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Familial liability for metoprolol-induced psychosis
General Hospital Psychiatry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Familial liability for metoprolol-induced psychosis L. Rietveld, M.D. a,⁎, T. van der Hoek, M.D. a,c, M.H.C.T. van Beek, M.D. a, A.F.A. Schellekens, M.D., Ph.D. a,b a b c
Radboud University Medical Centre, Department of Psychiatry, Nijmegen, the Netherlands Donders Institute for Brain Cognition and Behaviour, Centre for Neuroscience, Nijmegen, The Netherlands Mental Health Organization (MHO) GGZ Oost Brabant Land van Cuijk en Noord Limburg, Boxmeer, The Netherlands
a r t i c l e
i n f o
Article history: Received 11 February 2015 Revised 19 June 2015 Accepted 22 June 2015 Available online xxxx Keywords: Psychosis Familial Beta blockers Metoprolol
a b s t r a c t Objective: : Beta-blockers are commonly used in the treatment of hypertension and cardiac arrhythmias. The incidence of neuropsychiatric side effects is generally low. This case report shows the potential familial liability of a metoprolol-induced psychosis. Method: : We report a case of metoprolol-induced psychosis. Potential pharmocogenetic factors mediating this familial metoprolol-induced psychosis are discussed. Results: : A middle-aged man developed psychosis after starting metoprolol, which diminished after ceasing the medication. Two of his family members experienced similar symptoms after using metoprolol. All family members were genotyped as CYP2D6*4 allele carriers indicating reduced CYP2D6 enzyme activity. Conclusion: : The case presented here suggests a potential familial liability for metoprolol- induced psychosis. Pharmacokinetic mechanisms are hypothesized to mediate this familial liability through genetic variation in the CYP2D6 genotype. A family history of psychotic symptoms after treatment with beta-blockers should be taken into account, when prescribing this beta-blocker. © 2015 Elsevier Inc. All rights reserved.
Introduction Beta-blockers are commonly used in the treatment of cardiovascular disorders such as hypertension and cardiac arrhythmias. Beta-blockers are generally well tolerated but have also been associated with neuropsychiatric side effects, like sedation, delirium and psychosis [1,2]. Administered at clinical doses, the incidence of these neuropsychiatric side effects is generally considered to be low. Factors associated with increased risk of these side effects are old age, impaired liver function or cognitive deficits [1,2]. Here, we report a case of a male who developed a metoprolol-induced psychosis and had a positive family history for metoprolol-induced psychosis. Potential pharmacogenetic mechanisms will be discussed.
Case A 44-year-old Caucasian man was admitted to our psychiatric ward because of psychotic symptoms. He reported confusion since approximately 2 weeks after he began taking metoprolol 50 mg, prescribed by his general practitioner (GP) because of primary hypertension. He had discontinued metoprolol because he felt confused and restless and ⁎ Corresponding author at: Department of Psychiatry, Radboud University Medical Centre, Nijmegen, Department of Psychiatry, 966, PO Box 9101, Nijmegen, The Netherlands Tel.: +31-0-243-666-495; fax: +31-0-243-540-561. E-mail address: [email protected] (L. Rietveld).
had difficulty falling asleep. The symptoms diminished quickly after ceasing metoprolol. After resuming metoprolol several days later, chaotic thinking and delusional thoughts occurred. He thought people around him were actors. His GP prescribed him oxazepam 10 mg tid and mirtazapin 15 mg od. Explorative physical and laboratory tests were normal. Because of persisting psychotic symptoms, the patient was referred to our clinic. At admission, the patient had constant feelings of confusion and agitation. He had visual hallucinations of receiving messages from mirrors and delusions that his wife would leave him. He denied having other psychiatric symptoms. Patient had no medical or psychiatric history, including substance use disorders, and used no medication other than metoprolol. He had a family history of hypertension. At physical examination, no abnormalities were observed, including a normal blood pressure (80/ 120 mmHg) and slightly elevated pulse (95 bpm). At psychiatric examination, we observed delusional content of his thoughts, without signs of disorientation, variable consciousness or other cognitive impairments. Similarly, no signs of affective disorders were observed. After excluding other causes of psychosis with physical and neurological examination and lab tests, we interpreted the psychotic symptoms as caused by metoprolol. Olanzapine 10 mg bid was prescribed, and metoprolol was stopped. After a few days, his psychosis gradually diminished. His hypertension was treated with the calcium antagonist nifidepine (30 mg). Two weeks after admission, the patient was discharged from hospital without any psychiatric symptoms. The olanzapine was gradually tapered over the following 3 weeks. The psychotic symptoms remained absent.
