LETTERS TO THE EDITORS
Correlation of Haloperidol Concentration in Blood and Cerebrospinal Fluid A Pharmacokinetic Study To the Editors: aloperidol is often prescribed to older patients for the treatment of acute or chronic psychotic symptoms, such as delirium or behavioral symptoms in dementia. Its use is associated with adverse effects such as antipsychotic-induced parkinsonism (AIP) and tardive dyskinesia.1,2 Antipsychotic-induced parkinsonism is characterized by the presence of tremor, rigidity, and bradykinesia and is associated with impaired quality of life.3 In a study with 150 elderly patients, 46% of the patients treated with haloperidol in a dose varying from 0.3 to 5.0 mg/d developed AIP.4 In this group, a significant (but moderate) relationship was found between dose and serum concentration. Neither the dose nor the serum concentrations of haloperidol however were associated with the occurrence of AIP. It is unclear why some older patients develop AIP at a given dosage of haloperidol and others do not. There are different hypotheses that could explain the differences in sensitivity to antipsychotics. One possible explanation could be that interindividual variation in transport crosses the blood-brain barrier (BBB). The relationship between blood and cerebrospinal fluid (CSF) concentration of haloperidol has not been described earlier in an older population. The aim of this crosssectional study, therefore, was to determine this relationship in older patients. The study was conducted in a population of patients visiting the preoperative screening and delirium prevention outpatient clinic from the Department of Geriatric Medicine of the Jeroen Bosch Hospital, a large teaching hospital in ’s-Hertogenbosch, the Netherlands, between January 2012 and January 2013. In case of an increased risk of delirium, 1 mg/d of haloperidol for 5 days preoperative was prescribed by the geriatrician, according to hospital protocol. Inclusion criteria were age older than 64 years, elective surgery under spinal anesthesia, adequately started with 1 mg/d of haloperidol according to hospital protocol, mentally competent, and written informed consent. Approval was obtained from the regional
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Medical Research Ethics Committee. Informed consent was asked by 1 of the researchers. Elective surgery under spinal anesthesia made it possible to obtain 2 mL of CSF for research goals without patient burden such as a lumbar puncture. A blood sample (2 mL) was drawn by the anesthesiologist in addition. A published liquid chromatography-mass spectometrie method5 was adapted to perform the analysis of the samples. The quantification limit of haloperidol levels was 0.02 ng/mL. Only 1 patient had a haloperidol CSF concentration below this quantification limit. We changed the CSF concentration for this patient in 0.01 ng/mL. Using the Statistical Package for the Social Sciences (IBM, SPSS 20), frequencies and distributions were extracted. The correlation coefficient (R) was calculated by linear regression. R2 was used to express the percentage of explained variance between CSF and serum. We corrected in multiple linear regression analysis for age and sex. Twenty patients were included with an average age of 78.9 years (range, 68Y91 y). Four patients were women. Eighteen patients used a dosage of 1 mg/d of haloperidol for a 5-day period before CSF and serum concentrations were measured. Two patients deviated from this scheme; 1 patient used 2 mg of haloperidol instead of 1 mg on day 5. One patient used double dosage of 2 mg/d of haloperidol for a 5-day period. Haloperidol is metabolized by the cytochrome P450 enzyme 2D6 (CYP2D6). No patients used strong CYP2D6 inhibitors or strong CYP2D6 inducers.6 Patients 2 and 15 used darifenacin, patient 6 used mirtazepine, patient 11 used venlafaxine, and patient 13 used citalopram, all weak CYP2D6 inhibitors.6 Serum concentrations of haloperidol were averaged 0.52 Kg/L (range, 0.17Y0.99 Kg/L) and CSF concentrations were averaged 0.04 Kg/L (range, G0.017Y0.09 Kg/L; ratio average, 11.45%). The serum concentration at the same dose of haloperidol has a large, factor 6, variation. A strong and significant correlation between CSF and serum concentrations was found (r = 0.85, r 2 = 0.73, P G 0.01; Fig. 1); the CSF concentrations of haloperidol were 73% explained by the serum haloperidol concentration. The explained variance increased with only 4% when age was added to the modelVr 2 = 0.77, P G 0.01. Sex did not explain differences in CSF concentration nor did comedication explain differences in serum concentrations of haloperidol.
