Clinical Toxicology (2014), 52, 39–43 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2013.862258
CRITICAL CARE
Adverse effects associated with high-dose olanzapine therapy in patients admitted to inpatient psychiatric care A. B. PETERSEN, S. E. ANDERSEN, M. CHRISTENSEN, and H. L. LARSEN
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Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark
Context. In 2012, Danish psychiatrist raised concerns regarding the use of high-dose olanzapine in the treatment of patients. The present study was part of an audit carried out by the Mental Health Services of the Capitol Region of Denmark regarding this topic. Objective. To assess the potential risks associated with high-dose olanzapine treatment (⬎ 40 mg daily) in inpatient psychiatric units. Methods. The study was an observational case series based on review of patient charts. The main inclusion criterion was treatment with at least one daily dose ⬎ 40 mg olanzapine during the index admission in the period between 1st of January and 15th of March 2012. Six additional criteria were applied in order to target the subgroup of patients most likely to have experienced an adverse event due to treatment with olanzapine. The physician order entry system and the central patient register containing patient specific information about diagnoses and treatments were used for identification of study population. Results. The 91 patients included in the study received maximum daily doses of olanzapine ranging from 45 to 160 mg and in 25% of patients, the total antipsychotic load exceeded 2000 mg of chlorpromazine equivalents. Extrapyramidal symptoms and sedation were the most frequent adverse events with frequencies of 27% and 25%, respectively. Furthermore, other well-known adverse events such as weight gain (14%), hypotension (2%), neuroleptic malignant syndrome (2%) and corrected QT-interval (QTc) prolongation (1%) were also observed in some patients. Five patients died and in two of these cases, olanzapine was concluded to be a possible contributing cause of death. Conclusion. Increased frequency of extrapyramidal symptoms and sedation as well as severe toxicity was observed in patients treated with up to 160 mg olanzapine per day. In order to prevent harmful outcomes, the clinicians should be ready to act appropriately if toxic effects of olanzapine occur. Treatment cessation should be immediate if serious adverse events such as neuroleptic malignant syndrome arise. Keywords
Antipsychotic; Adverse drug reaction; Adverse event; Drug overdose
Introduction
The symptoms to an overdose to a great extent reflect a worsening of the AEs that can be seen when using therapeutic dose. Death has been reported following acute overdose with 450 mg olanzapine, while there are reports of patients surviving over-dosages of up to 2000 mg of olanzapine. The safety of olanzapine in approved dosages is welldescribed. However, doses larger than the maximum recommended are sometimes necessary in order to achieve the optimal clinical response. So far, only a few small studies have examined AEs in relation to high-dose (⬎ 40 mg daily) olanzapine treatment in clinical settings.3–5 These have reported AEs in the form of weight gain, anticholinergic symptoms and dystonia in relation to this high-dose treatment. In the summer of 2012 clinicians from a psychiatric center in the Capitol Region of Denmark went public with concerns regarding the use of high-dose olanzapine (⬎ 40 mg daily) in the treatment of psychiatric patients. This discussion appeared in nationwide newspapers and news shows and caught political attention, especially from the politicians responsible for the hospitals in the Capitol Region. As a result, the National Board of Health carried out an investigation in order to examine the extent of this
Olanzapine is an atypical antipsychotic and market approval was issued by both the American Food and Drug Administration and the European Medicines Agency in 1996. The drug is approved for the treatment of schizophrenia and bipolar disorder. A daily dose of olanzapine within the range of 5–20 mg is recommended,1 but a maximum recommended dose of 40 mg has been suggested by an American consensus guideline2 and this is currently the clinical practice in Denmark. Most common adverse events (AEs) in relation to treatment with olanzapine in recommended doses are sedation and weight gain, both of which are observed in more than 10% of patients. Neuroleptic malignant syndrome (NMS), extrapyramidal symptoms (EPS) and QTc prolongation are examples of less frequent AEs that also require attention by physicians.1
Received 13 June 2013; revised 27 October 2013; accepted 31 October 2013. Address correspondence to Andreas Brønden Petersen, Department of Clinical Pharmacology, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark. Tel: ⫹ 45 51922898. Fax: ⫹ 45 35313711. E-mail: [email protected]
39
40 A. B. Petersen et al. potential problem. This showed that nearly 10% of patients admitted to a psychiatric ward in the Capitol Region during July 2012 were treated with at least one daily dose above the maximum recommended 40 mg olanzapine. The Mental Health Services of the Capitol Region was subsequently requested to carry out an audit with the aim of assessing the potential risks associated with high-dose olanzapine treatment. This study was a part of this audit and had the objective of examining the incidence of AEs in relation to this high-dose treatment.