http://dx.doi.org/10.1016/j.genhosppsych.2015.06.016 0163-8343/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Rietveld L., et al, Familial liability for metoprolol-induced psychosis, Gen Hosp Psychiatry (2015), http://dx.doi.org/ 10.1016/j.genhosppsych.2015.06.016
2
L. Rietveld et al. / General Hospital Psychiatry xxx (2015) xxx–xxx
After full remission of the psychosis, the patient reported that both his mother and brother had experienced confusion and paranoia after taking metoprolol. Neither of them had a psychiatric history, risk factors for a metoprolol-induced psychosis or experienced any other side effect of metoprolol. Both had stopped metoprolol shortly after experiencing the symptoms, where after the symptoms diminished without further treatment with no reoccurrence of psychosis. The patient, his mother and brother were genotyped for the CYP2D6 genotype, showing that the patient and his mother were heterozygous for the CYP2D6*4 allele (reduced CYP2D6 enzyme activity). The brother was homozygous for CYP2D6*4, rs3892097 (reduced to absent CYP2D6 enzyme activity).
with psychotic symptoms despite their moderate to high lipophilicity and common usage [15]. Taken together, the case presented here shows metoprolol-induced psychosis with a potential familial liability. Pharmacokinetic mechanisms are hypothesized to mediate this familial liability through genetic variation in the CYP2D6 genotype. Since familial liability for neuropsychiatric side effects of metoprolol has not been described before, future studies should address its clinical relevance. However, a family history of psychotic symptoms after treatment with beta-blockers should be taken into account, when prescribing a beta-blocker. Insight in the neurobiological mechanism of metoprolol-induced psychosis could further enhance our insight in vulnerability factors for beta-blocker-induced psychotic symptoms.
Discussion Financial disclosures Although neuropsychiatric side effects of beta-blockers have previously been reported, this is the first report of familial liability for metoprolol-induced psychosis. Given the presence of the CYP2D6*4 genotype, indicating reduced CYP2D6 enzyme activity, a pharmacokinetic mechanism can be speculated. Homozygous carries of the CYP2D6*4 genotype taking a betablocker, like metoprolol, are at 4 times increased risk for side effects like bradycardia and low blood pressure [3]. It is unknown whether this also counts for neuropsychiatric side effects. Interestingly, all three persons experienced a metoprolol-induced psychosis, in the absence of other side effects or factors commonly associated with an increased risk for these side effects, like old age, high dosages, cognitive deficits or impaired liver function [1,2,4–6]. Since the psychotic symptoms remitted and recurred after discontinuation and readministration of the drug and similar side effects have been reported before, a causal relationship between metoprolol use and psychosis is very likely (Naranjo score: 9, indicating definite adverse drug reaction) [7]. The biological mechanism of a beta-blocker-induced psychosis is still poorly understood. Beta-blockers act on centrally located betaadrenoceptors, which may have cognitive behavioral effects. For example, adrenoceptors in the basolateral amygdala have been shown to be affected by propranolol, which is related to a diminished response to facial expressions [8]. Manipulation of beta-adrenoceptors has also been implicated in psychosis [9,10]. However, evidence for a