DISCUSSION This study shows a strong and significant correlation between the serum concentration and CSF concentration of haloperidol in older patients. Sex or age hardly influenced this relation nor did comedication explain the serum concentration. As far as we know, only 1 study was published studying haloperidol concentrations in CSF and in serum, however, not in older patients, but in younger schizophrenic patients. Rimo´n et al7 analyzed 12 chronic neuroleptic nonresponsive schizophrenic patients (mean age, 39 y) after 1 month on 60 mg of haloperidol daily. Cerebrospinal fluid concentrations of haloperidol were significantly correlated (r = 0.55 and P G 0.01) and averaged 4.3% of the serum concentrations.7 In our study, CSF concentrations of haloperidol were stronger correlated to the plasma concentration (r = 0.85); however, twice as high relative concentrations were measured (11.5% of serum concentration). One of the hypotheses of variability of response to haloperidol, variability in transport over the BBB, seems to be not an explanatory variable given these results. A possible explanation for a higher ratio between CSF and serum concentrations of haloperidol in our study (11.5% compared with 4.3%) could be age. It might be possible that older patients have a more permeable BBB than younger people; although no correlation of age (in our study aged 68Y91 y) and CSF concentrations (P = 0.09) was found and adding age to the model did hardly increase correlation, we could not underline that hypothesis. It should be taken into account that the range in age in this study population was quite small to do a proper analysis on age, so this could still be a possible hypothesis. The higher ratio could also be related to the much lower doses used, 1 versus 60 mg/d of haloperidol. This seems less likely to be the explanation because haloperidol is not a substrate of P-glycoprotein. P-glycoprotein is an efflux pump expressed at the BBB and limits drug access into the central nervous system. A previous study found that AIP could not be explained at all by dose or blood concentration of haloperidol.4 Taken together, although, by age, still, some variation in CSF concentration might be explained by future research, the main explanation seems to be plasma concentration of haloperidol, which is in line with a previous study. So, the interindividual variability of CSF
Journal of Clinical Psychopharmacology
&
Volume 34, Number 4, August 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology
&
Volume 34, Number 4, August 2014
Letters to the Editors
drugs in nursing home residents in three countries: Norway, Austria and England. Int J Geriatr Psychiatry. 2010;25(7): 725Y731. 3. Schouten HJ, Knol W, Egberts TC, et al. Quality of life of elderly patients with antipsychotic-induced parkinsonism: a cross-sectional study. J Am Med Dir Assoc. 2012;13(1):82.e1Y82.e5. 4. Knol W, van Marum RJ, Jansen PA, et al. Parkinsonism in elderly users of haloperidol: associated with dose, plasma concentration, and duration of use. J Clin Psychopharmacol. 2012;32(5):688Y693.
FIGURE 1. Correlation of CSF and serum concentration was r equals 0.853.
concentrations is unlikely to have a major role in the interindividual response to haloperidol at the level of AIP. Then, what could be the explanation instead? The concentration and density of dopamine transporters have consistently been reported to decline with age. This is a possible explanation for interindividual variation in effect and adverse effects of antipsychotic medication. In young patients with schizophrenia, occupancy of more than 80% of striatal D2 receptors with antipsychotics has been associated with extrapyramidal symptoms. This suggests that a minimum of 20% of the receptor population must be free for physiologic transmission to overcome extrapyramidal symptoms. With aging, there is a decline in D2 receptors, so a greater percentage of receptors must be free to provide an adequate level of physiologic transmission in elderly patients.8 The elderly have a decrease in the threshold for extrapyramidal symptoms. Taken together, this study shows that the main explanation for CSF concentration variation is the plasma concentration, not age or sex. Why this plasma concentration differs largely and why with the same CSF concentration some patients develop AIP and some do not are still unclear but might be caused by pharmacodynamic differences such as dopamine 2 receptor occupancy and need future research. This study contributes to a better understanding of the different factors of interindividual variation to haloperidol and in the end might lead to more evidencebased prescribing for older patients. ACKNOWLEDGMENTS The authors would like to thank the Department of Anesthesiology and Renate Paanakker and Peter de Crom for their cooperation. * 2014 Lippincott Williams & Wilkins
AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Astrid M. van Strien, MD Department of Geriatric Medicine Jeroen Bosch Hospital ’s-Hertogenbosch, the Netherlands [email protected]
Annemieke Vermeulen Windsant-van den Tweel, PharmD Hospital Pharmacy ZANOB ’s-Hertogenbosch, the Netherlands
5. Hoja H, Marquet P, Verneuil B, et al. Determination of haloperidol and its reduced metabolite in human plasma by liquid chromatography-mass spectrometry with electrospray ionization. J Chromatogr B Biomed Sci Appl. 1997;688:275Y280. 6. P450 drug interaction table, division of clinical pharmacology, Indiana University. Available at: http://medicine.iupui.edu/ clinpharm/DDIs/table.aspx. Accessed June 2013. 7. Rimo´n R, Averbuch I, Rozick P, et al. Serum and CSF levels of haloperidol by radioimmunoassay and radioreceptor assay during high-dose therapy of resistant schizophrenic patients. Psychopharmacology (Berl). 1981;73(2):197Y199. 8. Uchida H, Mamo DC, Mulsant BH, et al. Increased antipsychotic sensitivity in elderly patients: evidence and mechanisms. J Clin Psychiatry. 2009;70(3):397Y405.