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Method The study was an observational case series based on review of patient charts. Study population The Regional Mental Health Services that is providing health care services to a population of 1.7 million in the Capitol Region of Denmark identified patients, who had been treated with at least one daily dose ⬎ 40 mg of olanzapine during admission to one of nine psychiatric centers in the index period between 1st of January and 15th of March 2012. These data had been obtained by accessing the dispensing module of the physician order entry system. In order to target the subgroup of patients most likely to have experienced an AE due to treatment with olanzapine, six additional inclusion criteria were applied. A search in the Danish central patient register containing patient-specific information about diagnoses and treatments on the entire Danish population enabled this. The criteria included 1) death before 1st of September 2012, 2) consultation by specialist from a somatic specialty (e.g. internal medicine) during the index admission, 3) referral to a somatic outpatient clinic before 1st of September 2012, 4) admission to a somatic ward before 1st of September 2012, 5) foreign social security number and 6) treatment with at least one daily dose ⱖ 100 mg olanzapine. The patients had to fulfill at least one of these criteria to be included in the study population (Table 1). Foreign social security number was included as a risk factor of AEs due to difficulties of tracking these patients in the electronic patient charts in case of readmission during the index period. Table 1. The six additional inclusion criteria. Inclusion criteria Admission to a somatic outpatient clinic Consultation by specialist from a somatic specialty during the index admission Admission to a somatic ward before 1st of Sep 2012 Foreign social security number At least one daily dose of ⱖ 100 mg olanzapine Death (all causes)
n* 50 (55%) 22 (24%) 16 (18%) 7 (8%) 7 (8%) 5 (5%)
*The total n exceeds 91 due to the possibility of more than one inclusion criteria for each patient.
Review of patient charts The included patient charts were reviewed by two clinical pharmacologists. These two doctors performed the review independently and discussed severe AEs (e.g. death) to reach consensus regarding potential causality. The following information was extracted from the patient charts: Mental health center, age, sex, olanzapine dose, duration of admission in the psychiatric ward, smoking status, psychiatric diagnosis, co-morbidity, inclusion criteria, coercive olanzapine treatment, treatment with olanzapine prior to admission, duration of the treatment period with doses ⬎ 40 mg olanzapine daily and if the treatment effect and/or AEs had been registered and/or assessed. Furthermore, any AEs were registered and a causality assessment of the AE to olanzapine treatment was performed. A two-point scale was used—adverse event likely associated/not likely associated with olanzapine. The causality assessment was based on type of event (such as well-known AEs associated with olanzapine but other events were also considered); time to event from dose adjustment or initiation of olanzapine treatment, change in dose and/or treatment initiation of concomitant medicine; other possible explanations for the observed event such as aggravation of known co-morbidity not likely caused by olanzapine. The administration of fixed and pro re nata (PRN) doses of olanzapine as well as other medicine was obtained from the dispensing module of the physician order entry system. An estimate of maximum antipsychotic load was performed based on chlorpromazine equivalents, which is a commonly used tool for assessment of total antipsychotic doses.6 Treatment with 40 mg of olanzapine corresponds to 800 mg of chlorpromazine6 and chlorpromazine doses above 800 mg/day are considered high-dose.7 The study was part of a psychiatric quality assurance program that was initiated and approved by the hospital managers. Implying no biomedical research, no approval of the study from the ethics committee was required, which has been confirmed by the research ethics committee of the Capitol Region of Denmark. Additional audit An additional audit was conducted if olanzapine was suspected to have led to any severe AEs such as death or NMS. The audit panel comprised of two clinical pharmacologists, a professor of psychiatry and the head of clinic where the patients had been treated in addition to one or more of the attending psychiatrists. The course of treatment was discussed and a conclusion drawn on the causality between the olanzapine treatment and the AEs. Statistical analysis Descriptive statistics has been performed. Interquartile ranges in terms of age and duration of admission have been stated.
Results Of 103 patients initially included, 12 were subsequently excluded. One patient did not meet the inclusion Clinical Toxicology vol. 52 no. 1 2014
AEs associated with high-dose olanzapine treatment 41
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Patient characteristics The median age of patients was 39 years [32; 49] and median duration of admission was 47 days [18;94]. Nearly 90% of patients had a diagnosis within the schizophrenic spectrum or other psychotic disorders. Substance abuse was the most frequent co-morbidity. An overview of patient characteristics can be found in Table 2. Antipsychotic treatment About 50% of patients had been treated with olanzapine prior to index admission in a dose range of 5–80 mg daily. During admission the included patients were treated with maximum daily doses of 45–160 mg. In 80% of patients the maximum daily doses were between 50 and 80 mg (Fig. 1). Half of the patients were treated with other antipsychotic drugs by the time of the maximum dose of olanzapine. A quarter of the study population was exposed to chlorpromazine equivalents above 2000 mg and the frequency of psychotropic poly-pharmacy increased steadily with increasing total antipsychotic load (Fig. 2). No potentially serious interactions due to treatment with non-psychotropic drugs (e.g. anti-arrhythmics) were observed. Table 2. Overview of patient characteristics. Patient characteristics Median age (1–3. quartile) Male (n) Median duration of admission (1–3 quartile) Smokers (n)
n 39 years (32–49) 57 (63%) 47 days (18–94) 56 (62%)
Most frequent diagnosis at time of discharge Schizophrenia Psychosis Psychotic affective disorder Personality disorder
59 (65%) 10 (11%) 10 (11%) 4 (4%)
Most frequent co-morbidities None Substance abuse Lung disease Diabetes (Type 1 or 2) Obesity
25 (27%) 40 (44%) 8 (9%) 6 (7%) 4 (4%)
Olanzapine during index-admission Acute treatment (⬍ 3 days) Maintenance treatment
45 (49%) 46 (51%)
Involuntary treatment with olanzapine No Yes Both voluntary and involuntary treatment Unknown
70 (77%) 4 (4%) 13 (14%) 4 (4%)
Dosing schedule Only PRN Only fixed Both PRN and fixed
20 (22%) 7 (8%) 64 (70%)
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Maximum daily dose of olanzapine during index admission 40 35 30 n (patients)
criteria, nine had been admitted to outpatient clinics with diagnoses not believed to be associated with an AE caused by olanzapine (e.g. gynecology) and in two cases the charts were unavailable. In total, 91 patients were included.
