Atypical neuroleptic malignant syndrome in patients treated with aripiprazole and clozapine: a case-series study and short review.

OBJECTIVES: Neuroleptic malignant syndrome (NMS) requires emergency treatment and can be fatal. Combined aripiprazole and clozapine therapy is rarely used in clinical settings, and NMS related this combination still lacks evaluation. Herein, we present two cases of atypical NMS treated with aripiprazole and clozapine. METHODS: Case 1 was a schizophrenic male with a history of NMS under treatment with aripiprazole 20 mg. He was hospitalized and maintained with aripiprazole 5 mg and clozapine 225 mg. On the 25th day, atypical NMS occurred with rigidity, elevated creatine kinase, and stupor, which subsided with supportive therapy. He was discharged under treatment with aripiprazole 15 mg and fluoxetine 60 mg. Case 2 was a female with schizoaffective disorder without a history of NMS. She was hospitalized and maintained with clozapine 50 mg and aripirazole 30 mg. On the 11th day, atypical NMS occurred with mild fever, delirium, and rigidity, which subsided under supportive therapy. RESULTS AND CONCLUSIONS: Our cases highlight the atypical features of NMS in patients being treated with combined ari-piprazole and clozapine. Consciousness change, modest elevation of creatine kinase, and leukocytosis were the most consistent findings; hyperthermia accounts for only some of the cases. This is a reminder of the importance of earlier detection of the soft signs and atypical features of NMS under this combined treatment.

Neuroleptic malignant syndrome in an adolescent with CYP2D6 deficiency.

We describe a patient with dystonia and psychotic symptoms treated with standard doses of antipsychotics, who developed neuroleptic malignant syndrome (NMS). A 16-year-old male with a history of misuse of dextromethorphan and pseudoephedrine for recreational purpose presented with dystonia and a psychotic episode. Following continuous treatment with olanzapine (10 mg/day), repeated injections of levomepromazine (37.5 mg/day), and a single injection of haloperidol (2.5 mg), the patient developed NMS. Muscular rigidity, fever (up to 41 °C), hypotension (100/70 mmHg), tachycardia (120 beats per minute), tachypnea (26 breaths per minute), elevated leukocyte count (up to 16.6 × 10(3)/µL), and elevated serum creatinine phosphokinase (CPK) (up to 15,255 U/L) were observed. A diagnosis of NMS was made according to the DSM-IV TR criteria. Genotyping revealed that he was homozygous for a non-functional CYP2D6*4 allele. The case highlights the importance of therapeutic drug monitoring in identification and differentiation of drug-induced effects in psychiatric disorder to prevent NMS and its complications. In addition, genotyping of CYP2D6 might be considered in patients with symptoms suggestive of drug toxicity who are treated with neuroleptics metabolized via the CYP2D6 pathway, as carriage of one or more non-functional alleles may increase the risk for adverse reactions, such as NMS.

[Importance of creatine kinase psychiatry--truths and myths]. / Znaczenie kinazy kreatynowej w psychiatrii--prawda i mity.

Creatine kinase (CK) catalyzes the reversible transfer of the phosphoryl group from phosphocreatine to adenosine 5'-diphosphate (ADP), thus regenerating adenosine triphosphate (ATP). Creatine kinase genes are expressed in several tissues with high, fluctuating energy turnover, e.g. skeletal and cardiac muscle, brain and photoreceptor cells, and spermatozoa. Several isoenzymes of CK have been characterized: brain-type, muscle-type, and the hybrid isoenzymes, as well as the mitochondrial CK isoenzymes. Measurements of serum CK is a routine test in the diagnosis of acute myocardial infarction and various muscle disorders. Elevation of the serum CK level in psychiatric patients is a fairly nonspecific phenomenon. Most commonly, an elevated serum CK level is due to intramuscular injections, use of restraints or other intense isometric activity. Although it is still controversial, increased CK activity is one of basic criteria of neuroleptic malignant syndrome. Despite many studies on the importance of CK in postnatal brain and pathogenesis of psychiatric disorders, its role in psychiatry remains still mysterious.

High serum creatinine kinase level: possible risk factor for neuroleptic malignant syndrome.