Marije Leliveld-van den Heuvel, MD Department of Geriatric Medicine Rijnland Hospital Leiderdorp, the Netherlands
Manuela di Biase, MD Department of Anesthesiology Jeroen Bosch Hospital ’s-Hertogenbosch, the Netherlands
Adriaan J.C. van den Brule, PhD Laboratory for Molecular Diagnostics Jeroen Bosch Hospital ’s-Hertogenbosch, the Netherlands
Rob J. van Marum, MD, PhD Department of Geriatric Medicine Jeroen Bosch Hospital ’s-Hertogenbosch, the Netherlands and Department of General Practice and Elderly Care Medicine VU University Medical Center Amsterdam, the Netherlands
REFERENCES 1. Kamble P, Chen H, Sherer JT, et al. Use of antipsychotics among elderly nursing home residents with dementia in the US: an analysis of National Survey Data. Drugs Aging. 2009;26(6):483Y492. 2. Testad I, Auer S, Mittelman M, et al. Nursing home structure and association with agitation and use of psychotropic
Lack of Effect of Risperidone or Olanzapine Dose Reduction on Metabolic Parameters, Prolactin, and Corrected QT Interval in Stable Patients With Schizophrenia To the Editors: typical antipsychotics, although superior to their conventional counterparts in certain side effects (eg, extrapyramidal symptoms [EPS]), are not without risk and are, as well, associated with various other problematic adverse effects such as hyperprolactinemia and metabolic disturbances.1 However, to the best of our knowledge, no clinical trial to date has systematically evaluated the effects of atypical antipsychotic dose reduction on such adverse effects. Recently, we conducted an openlabel, 28-week, randomized controlled trial (UMIN000001834) to investigate the clinical impact of risperidone or olanzapine dose reduction in stable patients with
A
www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
517
Correlation of Haloperidol Concentration in Blood and Cerebrospinal Fluid A Pharmacokinetic Study To the Editors: aloperidol is often prescribed to older patients for the treatment of acute or chronic psychotic symptoms, such as delirium or behavioral symptoms in dementia. Its use is associated with adverse effects such as antipsychotic-induced parkinsonism (AIP) and tardive dyskinesia.1,2 Antipsychotic-induced parkinsonism is characterized by the presence of tremor, rigidity, and bradykinesia and is associated with impaired quality of life.3 In a study with 150 elderly patients, 46% of the patients treated with haloperidol in a dose varying from 0.3 to 5.0 mg/d developed AIP.4 In this group, a significant (but moderate) relationship was found between dose and serum concentration. Neither the dose nor the serum concentrations of haloperidol however were associated with the occurrence of AIP. It is unclear why some older patients develop AIP at a given dosage of haloperidol and others do not. There are different hypotheses that could explain the differences in sensitivity to antipsychotics. One possible explanation could be that interindividual variation in transport crosses the blood-brain barrier (BBB). The relationship between blood and cerebrospinal fluid (CSF) concentration of haloperidol has not been described earlier in an older population. The aim of this crosssectional study, therefore, was to determine this relationship in older patients. The study was conducted in a population of patients visiting the preoperative screening and delirium prevention outpatient clinic from the Department of Geriatric Medicine of the Jeroen Bosch Hospital, a large teaching hospital in ’s-Hertogenbosch, the Netherlands, between January 2012 and January 2013. In case of an increased risk of delirium, 1 mg/d of haloperidol for 5 days preoperative was prescribed by the geriatrician, according to hospital protocol. Inclusion criteria were age older than 64 years, elective surgery under spinal anesthesia, adequately started with 1 mg/d of haloperidol according to hospital protocol, mentally competent, and written informed consent. Approval was obtained from the regional
H
516
www.psychopharmacology.com
Medical Research Ethics Committee. Informed consent was asked by 1 of the researchers. Elective surgery under spinal anesthesia made it possible to obtain 2 mL of CSF for research goals without patient burden such as a lumbar puncture. A blood sample (2 mL) was drawn by the anesthesiologist in addition. A published liquid chromatography-mass spectometrie method5 was adapted to perform the analysis of the samples. The quantification limit of haloperidol levels was 0.02 ng/mL. Only 1 patient had a haloperidol CSF concentration below this quantification limit. We changed the CSF concentration for this patient in 0.01 ng/mL. Using the Statistical Package for the Social Sciences (IBM, SPSS 20), frequencies and distributions were extracted. The