25 20 15 10 5 0 45
50
60
70 80 90 Olanzapine (mg)
100
120
160
Fig. 1. Maximum daily doses of olanzapine in the range of 45–160 mg were observed.
Observation of AEs The effect of olanzapine treatment was described in 88 of 91 patient charts, whereas the occurrence of AEs was mentioned or assessed in 56 of the charts. In 45 of these cases, symptoms were specifically mentioned or indirectly documented as AEs. Prescription of biperiden for the treatment of EPS was an example of the latter. In the remaining 11 charts it was specifically mentioned that there were no AEs. Overall, 35 patient charts did not include any contemplations regarding AEs. In four of these cases, however the described symptoms and clinical findings were compatible with olanzapine-related AEs. A prolonged QTc interval of 510 ms was described in a single patient (1%). In the majority of patients, electrocardiography (ECG) had been recorded upon admission and only 4% of patient charts contained no ECG or an ECG description. Nevertheless, none of the case notes included a systematic observation of ECG, for example, in relation to increase in dose of antipsychotics or tachycardia. Thus, two patients were discharged with an 80 mg fixed daily dose of olanzapine without ECG examination at steady state. In some cases the charts stated that the clinical condition of patients made it impossible to perform ECG. CNS depression and EPS were the most frequent AEs with incidences of 25% and 27%, respectively. Other wellknown AEs to antipsychotic treatment such as increased bodyweight (13%), tachycardia—HR ⬎ 100 bpm (2%) and hypotension—systolic BP ⬍ 100 mmHg (2%) were also observed (Table 3). Severe AEs Five cases of severe AEs with suspected causal relation to olanzapine were observed: death (n ⫽ 2), NMS (n ⫽ 2) and serious EPS (n ⫽ 1). These were discussed at the additional audit. One patient treated with a combination of olanzapine 60 mg/day and clozapine 100 mg/day developed NMS. The antipsychotic treatment was discontinued for a period of weeks, but the patient had a relapse of NMS following reinstitution of single treatment with clozapine 200 mg/day. It was concluded that the condition was most likely caused by the latter. One patient developed pronounced EPS after treatment with olanzapine 60 mg/day and intramuscular injections of haloperidol 150 mg/week. Downward adjustment of the
42 A. B. Petersen et al. Maximum antipsychotic load during index admission 35 30 Black bars: Olanzapine Grey bars: Other antipsychotics
n (patients)
25 20 15 10 5
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0 900-1200 1201-1600 1601-2000 2001-2400 2400-2800 2801-3200 3201-3600 3601-4000 4001-4400 Chlorpromazine equivalents (mg)
Fig. 2. The black bars illustrate the average fraction of total antipsychotic load constituted by olanzapine and the gray bars the average fraction constituted by other antipsychotics.
haloperidol dose led to an improvement with respect to EPS and it was concluded that haloperidol was the main cause of the AE. There were two deaths possibly associated with olanzapine and in one of these cases, death was preceded by NMS. One patient took an overdose of olanzapine, clonazepam and methadone and the postmortem blood analysis revealed high blood concentrations of all three drugs. The coroner performing the postmortem examinations concluded that all three drugs could individually have been the cause of death. The last patient was treated with a combination of olanzapine and risperidone. Maximum dose of olanzapine was 60 mg, but most of the time during index admission the patient was treated with 40 mg olanzapine in combination with 6 mg risperidone, which is within recommended doses for both drugs. The patient developed symptoms of NMS (trouble swallowing and fluctuating levels of consciousness) after 1 month of admission and was transferred to the intensive care unit. During the following weeks the patient experienced complications in the form of cerebellar hemorrhage and sepsis and died. It was concluded that olanzapine probably was a contributing factor to the patient’s condition Table 3. AEs with suspected causal relation to olanzapine.
Adverse events Extrapyramidal symptoms CNS depression Increase in bodyweight s-prolactin increase/gynecomastia Worsening of dyslipidemia Neuroleptic malignant syndrome Death Tachycardia (HR ⬎ 100 bpm) Hypotension (systolic BP ⬍ 100 mmHG) Fall Diabetes/worsening of diabetes QTc prolongation Respiratory distress Elevated liver enzymes
n
Olanzapine dose (mg) on time of AE
25 (27%) 23 (25%) 13 (14%) 8 (9%) 3 (3%) 2 (2%) 2 (2%) 2 (2%) 2 (2%) 2 (2%) 2 (2%) 1 (1%) 1 (1%) 1 (1%)
50–120 45–120 45–100 50–70 60–100 50–90 50–100 45–90 60 60–70 60–70 90 50 60
and death. Furthermore, the question was raised whether or not sufficient action (e.g. discontinuation of antipsychotic treatment) in relation to the possible NMS had been taken in time.