direct relationship between central adrenoceptor blockade by metoprolol and subsequent psychosis is not available. Beta-blockers may also affect other neurotransmitter systems, like the brain serotonin (5-HT) system. For example, pindolol increases 5-HT synthesis in rats [11]. Serotonergic mechanisms have often been described to contribute to psychosis [12]. Though no serotonergic effects of metoprolol have been reported, a serotonergic mechanism cannot be ruled out. Beta-blockers differ with respect to their lipophilicity, which correlates with concentration in brain tissue [1]. Lipophilicity has been proposed to be related to the risk of developing adverse neuropsychiatric effects [1,13]. The incidence of neuropsyciatric side effects of betablockers seems to be highest for highly lipophilic agents (like propranolol) and lowest for more hydrophilic agents (like atenolol) [1]. With a brain/plasma concentration ratio about 20 times higher than atenolol, metoprolol has an intermediate position [13,14]. Yet, third generation beta-blockers (nebivolol and carvedilol) have not been associated
None. Conflict of interest None. Acknowledgments The department of genetics have contributed to this paper by processing the DNA samples and have advised in determining further actions. References [1] McAinsh J, Cruickshank JM. Beta-blockers and central nervous system side effects. Pharmacol Ther 1990;46:163–97. [2] Fisher AA, Davis M, Jeffery I. Acute delirium induced by metoprolol. Cardiovasc Drugs Ther 2002;16:161–5. [3] Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A, et al. Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther 2009;85(1):45–50. [4] Gengo FM, Ermer JC, Carey C, Kalonaros CG, McHugh WB. The relationship between serum concentrations and central nervous system actions of metoprolol. J Neurol Neurosurg Psychiatry 1985;48:101–6. [5] Hickey PL, McLean AJ, Angus PW, Choo EF, Morgan DJ. Increased sensitivity of propanolol clearance to reduced oxygen delivery in the isolated perfused cirrhotic rat liver. Gastroenterology 1996;111:1039–48. [6] Zhao Y, Xu W, Qiu L, Yang W. Metoprolol-induced psychosis in a young patient. Gen Hosp Psychiatry 2013;35:102.e1–2. [7] Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. [8] Hurlemann R, Walter H, Rehme K, Kukolja J, Santoro SC, Schmidt C, et al. Human amygdala reactivity is diminished by the b-noradrenergic antagonist propranolol. Psychol Med 2010;40:1839–48. [9] Blum I, Atsmon A. The possible role of beta-adrenergic and alpha-adrenergic antagonist sensitive systems in the brain in the mechanism of psychosis. Med Hypotheses 1976;2(3):104–6. [10] Conway J, Greenwood DT, Middlemiss DN. Central nervous actions of betaadrenoreceptor antagonists. Clin Sci Mol Med 1978;54(2):119–24. [11] Skelin I, Fikre-Merid M, Diksic M. Both acute and subchronic treatments with pindolol, a 5-HT1A and b1 and b2 adrenoceptor antagonist, elevate regional serotonin synthesis in the rat brain: An autoradiographic study. Neurochem Int 2012;61:1417–23. [12] Halberstadt AL, Geyer MA. Serotonergic hallucinogens as translational models relevant to schizophrenia. Int J Neuropsychopharmacol 2013;16(10):2165–80. [13] Neil-Dwyer G, Barlett J, McAinsh J, Cruickshank JM. Beta-adrenoceptor blockers and the bloodbrain barrier. Br J Clin Pharmacol 1981;11:549–53. [14] Cruickshank JM, Neil-Dwyer G. Betablocker brain concentration in man. Eur J Clin Pharmacol 1985;28:21–3. [15] Goldner JA. Metoprolol-induced visual hallucinations: a case series. J Med Case Rep 2012;6:65.
