International Journal of Neuropsychopharmacology (2014), 17, 819–821. doi:10.1017/S1461145713001624
© CINP 2014
L E T T E R TO T H E E D I TO R
A case of clozapine intoxication presenting with atypical NMS symptoms Received 17 July 2013; Reviewed 23 August 2013; Revised 17 November 2013; Accepted 2 December 2013; First published online 17 January 2014
Introduction Clozapine is an antipsychotic drug indicated for treatment-resistant schizophrenia. Clozapine at toxic doses may cause hyperthermia, alterations in consciousness, seizures, cardiac arrhythmias, excessive mucus production in bronchi, hypersalivation, miosis, blood dyscrasias, pancreatitis and hepatitis (Sartorius et al., 2002). Clozapine blood levels are influenced by age, gender, ethnicity, physical illnesses like liver failure, changes in the activity of the cytochrome oxidase enzymes due to genetic variability, concurrent medication use, smoking or caffeine consumption (Greenwood-Smith et al., 2003). Generally, plasma levels of over 1000 ng/ml are associated with central nervous system adverse effects (Varma et al., 2011). One potentially lethal side effect of antipsychotics including clozapine is neuroleptic malignant syndrome (NMS). Neuroleptic malignant syndrome is typically characterized by fever, altered mental status, leukocytosis, autonomic dysfunction and rigidity. Atypical antipsychotics including clozapine are associated less with NMS than typical antipsychotics, and when NMS occurs during treatment with atypical antipsychotics, associated symptoms are less typical (Trollor et al., 2012). In this case report, we present a patient using clozapine for treatment of schizophrenia who was admitted to the Emergency Room with NMS-like symptoms.
Case report We present a 53 yr old, female patient diagnosed with schizophrenia, who was on clozapine 500 mg/d for the past 3 yr. She had hyperlipidemia and chronic obstructive pulmonary disease (COPD) and was using rosuvastatin 20 mg/d. She was admitted to the Emergency Room (ER) with acute onset-confusion, shivering, meaningless talk and urinary incontinence. Her body temperature was 39.2 °C, blood pressure 90/50 mmHg, pulse rate 117/min, RR: 17/min, SaO2:%96. Electrocardiogram (ECG) was normal. Her Glasgow Coma Score was 15. Blood tests showed hyponatremia (133.2 mEq/l), increased levels of creatinine (1.52 mg/dl), BUN (23.68 mg/dl), uric acid (7.07 mg/dl) and decreased levels of phosphorus (2.50 mg/dl). Liver and thyroid function tests and
Address for correspondence: Dr Y. Ayhan, Department of Psychiatry, Faculty of Medicine, Hacettepe University, 06100 Sihhiye, Altindag, Ankara, Turkey. Tel.: +90 3123051440 Fax: +90 3123101938 Email: [email protected]
potassium, chloride and calcium levels were within normal range. Complete blood count (CBC) demonstrated leukocytosis (14.8 × 103/μl) and thrombocytopenia (107 × 103/μl and 74 × 103/μl on two consecutive measurements). D-dimer (3.76 g/ml) and fibrinogen (952 mg/dl) levels were high. Measurements of C reactive protein (CRP) 44.7 mg/dl, erythrocyte sedimentation rate (ESR) 58 mm/h and procalcitonin 114.6 ng/ml were increased. Peripheral smear, activated partial thromboplastin time (aPTT) and international normalized ratio (INR) were normal, not supportive of DIC. Venous doppler ultrasound of lower extremities and ventilation/perfusion (V/Q) scan did not reveal evidence for thromboembolism. On physical examination, she was seen to be coughing, had sputum production and bilateral rhonchi. Right-sided atalectasia was observed on chest X-ray, which was not considered as evidence for pneumonia. On neurological examination, pupils were bilaterally miotic and reactive to light and other than slight instability she had no localizing deficits. No rigidity was found and the speech pattern did not fit into any aphasic syndrome. Cranial CT and MRI scans, including