Discussion This retrospective study indicates that treatment with more than 40 mg olanzapine per day was fairly well tolerated in the majority of patients. Still, more than half of the patients seem to have experienced AEs ascribable to high-dose olanzapine. However, the vast majority of these were well known and manageable. If outweighed by the benefits, AEs may be acceptable. This retrospective study did not allow quantification of disease severity at admission or treatment effect and therefore it was not possible to assess whether or not this was the case in the included patients. Four patients experienced severe AEs, but in two of these cases other antipsychotics used in combination with olanzapine were most likely the cause of the AEs. Furthermore, one patient who died following high blood concentrations of olanzapine, clonazepam and methadone had most likely not been following treatment instructions. In the last case, olanzapine was concluded to be a possible contributing cause of NMS and the subsequent complications and death. This patient was treated with a maximum of 60 mg olanzapine daily during admission and this maximum dose was administered for only a single day. The finding that most AEs were well tolerated is in accordance with the sparse literature on high-dose olanzapine treatment. Thus, Kelly et al. conducted a cross-over study in 13 patients treated with 50 mg olanzapine/450 mg clozapine daily and found that weight gain and anticholinergic AEs such as dry mouth and blurred vision were frequently observed following treatment with olanzapine.3 Another study has reported beneficial clinical response and no AEs in a patient with treatment-refractory schizophrenia treated with 60 mg of olanzapine daily.4 Finally, a study has described a good clinical response in two patients with refractory psychosis after treatment with 50 mg olanzapine daily. One of these Clinical Toxicology vol. 52 no. 1 2014
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AEs associated with high-dose olanzapine treatment 43 patients had some dystonia in relation to this high-dose treatment, but felt them preferable to hallucinations.5 A consensus report regarding the advantages and disadvantages of combined therapy with more than one antipsychotic was conducted by the United Kingdom National Institute of Clinical Excellence in 2008. It was stated that the evidence of improved treatment effect in relation to antipsychotic poly-pharmacy was inconclusive. Furthermore, combination therapy may often result in more AEs.8 Despite this fact, studies have shown that about 20% of patients with schizophrenia are treated with antipsychotic combination therapy.8 High-dose olanzapine could be a reasonable approach in order to avoid antipsychotic poly-pharmacy. However, we found that about 50% of patients were treated with other antipsychotics in addition to high-dose olanzapine. The strength of the present study is the relatively large number of patients included from clinical settings when compared with previous studies on this topic. A weakness of the present study is the retrospective design. Naturally, there is no guarantee that all relevant information had been documented in the patient charts and therefore we might not have been presented with the full picture. Another weakness associated with the retrospective study design was the risk of including a selected population of olanzapine-treated patients, which may hamper generalizability of the findings. The use of involuntary medical treatment was much more frequent in the study population than in the general psychiatric population (17% vs. ⬍ 3%), which could indicate a group of patients with high morbidity.9 The frequency of substance abuse as a comorbidity was comparable between the study group and the general schizophrenic population (44% vs. 50%).9 Data were systematically extracted from charts and ambiguities were discussed during the process. However, the review of charts was performed independently by two doctors, which could question the reproducibility of findings. High occurrence of antipsychotic poly-pharmacy was a potential challenge with respect to assessment of causality between olanzapine and AEs. All AEs documented in patient charts were registered, also the ones hitherto undocumented in relation to olanzapine and not listed in the summary of product characteristics (SPC), and a causality assessment was performed.
Conclusion Our findings indicate that daily doses of olanzapine above the maximum recommended 40 mg are fairly well tolerated in the majority of patients. Nevertheless, our study also supports the general notion of an increased risk of well-known AEs when high-dose treatment with olanzapine is employed,
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at least when compared with the frequencies of AEs listed in the SPC for olanzapine. Importantly, severe toxicity with causal relation to olanzapine was observed in two of 91 cases, both in relation to treatment with doses just above the maximum recommended dose and after intended overdose with a presumably very high dose of olanzapine. We therefore advocate that clinicians carefully monitor olanzapine toxicity and in particular during high-dose olanzapine treatment they should be ready to act appropriately if toxic effects of olanzapine should occur. Treatment cessation should be immediate if serious AEs such as NMS arise.
Acknowledgments The authors would like to thank Troels Roesbjerg for assisting with data extraction from the physician order entry system.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
References 1. European Medicines Agency. Zyprexa: EPAR – Product Information. London: European Medicines Agency; 2009 [updated June 7, 2013; cited June 11, 2013]. Available from: http://www.ema.europa.eu/ ema/index.jsp?curl ⫽ pages/medicines/human/medicines/000115/ human_med_001189.jsp&mid ⫽ WC0b01ac058001d124. Accessed June 11, 2013. 2. Kane JM, Leucht S, Carpenter D, Docherty JP; Expert Consensus Panel for Optimizing Pharmacologic Treatment of Psychotic Disorders. The expert consensus guideline series. Optimizing pharmacologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry 2003; 64:5–19. 3. Kelly DL, Conley RR, Richardson CM, Tamminga CA, Carpenter WT. Adverse effects and laboratory parameters of high-dose olanzapine vs. clozapine in treatment-resistant schizophrenia. Ann Clin Psychiatry 2003; 15:181–186. 4. Lerner V. High-dose olanzapine for treatment-refractory schizophrenia. Clin Neuropharmacol 2003; 26:58–61. 5. Reich J. Use of high-dose olanzapine in refractory psychosis. Am J Psychiatry 1999; 156:661. 6. Woods SW. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry 2003; 64:663–667. 7. Liu X, De Haan S. Chlorpromazine dose for people with schizophrenia. Cochrane Database Syst Rev 2009; 15:CD007778. 8. Goodwin G, Fleischhacker W, Arango C, Baumann P, Davidson M, de Hert M, et al. Advantages and disadvantages of combination treatment with antipsychotics ECNP Consensus Meeting, March 2008, Nice. Eur Neuropsychopharmacol 2009; 19:520–532. 9. Mental Health Services - Capital Region of Denmark. Available from: http://www.psykiatri-regionh.dk. Accessed June 11, 2013.