Please cite this article as: Rietveld L., et al, Familial liability for metoprolol-induced psychosis, Gen Hosp Psychiatry (2015), http://dx.doi.org/ 10.1016/j.genhosppsych.2015.06.016
Contents lists available at ScienceDirect
General Hospital Psychiatry journal homepage: http://www.ghpjournal.com
Familial liability for metoprolol-induced psychosis L. Rietveld, M.D. a,⁎, T. van der Hoek, M.D. a,c, M.H.C.T. van Beek, M.D. a, A.F.A. Schellekens, M.D., Ph.D. a,b a b c
Radboud University Medical Centre, Department of Psychiatry, Nijmegen, the Netherlands Donders Institute for Brain Cognition and Behaviour, Centre for Neuroscience, Nijmegen, The Netherlands Mental Health Organization (MHO) GGZ Oost Brabant Land van Cuijk en Noord Limburg, Boxmeer, The Netherlands
a r t i c l e
i n f o
Article history: Received 11 February 2015 Revised 19 June 2015 Accepted 22 June 2015 Available online xxxx Keywords: Psychosis Familial Beta blockers Metoprolol
a b s t r a c t Objective: : Beta-blockers are commonly used in the treatment of hypertension and cardiac arrhythmias. The incidence of neuropsychiatric side effects is generally low. This case report shows the potential familial liability of a metoprolol-induced psychosis. Method: : We report a case of metoprolol-induced psychosis. Potential pharmocogenetic factors mediating this familial metoprolol-induced psychosis are discussed. Results: : A middle-aged man developed psychosis after starting metoprolol, which diminished after ceasing the medication. Two of his family members experienced similar symptoms after using metoprolol. All family members were genotyped as CYP2D6*4 allele carriers indicating reduced CYP2D6 enzyme activity. Conclusion: : The case presented here suggests a potential familial liability for metoprolol- induced psychosis. Pharmacokinetic mechanisms are hypothesized to mediate this familial liability through genetic variation in the CYP2D6 genotype. A family history of psychotic symptoms after treatment with beta-blockers should be taken into account, when prescribing this beta-blocker. © 2015 Elsevier Inc. All rights reserved.
Introduction Beta-blockers are commonly used in the treatment of cardiovascular disorders such as hypertension and cardiac arrhythmias. Beta-blockers are generally well tolerated but have also been associated with neuropsychiatric side effects, like sedation, delirium and psychosis [1,2]. Administered at clinical doses, the incidence of these neuropsychiatric side effects is generally considered to be low. Factors associated with increased risk of these side effects are old age, impaired liver function or cognitive deficits [1,2]. Here, we report a case of a male who developed a metoprolol-induced psychosis and had a positive family history for metoprolol-induced psychosis. Potential pharmacogenetic mechanisms will be discussed.
Case A 44-year-old Caucasian man was admitted to our psychiatric ward because of psychotic symptoms. He reported confusion since approximately 2 weeks after he began taking metoprolol 50 mg, prescribed by his general practitioner (GP) because of primary hypertension. He had discontinued metoprolol because he felt confused and restless and ⁎ Corresponding author at: Department of Psychiatry, Radboud University Medical Centre, Nijmegen, Department of Psychiatry, 966, PO Box 9101, Nijmegen, The Netherlands Tel.: +31-0-243-666-495; fax: +31-0-243-540-561. E-mail address: [email protected] (L. Rietveld).
had difficulty falling asleep. The symptoms diminished quickly after ceasing metoprolol. After resuming metoprolol several days later, chaotic thinking and delusional thoughts occurred. He thought people around him were actors. His GP prescribed him oxazepam 10 mg tid and mirtazapin 15 mg od. Explorative physical and laboratory tests were normal. Because of persisting psychotic symptoms, the patient was referred to our clinic. At admission, the patient had constant feelings of confusion and agitation. He had visual hallucinations of receiving messages from mirrors and delusions that his wife would leave him. He denied having other psychiatric symptoms. Patient had no medical or psychiatric history, including substance use disorders, and used no medication other than metoprolol. He had a family history of hypertension. At physical examination, no abnormalities were observed, including a normal blood pressure (80/ 120 mmHg) and slightly elevated pulse (95 bpm). At psychiatric examination, we observed delusional content of his thoughts, without signs of disorientation, variable consciousness or other cognitive impairments. Similarly, no signs of affective disorders were observed. After excluding other causes of psychosis with physical and neurological examination and lab tests, we interpreted the psychotic symptoms as caused by metoprolol. Olanzapine 10 mg bid was prescribed, and metoprolol was stopped. After a few days, his psychosis gradually diminished. His hypertension was treated with the calcium antagonist nifidepine (30 mg). Two weeks after admission, the patient was discharged from hospital without any psychiatric symptoms. The olanzapine was gradually tapered over the following 3 weeks. The psychotic symptoms remained absent.