correlation coefficient (R) was calculated by linear regression. R2 was used to express the percentage of explained variance between CSF and serum. We corrected in multiple linear regression analysis for age and sex. Twenty patients were included with an average age of 78.9 years (range, 68Y91 y). Four patients were women. Eighteen patients used a dosage of 1 mg/d of haloperidol for a 5-day period before CSF and serum concentrations were measured. Two patients deviated from this scheme; 1 patient used 2 mg of haloperidol instead of 1 mg on day 5. One patient used double dosage of 2 mg/d of haloperidol for a 5-day period. Haloperidol is metabolized by the cytochrome P450 enzyme 2D6 (CYP2D6). No patients used strong CYP2D6 inhibitors or strong CYP2D6 inducers.6 Patients 2 and 15 used darifenacin, patient 6 used mirtazepine, patient 11 used venlafaxine, and patient 13 used citalopram, all weak CYP2D6 inhibitors.6 Serum concentrations of haloperidol were averaged 0.52 Kg/L (range, 0.17Y0.99 Kg/L) and CSF concentrations were averaged 0.04 Kg/L (range, G0.017Y0.09 Kg/L; ratio average, 11.45%). The serum concentration at the same dose of haloperidol has a large, factor 6, variation. A strong and significant correlation between CSF and serum concentrations was found (r = 0.85, r 2 = 0.73, P G 0.01; Fig. 1); the CSF concentrations of haloperidol were 73% explained by the serum haloperidol concentration. The explained variance increased with only 4% when age was added to the modelVr 2 = 0.77, P G 0.01. Sex did not explain differences in CSF concentration nor did comedication explain differences in serum concentrations of haloperidol.
DISCUSSION This study shows a strong and significant correlation between the serum concentration and CSF concentration of haloperidol in older patients. Sex or age hardly influenced this relation nor did comedication explain the serum concentration. As far as we know, only 1 study was published studying haloperidol concentrations in CSF and in serum, however, not in older patients, but in younger schizophrenic patients. Rimo´n et al7 analyzed 12 chronic neuroleptic nonresponsive schizophrenic patients (mean age, 39 y) after 1 month on 60 mg of haloperidol daily. Cerebrospinal fluid concentrations of haloperidol were significantly correlated (r = 0.55 and P G 0.01) and averaged 4.3% of the serum concentrations.7 In our study, CSF concentrations of haloperidol were stronger correlated to the plasma concentration (r = 0.85); however, twice as high relative concentrations were measured (11.5% of serum concentration). One of the hypotheses of variability of response to haloperidol, variability in transport over the BBB, seems to be not an explanatory variable given these results. A possible explanation for a higher ratio between CSF and serum concentrations of haloperidol in our study (11.5% compared with 4.3%) could be age. It might be possible that older patients have a more permeable BBB than younger people; although no correlation of age (in our study aged 68Y91 y) and CSF concentrations (P = 0.09) was found and adding age to the model did hardly increase correlation, we could not underline that hypothesis. It should be taken into account that the range in age in this study population was quite small to do a proper analysis on age, so this could still be a possible hypothesis. The higher ratio could also be related to the much lower doses used, 1 versus 60 mg/d of haloperidol. This seems less likely to be the explanation because haloperidol is not a substrate of P-glycoprotein. P-glycoprotein is an efflux pump expressed at the BBB and limits drug access into the central nervous system. A previous study found that AIP could not be explained at all by dose or blood concentration of haloperidol.4 Taken together, although, by age, still, some variation in CSF concentration might be explained by future research, the main explanation seems to be plasma concentration of haloperidol, which is in line with a previous study. So, the interindividual variability of CSF
Journal of Clinical Psychopharmacology
&
Volume 34, Number 4, August 2014
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology
&
Volume 34, Number 4, August 2014
Letters to the Editors
drugs in nursing home residents in three countries: Norway, Austria and England. Int J Geriatr Psychiatry. 2010;25(7): 725Y731. 3. Schouten HJ, Knol W, Egberts TC, et al. Quality of life of elderly patients with antipsychotic-induced parkinsonism: a cross-sectional study. J Am Med Dir Assoc. 2012;13(1):82.e1Y82.e5. 4. Knol W, van Marum RJ, Jansen PA, et al. Parkinsonism in elderly users of haloperidol: associated with dose, plasma concentration, and duration of use. J Clin Psychopharmacol. 2012;32(5):688Y693.