CRITICAL CARE
Adverse effects associated with high-dose olanzapine therapy in patients admitted to inpatient psychiatric care A. B. PETERSEN, S. E. ANDERSEN, M. CHRISTENSEN, and H. L. LARSEN
Clinical Toxicology Downloaded from informahealthcare.com by The University of Manchester on 12/21/14 For personal use only.
Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark
Context. In 2012, Danish psychiatrist raised concerns regarding the use of high-dose olanzapine in the treatment of patients. The present study was part of an audit carried out by the Mental Health Services of the Capitol Region of Denmark regarding this topic. Objective. To assess the potential risks associated with high-dose olanzapine treatment (⬎ 40 mg daily) in inpatient psychiatric units. Methods. The study was an observational case series based on review of patient charts. The main inclusion criterion was treatment with at least one daily dose ⬎ 40 mg olanzapine during the index admission in the period between 1st of January and 15th of March 2012. Six additional criteria were applied in order to target the subgroup of patients most likely to have experienced an adverse event due to treatment with olanzapine. The physician order entry system and the central patient register containing patient specific information about diagnoses and treatments were used for identification of study population. Results. The 91 patients included in the study received maximum daily doses of olanzapine ranging from 45 to 160 mg and in 25% of patients, the total antipsychotic load exceeded 2000 mg of chlorpromazine equivalents. Extrapyramidal symptoms and sedation were the most frequent adverse events with frequencies of 27% and 25%, respectively. Furthermore, other well-known adverse events such as weight gain (14%), hypotension (2%), neuroleptic malignant syndrome (2%) and corrected QT-interval (QTc) prolongation (1%) were also observed in some patients. Five patients died and in two of these cases, olanzapine was concluded to be a possible contributing cause of death. Conclusion. Increased frequency of extrapyramidal symptoms and sedation as well as severe toxicity was observed in patients treated with up to 160 mg olanzapine per day. In order to prevent harmful outcomes, the clinicians should be ready to act appropriately if toxic effects of olanzapine occur. Treatment cessation should be immediate if serious adverse events such as neuroleptic malignant syndrome arise. Keywords
Antipsychotic; Adverse drug reaction; Adverse event; Drug overdose
Introduction
The symptoms to an overdose to a great extent reflect a worsening of the AEs that can be seen when using therapeutic dose. Death has been reported following acute overdose with 450 mg olanzapine, while there are reports of patients surviving over-dosages of up to 2000 mg of olanzapine. The safety of olanzapine in approved dosages is welldescribed. However, doses larger than the maximum recommended are sometimes necessary in order to achieve the optimal clinical response. So far, only a few small studies have examined AEs in relation to high-dose (⬎ 40 mg daily) olanzapine treatment in clinical settings.3–5 These have reported AEs in the form of weight gain, anticholinergic symptoms and dystonia in relation to this high-dose treatment. In the summer of 2012 clinicians from a psychiatric center in the Capitol Region of Denmark went public with concerns regarding the use of high-dose olanzapine (⬎ 40 mg daily) in the treatment of psychiatric patients. This discussion appeared in nationwide newspapers and news shows and caught political attention, especially from the politicians responsible for the hospitals in the Capitol Region. As a result, the National Board of Health carried out an investigation in order to examine the extent of this
Olanzapine is an atypical antipsychotic and market approval was issued by both the American Food and Drug Administration and the European Medicines Agency in 1996. The drug is approved for the treatment of schizophrenia and bipolar disorder. A daily dose of olanzapine within the range of 5–20 mg is recommended,1 but a maximum recommended dose of 40 mg has been suggested by an American consensus guideline2 and this is currently the clinical practice in Denmark. Most common adverse events (AEs) in relation to treatment with olanzapine in recommended doses are sedation and weight gain, both of which are observed in more than 10% of patients. Neuroleptic malignant syndrome (NMS), extrapyramidal symptoms (EPS) and QTc prolongation are examples of less frequent AEs that also require attention by physicians.1
Received 13 June 2013; revised 27 October 2013; accepted 31 October 2013. Address correspondence to Andreas Brønden Petersen, Department of Clinical Pharmacology, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark. Tel: ⫹ 45 51922898. Fax: ⫹ 45 35313711. E-mail: [email protected]
39
40 A. B. Petersen et al. potential problem. This showed that nearly 10% of patients admitted to a psychiatric ward in the Capitol Region during July 2012 were treated with at least one daily dose above the maximum recommended 40 mg olanzapine. The Mental Health Services of the Capitol Region was subsequently requested to carry out an audit with the aim of assessing the potential risks associated with high-dose olanzapine treatment. This study was a part of this audit and had the objective of examining the incidence of AEs in relation to this high-dose treatment.