High creatinine kinase (CK) levels and leukocytosis are known to be associated with neuroleptic malignant syndrome (NMS). The authors sought to determine if their presence during non-NMS psychotic episodes is predictive of the later development of NMS. Sixteen psychotic inpatients who met the criteria for NMS were included. For statistical comparison, two control groups were formed by matching each study patient with two non-NMS patients for age, gender, ethnicity, and year and ward of hospitalization (n = 32). The maximal individual serum levels of CK, lactate dehydrogenase (LDH), serum glutamic oxaloacetic transaminase (SGOT), and white blood cell count (WBC) during all non-NMS psychotic episodes (Brief Psychiatric Rating Scale 40) were averaged. To normalize the distribution, the individual averages were transformed to natural logarithms (Ln). Mean Ln (average [CK]) in the patients with NMS was found to be 6.46 +/- 0.91 IU/L, and in the non-NMS patients, 5.24 +/- 0.90 IU/L (actual serum CK levels, 911 +/- 747 IU/L and 343 +/- 620 IU/L, respectively). This difference was statistically significant (F [2,15] = 10.5, p < 0.0001). In addition, CK levels above the upper limit of normal were noted in 76% of psychotic episodes in the patients with NMS and in only 30% of psychotic episodes in the non-NMS patients (p < 0.0001). There was no significant difference between the NMS and non-NMS groups in Ln(LDH), Ln(SGOT), or Ln(WBC) (F [2,15] = 1.4, 2.1, and 0.9, respectively). The authors concluded that high serum CK level during non-NMS psychotic episodes seems to be a risk factor for future NMS. Therefore, CK measurement may be justified on admission of acutely psychotic patients who have other risk factors and a history of psychosis-associated CKemia.

An autopsy case of neuroleptic malignant syndrome (NMS) and its immunohistochemical findings of muscle-associated proteins and mitochondria.

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal disorder. In forensic cases, post-mortem diagnosis of NMS is sometimes difficult if ante-mortem information, such as neuroleptic ingestion or signs and symptoms, cannot be obtained. A 39-year-old Japanese male on a neuroleptic treatment regimen suddenly became agitated and died. Autopsy revealed muscle rigidity and hyperthermia. Post-mortem examination of blood revealed elevation of creatine phosphokinase-MM (CK-MM) and lactate dehydrogenase-4 and dehydrogenase-5 (LDH-4 and LDH-5). In renal glomeruli and tubules, myoglobin was stained immunohistochemically. From these findings, the cause of death was considered to be NMS. To support the diagnosis of NMS, both skeletal and cardiac muscles were stained with actin, myoglobin, desmin and mitochondria antibodies immunohistochemically. Actin, myoglobin, desmin, and mitochondria had been lost from skeletal, but not from the cardiac muscle, which suggested that only the skeletal muscle was damaged. Moreover, because mitochondria had disappeared only from the skeletal muscle, it was considered that skeletal muscle degeneration was caused by mitochondrial damage. Therefore, it is suggested that immunostaining of skeletal muscle by antibodies for muscle-associated proteins and mitochondria is useful to corroborate a diagnosis of NMS.

Lack of association in Japanese patients between neuroleptic malignant syndrome and a debrisoquine 4-hydroxylase genotype with low enzyme activity.

Decreased activity of debrisoquine 4-hydroxylase (CYP2D6), which participates in hepatic metabolism of several frequently used neuroleptics and antidepressants, is inherited as an autosomal recessive trait through polymorphic CYP2D6 gene alleles. In eastern Orientals, a C --> T substitution at nucleotide 188 (Pro34Ser) is primarily responsible for decreased ability to metabolize CYP2D6 substrates. We therefore studied a possible association between neuroleptic malignant syndrome (NMS) and the C188T mutation. We examined the frequency of the C188T mutation by polymerase chain reaction and restriction fragment length polymorphism analysis in 36 Japanese patients previously diagnosed with NMS and 107 neuroleptic-treated schizophrenic patients with no NMS history. The C188T allele frequency was 0.417 in NMS patients and 0.463 in patients without NMS. No significant allele or genotype associations were observed. We cannot conclude that low CYP2D6 activity genotype causes susceptibility to NMS in Japanese patients.

Acute hypernatremia and neuroleptic malignant syndrome in Parkinson disease.