FIGURE 1. Correlation of CSF and serum concentration was r equals 0.853.
concentrations is unlikely to have a major role in the interindividual response to haloperidol at the level of AIP. Then, what could be the explanation instead? The concentration and density of dopamine transporters have consistently been reported to decline with age. This is a possible explanation for interindividual variation in effect and adverse effects of antipsychotic medication. In young patients with schizophrenia, occupancy of more than 80% of striatal D2 receptors with antipsychotics has been associated with extrapyramidal symptoms. This suggests that a minimum of 20% of the receptor population must be free for physiologic transmission to overcome extrapyramidal symptoms. With aging, there is a decline in D2 receptors, so a greater percentage of receptors must be free to provide an adequate level of physiologic transmission in elderly patients.8 The elderly have a decrease in the threshold for extrapyramidal symptoms. Taken together, this study shows that the main explanation for CSF concentration variation is the plasma concentration, not age or sex. Why this plasma concentration differs largely and why with the same CSF concentration some patients develop AIP and some do not are still unclear but might be caused by pharmacodynamic differences such as dopamine 2 receptor occupancy and need future research. This study contributes to a better understanding of the different factors of interindividual variation to haloperidol and in the end might lead to more evidencebased prescribing for older patients. ACKNOWLEDGMENTS The authors would like to thank the Department of Anesthesiology and Renate Paanakker and Peter de Crom for their cooperation. * 2014 Lippincott Williams & Wilkins
AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Astrid M. van Strien, MD Department of Geriatric Medicine Jeroen Bosch Hospital ’s-Hertogenbosch, the Netherlands [email protected]
Annemieke Vermeulen Windsant-van den Tweel, PharmD Hospital Pharmacy ZANOB ’s-Hertogenbosch, the Netherlands
5. Hoja H, Marquet P, Verneuil B, et al. Determination of haloperidol and its reduced metabolite in human plasma by liquid chromatography-mass spectrometry with electrospray ionization. J Chromatogr B Biomed Sci Appl. 1997;688:275Y280. 6. P450 drug interaction table, division of clinical pharmacology, Indiana University. Available at: http://medicine.iupui.edu/ clinpharm/DDIs/table.aspx. Accessed June 2013. 7. Rimo´n R, Averbuch I, Rozick P, et al. Serum and CSF levels of haloperidol by radioimmunoassay and radioreceptor assay during high-dose therapy of resistant schizophrenic patients. Psychopharmacology (Berl). 1981;73(2):197Y199. 8. Uchida H, Mamo DC, Mulsant BH, et al. Increased antipsychotic sensitivity in elderly patients: evidence and mechanisms. J Clin Psychiatry. 2009;70(3):397Y405.
Marije Leliveld-van den Heuvel, MD Department of Geriatric Medicine Rijnland Hospital Leiderdorp, the Netherlands
Manuela di Biase, MD Department of Anesthesiology Jeroen Bosch Hospital ’s-Hertogenbosch, the Netherlands
Adriaan J.C. van den Brule, PhD Laboratory for Molecular Diagnostics Jeroen Bosch Hospital ’s-Hertogenbosch, the Netherlands
Rob J. van Marum, MD, PhD Department of Geriatric Medicine Jeroen Bosch Hospital ’s-Hertogenbosch, the Netherlands and Department of General Practice and Elderly Care Medicine VU University Medical Center Amsterdam, the Netherlands
REFERENCES 1. Kamble P, Chen H, Sherer JT, et al. Use of antipsychotics among elderly nursing home residents with dementia in the US: an analysis of National Survey Data. Drugs Aging. 2009;26(6):483Y492. 2. Testad I, Auer S, Mittelman M, et al. Nursing home structure and association with agitation and use of psychotropic
Lack of Effect of Risperidone or Olanzapine Dose Reduction on Metabolic Parameters, Prolactin, and Corrected QT Interval in Stable Patients With Schizophrenia To the Editors: typical antipsychotics, although superior to their conventional counterparts in certain side effects (eg, extrapyramidal symptoms [EPS]), are not without risk and are, as well, associated with various other problematic adverse effects such as hyperprolactinemia and metabolic disturbances.1 However, to the best of our knowledge, no clinical trial to date has systematically evaluated the effects of atypical antipsychotic dose reduction on such adverse effects. Recently, we conducted an openlabel, 28-week, randomized controlled trial (UMIN000001834) to investigate the clinical impact of risperidone or olanzapine dose reduction in stable patients with
A
www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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