Clinical Toxicology Downloaded from informahealthcare.com by The University of Manchester on 12/21/14 For personal use only.
Method The study was an observational case series based on review of patient charts. Study population The Regional Mental Health Services that is providing health care services to a population of 1.7 million in the Capitol Region of Denmark identified patients, who had been treated with at least one daily dose ⬎ 40 mg of olanzapine during admission to one of nine psychiatric centers in the index period between 1st of January and 15th of March 2012. These data had been obtained by accessing the dispensing module of the physician order entry system. In order to target the subgroup of patients most likely to have experienced an AE due to treatment with olanzapine, six additional inclusion criteria were applied. A search in the Danish central patient register containing patient-specific information about diagnoses and treatments on the entire Danish population enabled this. The criteria included 1) death before 1st of September 2012, 2) consultation by specialist from a somatic specialty (e.g. internal medicine) during the index admission, 3) referral to a somatic outpatient clinic before 1st of September 2012, 4) admission to a somatic ward before 1st of September 2012, 5) foreign social security number and 6) treatment with at least one daily dose ⱖ 100 mg olanzapine. The patients had to fulfill at least one of these criteria to be included in the study population (Table 1). Foreign social security number was included as a risk factor of AEs due to difficulties of tracking these patients in the electronic patient charts in case of readmission during the index period. Table 1. The six additional inclusion criteria. Inclusion criteria Admission to a somatic outpatient clinic Consultation by specialist from a somatic specialty during the index admission Admission to a somatic ward before 1st of Sep 2012 Foreign social security number At least one daily dose of ⱖ 100 mg olanzapine Death (all causes)
n* 50 (55%) 22 (24%) 16 (18%) 7 (8%) 7 (8%) 5 (5%)
*The total n exceeds 91 due to the possibility of more than one inclusion criteria for each patient.
Review of patient charts The included patient charts were reviewed by two clinical pharmacologists. These two doctors performed the review independently and discussed severe AEs (e.g. death) to reach consensus regarding potential causality. The following information was extracted from the patient charts: Mental health center, age, sex, olanzapine dose, duration of admission in the psychiatric ward, smoking status, psychiatric diagnosis, co-morbidity, inclusion criteria, coercive olanzapine treatment, treatment with olanzapine prior to admission, duration of the treatment period with doses ⬎ 40 mg olanzapine daily and if the treatment effect and/or AEs had been registered and/or assessed. Furthermore, any AEs were registered and a causality assessment of the AE to olanzapine treatment was performed. A two-point scale was used—adverse event likely associated/not likely associated with olanzapine. The causality assessment was based on type of event (such as well-known AEs associated with olanzapine but other events were also considered); time to event from dose adjustment or initiation of olanzapine treatment, change in dose and/or treatment initiation of concomitant medicine; other possible explanations for the observed event such as aggravation of known co-morbidity not likely caused by olanzapine. The administration of fixed and pro re nata (PRN) doses of olanzapine as well as other medicine was obtained from the dispensing module of the physician order entry system. An estimate of maximum antipsychotic load was performed based on chlorpromazine equivalents, which is a commonly used tool for assessment of total antipsychotic doses.6 Treatment with 40 mg of olanzapine corresponds to 800 mg of chlorpromazine6 and chlorpromazine doses above 800 mg/day are considered high-dose.7 The study was part of a psychiatric quality assurance program that was initiated and approved by the hospital managers. Implying no biomedical research, no approval of the study from the ethics committee was required, which has been confirmed by the research ethics committee of the Capitol Region of Denmark. Additional audit An additional audit was conducted if olanzapine was suspected to have led to any severe AEs such as death or NMS. The audit panel comprised of two clinical pharmacologists, a professor of psychiatry and the head of clinic where the patients had been treated in addition to one or more of the attending psychiatrists. The course of treatment was discussed and a conclusion drawn on the causality between the olanzapine treatment and the AEs. Statistical analysis Descriptive statistics has been performed. Interquartile ranges in terms of age and duration of admission have been stated.