diffusion-weighted sequences did not reveal any pathology, thus cerebrovascular accident (CVA) was ruled out. In her follow-up, her temperature remained to be over 39 °C. Urine and blood cultures were negative and lumbar puncture (L/P) did not display an abnormality (CSF total cell count 2000/mm3, white cell count 10/mm3 on microscopy, no microorganisms observed; cerebrospinal fluid (CSF) protein: 126 mg/dl, Cl: 124 mEq/l, glucose: 88 mg/dl while serum glucose: 135 mg/dl; CSF culture was negative). She was awake during her psychiatric evaluation. She had spontaneous but incomprehensible speech. She was responding well to simple commands but not to complex orders. She was not able to construct complex sentences and was reiterating meaningless syllables. Perseveration, verbigeration and echolalia were noted. Naming was impaired. Creatine kinase (CK) levels were elevated (2158 U/l). She was admitted to the inpatient psychiatry unit with an initial diagnosis of NMS. During clinical follow-up, psychotropic medications were ceased and the supportive treatment started at the ER was continued. Her temperature and CK measurement (221 U/l) returned to normal levels on the sixth day of admission to the ER. Confusion disappeared, but she remained amnestic for the first week of her illness. Her comprehension and speech improved, her attention normalized gradually. Her vital signs remained stable except for one day when systolic arterial pressure increased
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by 20 mmHg (up to 150 mmHg) and ventricular extrasystoles were observed when ipratropium bromide and salbutamol sulphate monohydrate was initiated for COPD. These were discontinued and budenoside was started. Platelet count returned to normal in 4 d, CRP, procalcitonin and ESR returned to normal in 1 wk. Other signs of NMS, including diaphoresis, dysphagia and tremor were not evident. EEG, on the fourth day of admission, did not display an epileptiform abnormality. Immediately after her recovery, clozapine levels from the samples obtained at the ER were received. Both clozapine and nor-clozapine levels were at toxic levels (1439 and 332.6 ng/ml, respectively). The levels dropped after 8 d (both clozapine and norclozapine
© CINP 2014
L E T T E R TO T H E E D I TO R
A case of clozapine intoxication presenting with atypical NMS symptoms Received 17 July 2013; Reviewed 23 August 2013; Revised 17 November 2013; Accepted 2 December 2013; First published online 17 January 2014
Introduction Clozapine is an antipsychotic drug indicated for treatment-resistant schizophrenia. Clozapine at toxic doses may cause hyperthermia, alterations in consciousness, seizures, cardiac arrhythmias, excessive mucus production in bronchi, hypersalivation, miosis, blood dyscrasias, pancreatitis and hepatitis (Sartorius et al., 2002). Clozapine blood levels are influenced by age, gender, ethnicity, physical illnesses like liver failure, changes in the activity of the cytochrome oxidase enzymes due to genetic variability, concurrent medication use, smoking or caffeine consumption (Greenwood-Smith et al., 2003). Generally, plasma levels of over 1000 ng/ml are associated with central nervous system adverse effects (Varma et al., 2011). One potentially lethal side effect of antipsychotics including clozapine is neuroleptic malignant syndrome (NMS). Neuroleptic malignant syndrome is typically characterized by fever, altered mental status, leukocytosis, autonomic dysfunction and rigidity. Atypical antipsychotics including clozapine are associated less with NMS than typical antipsychotics, and when NMS occurs during treatment with atypical antipsychotics, associated symptoms are less typical (Trollor et al., 2012). In this case report, we present a patient using clozapine for treatment of schizophrenia who was admitted to the Emergency Room with NMS-like symptoms.