Neuroleptic malignant syndrome is a clinical syndrome characterized by fever, muscle rigidity, and mutism. Some patients with neuroleptic syndrome may have elevated creatine phosphokinase values and abnormal liver aminotransferase values. Precipitating factors are important clues for prompt diagnosis. Typical precipitating factors include antipsychotic agents and major tranquilizers. In Parkinson disease, drug withdrawal, menstruation, and hyponatremia are precipitating factors. We report a case of neuroleptic malignant syndrome in a patient with Parkinson disease and hypernatremia. In addition, we hypothesized that sudden change of sodium concentrations in the central nervous system could trigger neuroleptic malignant syndrome in patients with Parkinson disease. According to our experience, neuroleptic malignant syndrome is a clinical diagnosis and prompt diagnosis avoids unnecessary, expensive work-ups.

Mutation involving cytochrome P450IID6 in two Japanese patients with neuroleptic malignant syndrome.

Cytochrome P450IID6 (CYP2D6) plays an important role in the hepatic metabolism of various psychotropic drugs. We detected a mutation of the CYP2D6 gene in two patients who previously had episodes of neuroleptic malignant syndrome (NMS). They were homozygous for a mutated CYP2D6J allele conferring a poor-metabolizer phenotype. Possession of this trait may contribute to susceptibility to NMS.

Neuroleptic malignant syndrome and hydroxylase gene mutations: no association with CYP2D6A or CYP2D6B.

To examine a possible association between debrisoquine 4-hydroxylase gene mutations and neuroleptic malignant syndrome, we assessed frequencies of wild type and A and B mutant alleles of the CYP2D6 gene in 24 patients with a history of neuroleptic malignant syndrome, 50 patients with neuroleptic-treated schizophrenia but no history of neuroleptic malignant syndrome, and 50 healthy controls. Allele frequencies did not differ significantly between these groups. Homozygotes for CYP2D6A and for CYP2D6B, which indicate a poor-metabolizer phenotype for the CYP2D6 substrate, were not detected among the neuroleptic malignant syndrome cases. This result indicates no excess of poor CYP2D6 metabolizers in neuroleptic malignant syndrome. The aetiology of neuroleptic malignant syndrome is not explainable in terms of CYP2D6 gene mutations.

[Rhabdomyolysis in neuroleptic therapy: an abortive malignant neuroleptic syndrome?]. / Rhabdomyolyse unter Neuroleptikatherapie: ein abortives malignes neuroleptisches Syndrom?

We report on the case of a 24 year old female patient, who, at first developed during 8 weeks of neuroleptic therapy parkinsonism and then, after improvement of psychopathology an acute rhabdomyolysis. Hyper-Ck-aemia up to 11,340 U/l was observed. Laboratory parameters normalized shortly after neuroleptics had been withdrawn and no further complications followed. Symptomatology is discussed with special reference to the possibility of an abortive malignant neuroleptic syndrome.

All elevated creatine kinase is not neuroleptic malignant syndrome.

Creatine kinase (CK) is an enzyme that is found widely in muscle tissues. Raised levels would occur when there is muscle damage. Raised levels are used as one of the diagnostic criteria for Neuroleptic Malignant Syndrome (NMS). This study looks at CK levels in 30 psychotic inpatients without NMS and compares them with 10 patients with NMS. It was found that 67% of the patients without NMS had raised CK levels, 20% of whom had levels in excess of 1000 IU/L. The rest had a two to five-fold increase over normal limits. Raised levels were associated with the use of intramuscular injections and physical restraints, situations which are well known to result in muscle injury. All the NMS patients had raised CK levels but 40% had levels below 1000 IU/L. Our findings support the idea that CK levels, though helpful, should be interpreted with care as raised levels are nonspecific.

The clinical significance of serial creatine phosphokinase estimations in acute ward admissions.

The aim of the study was to assess the effects of a number of physical factors on serial total creatine phosphokinase (CK) levels within the first few days of admission to an acute psychiatric ward. Patients (n = 17) who received parenteral injections within 48 hours of admission were compared with those (n = 30) who did not, looking at factors such as method of admission, alcohol use, presence of restraint and serial CK estimations. Those receiving injections had significantly raised CK levels over the first few days post-admission; these levels tended to normalise over 72 hours of admission. A small number of the patients who were given intramuscular injections demonstrated CK levels of over 1000 U/L. It is suggested that where CK levels are elevated, NMS should be excluded on clinical grounds. CK levels should return to normal over the next 72 hours (in the absence of NMS) if there are no further intramuscular injections.