Results Of 103 patients initially included, 12 were subsequently excluded. One patient did not meet the inclusion Clinical Toxicology vol. 52 no. 1 2014
AEs associated with high-dose olanzapine treatment 41
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Patient characteristics The median age of patients was 39 years [32; 49] and median duration of admission was 47 days [18;94]. Nearly 90% of patients had a diagnosis within the schizophrenic spectrum or other psychotic disorders. Substance abuse was the most frequent co-morbidity. An overview of patient characteristics can be found in Table 2. Antipsychotic treatment About 50% of patients had been treated with olanzapine prior to index admission in a dose range of 5–80 mg daily. During admission the included patients were treated with maximum daily doses of 45–160 mg. In 80% of patients the maximum daily doses were between 50 and 80 mg (Fig. 1). Half of the patients were treated with other antipsychotic drugs by the time of the maximum dose of olanzapine. A quarter of the study population was exposed to chlorpromazine equivalents above 2000 mg and the frequency of psychotropic poly-pharmacy increased steadily with increasing total antipsychotic load (Fig. 2). No potentially serious interactions due to treatment with non-psychotropic drugs (e.g. anti-arrhythmics) were observed. Table 2. Overview of patient characteristics. Patient characteristics Median age (1–3. quartile) Male (n) Median duration of admission (1–3 quartile) Smokers (n)
n 39 years (32–49) 57 (63%) 47 days (18–94) 56 (62%)
Most frequent diagnosis at time of discharge Schizophrenia Psychosis Psychotic affective disorder Personality disorder
59 (65%) 10 (11%) 10 (11%) 4 (4%)
Most frequent co-morbidities None Substance abuse Lung disease Diabetes (Type 1 or 2) Obesity
25 (27%) 40 (44%) 8 (9%) 6 (7%) 4 (4%)
Olanzapine during index-admission Acute treatment (⬍ 3 days) Maintenance treatment
45 (49%) 46 (51%)
Involuntary treatment with olanzapine No Yes Both voluntary and involuntary treatment Unknown
70 (77%) 4 (4%) 13 (14%) 4 (4%)
Dosing schedule Only PRN Only fixed Both PRN and fixed
20 (22%) 7 (8%) 64 (70%)
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Maximum daily dose of olanzapine during index admission 40 35 30 n (patients)
criteria, nine had been admitted to outpatient clinics with diagnoses not believed to be associated with an AE caused by olanzapine (e.g. gynecology) and in two cases the charts were unavailable. In total, 91 patients were included.
25 20 15 10 5 0 45
50
60
70 80 90 Olanzapine (mg)
100
120
160
Fig. 1. Maximum daily doses of olanzapine in the range of 45–160 mg were observed.
Observation of AEs The effect of olanzapine treatment was described in 88 of 91 patient charts, whereas the occurrence of AEs was mentioned or assessed in 56 of the charts. In 45 of these cases, symptoms were specifically mentioned or indirectly documented as AEs. Prescription of biperiden for the treatment of EPS was an example of the latter. In the remaining 11 charts it was specifically mentioned that there were no AEs. Overall, 35 patient charts did not include any contemplations regarding AEs. In four of these cases, however the described symptoms and clinical findings were compatible with olanzapine-related AEs. A prolonged QTc interval of 510 ms was described in a single patient (1%). In the majority of patients, electrocardiography (ECG) had been recorded upon admission and only 4% of patient charts contained no ECG or an ECG description. Nevertheless, none of the case notes included a systematic observation of ECG, for example, in relation to increase in dose of antipsychotics or tachycardia. Thus, two patients were discharged with an 80 mg fixed daily dose of olanzapine without ECG examination at steady state. In some cases the charts stated that the clinical condition of patients made it impossible to perform ECG. CNS depression and EPS were the most frequent AEs with incidences of 25% and 27%, respectively. Other wellknown AEs to antipsychotic treatment such as increased bodyweight (13%), tachycardia—HR ⬎ 100 bpm (2%) and hypotension—systolic BP ⬍ 100 mmHg (2%) were also observed (Table 3). Severe AEs Five cases of severe AEs with suspected causal relation to olanzapine were observed: death (n ⫽ 2), NMS (n ⫽ 2) and serious EPS (n ⫽ 1). These were discussed at the additional audit. One patient treated with a combination of olanzapine 60 mg/day and clozapine 100 mg/day developed NMS. The antipsychotic treatment was discontinued for a period of weeks, but the patient had a relapse of NMS following reinstitution of single treatment with clozapine 200 mg/day. It was concluded that the condition was most likely caused by the latter. One patient developed pronounced EPS after treatment with olanzapine 60 mg/day and intramuscular injections of haloperidol 150 mg/week. Downward adjustment of the
42 A. B. Petersen et al. Maximum antipsychotic load during index admission 35 30 Black bars: Olanzapine Grey bars: Other antipsychotics
n (patients)
25 20 15 10 5
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0 900-1200 1201-1600 1601-2000 2001-2400 2400-2800 2801-3200 3201-3600 3601-4000 4001-4400 Chlorpromazine equivalents (mg)
Fig. 2. The black bars illustrate the average fraction of total antipsychotic load constituted by olanzapine and the gray bars the average fraction constituted by other antipsychotics.
haloperidol dose led to an improvement with respect to EPS and it was concluded that haloperidol was the main cause of the AE. There were two deaths possibly associated with olanzapine and in one of these cases, death was preceded by NMS. One patient took an overdose of olanzapine, clonazepam and methadone and the postmortem blood analysis revealed high blood concentrations of all three drugs. The coroner performing the postmortem examinations concluded that all three drugs could individually have been the cause of death. The last patient was treated with a combination of olanzapine and risperidone. Maximum dose of olanzapine was 60 mg, but most of the time during index admission the patient was treated with 40 mg olanzapine in combination with 6 mg risperidone, which is within recommended doses for both drugs. The patient developed symptoms of NMS (trouble swallowing and fluctuating levels of consciousness) after 1 month of admission and was transferred to the intensive care unit. During the following weeks the patient experienced complications in the form of cerebellar hemorrhage and sepsis and died. It was concluded that olanzapine probably was a contributing factor to the patient’s condition Table 3. AEs with suspected causal relation to olanzapine.