Case report We present a 53 yr old, female patient diagnosed with schizophrenia, who was on clozapine 500 mg/d for the past 3 yr. She had hyperlipidemia and chronic obstructive pulmonary disease (COPD) and was using rosuvastatin 20 mg/d. She was admitted to the Emergency Room (ER) with acute onset-confusion, shivering, meaningless talk and urinary incontinence. Her body temperature was 39.2 °C, blood pressure 90/50 mmHg, pulse rate 117/min, RR: 17/min, SaO2:%96. Electrocardiogram (ECG) was normal. Her Glasgow Coma Score was 15. Blood tests showed hyponatremia (133.2 mEq/l), increased levels of creatinine (1.52 mg/dl), BUN (23.68 mg/dl), uric acid (7.07 mg/dl) and decreased levels of phosphorus (2.50 mg/dl). Liver and thyroid function tests and
Address for correspondence: Dr Y. Ayhan, Department of Psychiatry, Faculty of Medicine, Hacettepe University, 06100 Sihhiye, Altindag, Ankara, Turkey. Tel.: +90 3123051440 Fax: +90 3123101938 Email: [email protected]
potassium, chloride and calcium levels were within normal range. Complete blood count (CBC) demonstrated leukocytosis (14.8 × 103/μl) and thrombocytopenia (107 × 103/μl and 74 × 103/μl on two consecutive measurements). D-dimer (3.76 g/ml) and fibrinogen (952 mg/dl) levels were high. Measurements of C reactive protein (CRP) 44.7 mg/dl, erythrocyte sedimentation rate (ESR) 58 mm/h and procalcitonin 114.6 ng/ml were increased. Peripheral smear, activated partial thromboplastin time (aPTT) and international normalized ratio (INR) were normal, not supportive of DIC. Venous doppler ultrasound of lower extremities and ventilation/perfusion (V/Q) scan did not reveal evidence for thromboembolism. On physical examination, she was seen to be coughing, had sputum production and bilateral rhonchi. Right-sided atalectasia was observed on chest X-ray, which was not considered as evidence for pneumonia. On neurological examination, pupils were bilaterally miotic and reactive to light and other than slight instability she had no localizing deficits. No rigidity was found and the speech pattern did not fit into any aphasic syndrome. Cranial CT and MRI scans, including diffusion-weighted sequences did not reveal any pathology, thus cerebrovascular accident (CVA) was ruled out. In her follow-up, her temperature remained to be over 39 °C. Urine and blood cultures were negative and lumbar puncture (L/P) did not display an abnormality (CSF total cell count 2000/mm3, white cell count 10/mm3 on microscopy, no microorganisms observed; cerebrospinal fluid (CSF) protein: 126 mg/dl, Cl: 124 mEq/l, glucose: 88 mg/dl while serum glucose: 135 mg/dl; CSF culture was negative). She was awake during her psychiatric evaluation. She had spontaneous but incomprehensible speech. She was responding well to simple commands but not to complex orders. She was not able to construct complex sentences and was reiterating meaningless syllables. Perseveration, verbigeration and echolalia were noted. Naming was impaired. Creatine kinase (CK) levels were elevated (2158 U/l). She was admitted to the inpatient psychiatry unit with an initial diagnosis of NMS. During clinical follow-up, psychotropic medications were ceased and the supportive treatment started at the ER was continued. Her temperature and CK measurement (221 U/l) returned to normal levels on the sixth day of admission to the ER. Confusion disappeared, but she remained amnestic for the first week of her illness. Her comprehension and speech improved, her attention normalized gradually. Her vital signs remained stable except for one day when systolic arterial pressure increased
820
G. Z. Kamış et al.
by 20 mmHg (up to 150 mmHg) and ventricular extrasystoles were observed when ipratropium bromide and salbutamol sulphate monohydrate was initiated for COPD. These were discontinued and budenoside was started. Platelet count returned to normal in 4 d, CRP, procalcitonin and ESR returned to normal in 1 wk. Other signs of NMS, including diaphoresis, dysphagia and tremor were not evident. EEG, on the fourth day of admission, did not display an epileptiform abnormality. Immediately after her recovery, clozapine levels from the samples obtained at the ER were received. Both clozapine and nor-clozapine levels were at toxic levels (1439 and 332.6 ng/ml, respectively). The levels dropped after 8 d (both clozapine and norclozapine