http://dx.doi.org/10.1016/j.genhosppsych.2015.06.016 0163-8343/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Rietveld L., et al, Familial liability for metoprolol-induced psychosis, Gen Hosp Psychiatry (2015), http://dx.doi.org/ 10.1016/j.genhosppsych.2015.06.016
2
L. Rietveld et al. / General Hospital Psychiatry xxx (2015) xxx–xxx
After full remission of the psychosis, the patient reported that both his mother and brother had experienced confusion and paranoia after taking metoprolol. Neither of them had a psychiatric history, risk factors for a metoprolol-induced psychosis or experienced any other side effect of metoprolol. Both had stopped metoprolol shortly after experiencing the symptoms, where after the symptoms diminished without further treatment with no reoccurrence of psychosis. The patient, his mother and brother were genotyped for the CYP2D6 genotype, showing that the patient and his mother were heterozygous for the CYP2D6*4 allele (reduced CYP2D6 enzyme activity). The brother was homozygous for CYP2D6*4, rs3892097 (reduced to absent CYP2D6 enzyme activity).
with psychotic symptoms despite their moderate to high lipophilicity and common usage [15]. Taken together, the case presented here shows metoprolol-induced psychosis with a potential familial liability. Pharmacokinetic mechanisms are hypothesized to mediate this familial liability through genetic variation in the CYP2D6 genotype. Since familial liability for neuropsychiatric side effects of metoprolol has not been described before, future studies should address its clinical relevance. However, a family history of psychotic symptoms after treatment with beta-blockers should be taken into account, when prescribing a beta-blocker. Insight in the neurobiological mechanism of metoprolol-induced psychosis could further enhance our insight in vulnerability factors for beta-blocker-induced psychotic symptoms.
Discussion Financial disclosures Although neuropsychiatric side effects of beta-blockers have previously been reported, this is the first report of familial liability for metoprolol-induced psychosis. Given the presence of the CYP2D6*4 genotype, indicating reduced CYP2D6 enzyme activity, a pharmacokinetic mechanism can be speculated. Homozygous carries of the CYP2D6*4 genotype taking a betablocker, like metoprolol, are at 4 times increased risk for side effects like bradycardia and low blood pressure [3]. It is unknown whether this also counts for neuropsychiatric side effects. Interestingly, all three persons experienced a metoprolol-induced psychosis, in the absence of other side effects or factors commonly associated with an increased risk for these side effects, like old age, high dosages, cognitive deficits or impaired liver function [1,2,4–6]. Since the psychotic symptoms remitted and recurred after discontinuation and readministration of the drug and similar side effects have been reported before, a causal relationship between metoprolol use and psychosis is very likely (Naranjo score: 9, indicating definite adverse drug reaction) [7]. The biological mechanism of a beta-blocker-induced psychosis is still poorly understood. Beta-blockers act on centrally located betaadrenoceptors, which may have cognitive behavioral effects. For example, adrenoceptors in the basolateral amygdala have been shown to be affected by propranolol, which is related to a diminished response to facial expressions [8]. Manipulation of beta-adrenoceptors has also been implicated in psychosis [9,10]. However, evidence for a direct relationship between central adrenoceptor blockade by metoprolol and subsequent psychosis