Adverse events Extrapyramidal symptoms CNS depression Increase in bodyweight s-prolactin increase/gynecomastia Worsening of dyslipidemia Neuroleptic malignant syndrome Death Tachycardia (HR ⬎ 100 bpm) Hypotension (systolic BP ⬍ 100 mmHG) Fall Diabetes/worsening of diabetes QTc prolongation Respiratory distress Elevated liver enzymes
n
Olanzapine dose (mg) on time of AE
25 (27%) 23 (25%) 13 (14%) 8 (9%) 3 (3%) 2 (2%) 2 (2%) 2 (2%) 2 (2%) 2 (2%) 2 (2%) 1 (1%) 1 (1%) 1 (1%)
50–120 45–120 45–100 50–70 60–100 50–90 50–100 45–90 60 60–70 60–70 90 50 60
and death. Furthermore, the question was raised whether or not sufficient action (e.g. discontinuation of antipsychotic treatment) in relation to the possible NMS had been taken in time.
Discussion This retrospective study indicates that treatment with more than 40 mg olanzapine per day was fairly well tolerated in the majority of patients. Still, more than half of the patients seem to have experienced AEs ascribable to high-dose olanzapine. However, the vast majority of these were well known and manageable. If outweighed by the benefits, AEs may be acceptable. This retrospective study did not allow quantification of disease severity at admission or treatment effect and therefore it was not possible to assess whether or not this was the case in the included patients. Four patients experienced severe AEs, but in two of these cases other antipsychotics used in combination with olanzapine were most likely the cause of the AEs. Furthermore, one patient who died following high blood concentrations of olanzapine, clonazepam and methadone had most likely not been following treatment instructions. In the last case, olanzapine was concluded to be a possible contributing cause of NMS and the subsequent complications and death. This patient was treated with a maximum of 60 mg olanzapine daily during admission and this maximum dose was administered for only a single day. The finding that most AEs were well tolerated is in accordance with the sparse literature on high-dose olanzapine treatment. Thus, Kelly et al. conducted a cross-over study in 13 patients treated with 50 mg olanzapine/450 mg clozapine daily and found that weight gain and anticholinergic AEs such as dry mouth and blurred vision were frequently observed following treatment with olanzapine.3 Another study has reported beneficial clinical response and no AEs in a patient with treatment-refractory schizophrenia treated with 60 mg of olanzapine daily.4 Finally, a study has described a good clinical response in two patients with refractory psychosis after treatment with 50 mg olanzapine daily. One of these Clinical Toxicology vol. 52 no. 1 2014
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AEs associated with high-dose olanzapine treatment 43 patients had some dystonia in relation to this high-dose treatment, but felt them preferable to hallucinations.5 A consensus report regarding the advantages and disadvantages of combined therapy with more than one antipsychotic was conducted by the United Kingdom National Institute of Clinical Excellence in 2008. It was stated that the evidence of improved treatment effect in relation to antipsychotic poly-pharmacy was inconclusive. Furthermore, combination therapy may often result in more AEs.8 Despite this fact, studies have shown that about 20% of patients with schizophrenia are treated with antipsychotic combination therapy.8 High-dose olanzapine could be a reasonable approach in order to avoid antipsychotic poly-pharmacy. However, we found that about 50% of patients were treated with other antipsychotics in addition to high-dose olanzapine. The strength of the present study is the relatively large number of patients included from clinical settings when compared with previous studies on this topic. A weakness of the present study is the retrospective design. Naturally, there is no guarantee that all relevant information had been documented in the patient charts and therefore we might not have been presented with the full picture. Another weakness associated with the retrospective study design was the risk of including a selected population of olanzapine-treated patients, which may hamper generalizability of the findings. The use of involuntary medical treatment was much more frequent in the study population than in the general psychiatric population (17% vs. ⬍ 3%), which could indicate a group of patients with high morbidity.9 The frequency of substance abuse as a comorbidity was comparable between the study group and the general schizophrenic population (44% vs. 50%).9 Data were systematically extracted from charts and ambiguities were discussed during the process. However, the review of charts was performed independently by two doctors, which could question the reproducibility of findings. High occurrence of antipsychotic poly-pharmacy was a potential challenge with respect to assessment of causality between olanzapine and AEs. All AEs documented in patient charts were registered, also the ones hitherto undocumented in relation to olanzapine and not listed in the summary of product characteristics (SPC), and a causality assessment was performed.
Conclusion Our findings indicate that daily doses of olanzapine above the maximum recommended 40 mg are fairly well tolerated in the majority of patients. Nevertheless, our study also supports the general notion of an increased risk of well-known AEs when high-dose treatment with olanzapine is employed,
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at least when compared with the frequencies of AEs listed in the SPC for olanzapine. Importantly, severe toxicity with causal relation to olanzapine was observed in two of 91 cases, both in relation to treatment with doses just above the maximum recommended dose and after intended overdose with a presumably very high dose of olanzapine. We therefore advocate that clinicians carefully monitor olanzapine toxicity and in particular during high-dose olanzapine treatment they should be ready to act appropriately if toxic effects of olanzapine should occur. Treatment cessation should be immediate if serious AEs such as NMS arise.
Acknowledgments The authors would like to thank Troels Roesbjerg for assisting with data extraction from the physician order entry system.
Declaration of interest The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.
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