenia patients resistant to high doses of haloperidol and to have none of the adverse neurologic effects typical of older antipsychotic agents.3 Clozapine was considered "atypical" in having a very low risk of adverse extrapyramidal symptoms. This term has since been applied broadly and uncritically to antipsychotic drugs marketed in the past decade, despite their striking chemical, pharmacologic and clinical heterogeneity. 4 In this overview we consider the neuropharmacology, efficacy and adverse effects of conventional antipsychotics and specific modern antipsychotic drugs. NeuropharmacologyThe venerable hypothesis that schizophrenia is caused by increased cerebral activity of the neurotransmitter dopamine was based primarily on the finding that dopamine agonists produced or worsened psychosis and that antagonists were clinically effective against psychotic and manic symptoms. 5 Blocking dopamine D 2 receptors may be a critical or even sufficient neuropharmacologic action of most clinically effective antipsychotic drugs, especially against hallucinations and delusions, but it is not necessarily the only mechanism for antipsychotic activity. Moreover, this activity, and subsequent pharmacocentric and circular speculations about altered dopaminergic function, have not led to a better understanding of the pathophysiology or causes of the several still idiopathic psychotic disorders, nor have they provided a non-empirical, theoretical basis for the design or discovery of improved treatments for psychotic disorders.The neuropharmacodynamics of specific modern antipsychotic drugs vary greatly, with little evidence for a unifying theory of antipsychotic activity or of drug design (Table 2). Clozapine in particular is complex: it binds loosely and transiently to D 2 receptors and interacts at dopamine (D 1 , D 3 and D 4 ), histamine (H 1 ), acetylcholine muscarinic (M 1 ) and serotonin (5-HT 2A , 5-HT 2C , 5-HT 6 and 5-HT 7 ) receptors and α 1 adrenoceptors. [6][7][8] This complexity leaves the very low risk of extrapyramidal symptoms and unexcelled antipsychotic effectiveness of clozapine unexplained.9 Postural dizziness, sedation and increased appetite may reflect actions of clozapine and some other antipsychotic agents at α 1 , H 1 and 5-HT 2C receptors respectively. Olanzapine demonstrates significant anti-...

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“…Therefore, NMS cases induced by clozapine are not prevalent as reported in the literature. Atypical NMS associated with atypical antipsychotics has been defined as rare small increases in CK, minor muscle rigidity and mild fever 8 . In the presented case, the complete NMS presentation with severe muscle rigidity and unusually elevated CK differentiated this condition from most other clozapine-induced cases, which have been rarely reported in the literature.…”

Section: Discussionmentioning

confidence: 99%

Neuroleptic Malignant Syndrome Induced by Clozapine: A Case Report and Discussion

Wang

Xiao

et al. 2014

Klinik Psikofarmakoloji Bülteni-Bulletin of Clinical Psychophar

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Objective: Neuroleptic malignant syndrome (NMS) is a rare, but life-threatening condition associated with the use of antipsychotics. Although NMS is mainly associated with typical antipsychotics, it can also be induced by atypical antipsychotics. In this paper, we report a case of NMS associated with clozapine use and describe the classic and atypical manifestations of NMS. The case and discussion highlight the importance of considering NMS as part of the differential diagnosis for any patient using neuroleptics. Case: This case was about a 52-year-old female suffering from pneumonia, who was diagnosed as having NMS after a dosage increase of clozapine. NMS is a rare but serious adverse reaction to an antipsychotic drug. It is essentially characterized by hyperthermia, and muscle rigidity, which may be accompanied by other extra pyramidal effects (EPS), autonomic instability and mental status changes. Laboratory examinations showed significantly higher creatine kinase. A typical treatment usually involves supportive medication and an immediate withdrawal of the antipsychotic drug. Conclusion: Incomplete or extraordinary NMS cases have been reported due to clozapine. However, this case was remarkably associated with the complete and typical presentation of NMS. Given the routine and regular writing of prescriptions of neuroleptics by physicians in a variety of medical disciplines, physicians need to recognize and appropriately manage NMS.

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Clozapine-Associated Neuroleptic Malignant Syndrome: Two New Cases and a Review of the Literature

Cited by 127 publications

References 25 publications

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Modern antipsychotic drugs: a critical overview

Neuroleptic Malignant Syndrome Induced by Clozapine: A Case Report and Discussion

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