is not available. Beta-blockers may also affect other neurotransmitter systems, like the brain serotonin (5-HT) system. For example, pindolol increases 5-HT synthesis in rats [11]. Serotonergic mechanisms have often been described to contribute to psychosis [12]. Though no serotonergic effects of metoprolol have been reported, a serotonergic mechanism cannot be ruled out. Beta-blockers differ with respect to their lipophilicity, which correlates with concentration in brain tissue [1]. Lipophilicity has been proposed to be related to the risk of developing adverse neuropsychiatric effects [1,13]. The incidence of neuropsyciatric side effects of betablockers seems to be highest for highly lipophilic agents (like propranolol) and lowest for more hydrophilic agents (like atenolol) [1]. With a brain/plasma concentration ratio about 20 times higher than atenolol, metoprolol has an intermediate position [13,14]. Yet, third generation beta-blockers (nebivolol and carvedilol) have not been associated
None. Conflict of interest None. Acknowledgments The department of genetics have contributed to this paper by processing the DNA samples and have advised in determining further actions. References [1] McAinsh J, Cruickshank JM. Beta-blockers and central nervous system side effects. Pharmacol Ther 1990;46:163–97. [2] Fisher AA, Davis M, Jeffery I. Acute delirium induced by metoprolol. Cardiovasc Drugs Ther 2002;16:161–5. [3] Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A, et al. Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther 2009;85(1):45–50. [4] Gengo FM, Ermer JC, Carey C, Kalonaros CG, McHugh WB. The relationship between serum concentrations and central nervous system actions of metoprolol. J Neurol Neurosurg Psychiatry 1985;48:101–6. [5] Hickey PL, McLean AJ, Angus PW, Choo EF, Morgan DJ. Increased sensitivity of propanolol clearance to reduced oxygen delivery in the isolated perfused cirrhotic rat liver. Gastroenterology 1996;111:1039–48. [6] Zhao Y, Xu W, Qiu L, Yang W. Metoprolol-induced psychosis in a young patient. Gen Hosp Psychiatry 2013;35:102.e1–2. [7] Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. [8] Hurlemann R, Walter H, Rehme K, Kukolja J, Santoro SC, Schmidt C, et al. Human amygdala reactivity is diminished by the b-noradrenergic antagonist propranolol. Psychol Med 2010;40:1839–48. [9] Blum I, Atsmon A. The possible role of beta-adrenergic and alpha-adrenergic antagonist sensitive systems in the brain in the mechanism of psychosis. Med Hypotheses 1976;2(3):104–6. [10] Conway J, Greenwood DT, Middlemiss DN. Central nervous actions of betaadrenoreceptor antagonists. Clin Sci Mol Med 1978;54(2):119–24. [11] Skelin I, Fikre-Merid M, Diksic M. Both acute and subchronic treatments with pindolol, a 5-HT1A and b1 and b2 adrenoceptor antagonist, elevate regional serotonin synthesis in the rat brain: An autoradiographic study. Neurochem Int 2012;61:1417–23. [12] Halberstadt AL, Geyer MA. Serotonergic hallucinogens as translational models relevant to schizophrenia. Int J Neuropsychopharmacol 2013;16(10):2165–80. [13] Neil-Dwyer G, Barlett J, McAinsh J, Cruickshank JM. Beta-adrenoceptor blockers and the bloodbrain barrier. Br J Clin Pharmacol 1981;11:549–53. [14] Cruickshank JM, Neil-Dwyer G. Betablocker brain concentration in man. Eur J Clin Pharmacol 1985;28:21–3. [15] Goldner JA. Metoprolol-induced visual hallucinations: a case series. J Med Case Rep 2012;6:65.
Please cite this article as: Rietveld L., et al, Familial liability for metoprolol-induced psychosis, Gen Hosp Psychiatry (2015), http://dx.doi.org/ 10.1016/j.genhosppsych.2015.06.016