Journal of Clinical Psychopharmacology
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AUTHOR DISCLOSURE INFORMATION Dr Michele Raja is on the speaker’s bureau of Lundbeck and Chiesi Farmaceutici. Dr Silvia Raja declares no conflict of interest. Michele Raja, MD Centro ‘‘Gaetano Perusini’’ Rome, Italy [email protected] [email protected]
Silvia Raja, MD Universita` degli Studi di Roma ‘‘La Sapienza’’ Rome, Italy
REFERENCES 1. De la Hoz-Aizpurua J-L, Dı´az-Alonso E, LaTouche-Arbizu R, et al. Sleep bruxism. Conceptual review and update. Med Oral Patol Oral Cir Bucal. 2011;16(2):e231Ye238. 2. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep. 1994;17(8):739Y743. 3. Hublin C, Kaprio J, Partinen M, et al. Sleep bruxism based on self-report in a nationwide twin cohort. J Sleep Res. 1998;7(1):61Y67. 4. Lavigne GJ, Rompre´ PH, Guitard F, et al. Lower number of K-complexes and K-alphas in sleep bruxism: a controlled quantitative study. Clin Neurophysiol. 2002;113(5):686Y693. 5. Schneider C, Schaefer R, Ommerborn MA, et al. Maladaptive coping strategies in patients with bruxism compared to non-bruxing controls. Int J Behav Med. 2007;14(4):257Y261. 6. Feu D, Catharino F, Quinta˜o CC, et al. A systematic review of etiological and risk factors associated with bruxism. J Orthod. 2013;40(2):163Y171. 7. Micheli F, Fernandez Pardal M, Gatto M, et al. Bruxism secondary to chronic antidopaminergic exposure. Clin Neuropharmacol. 1993;16(4):315Y323. 8. Brown ES, Hong SC. Antidepressant-induced bruxism successfully treated with gabapentin. J Am Dent Assoc. 1999;130(10):1467Y1469. 9. Jaffee MS, Bostwick JM. Buspirone as an antidote to venlafaxine-induce bruxism. Psychosomatics. 2000;41(6):535Y536. 10. Kuloglu M, Ekinci O, Caykoylu A. Venlafaxine-associated nocturnal bruxism in a depressive patient successfully treated with buspirone. J Psychopharmacol. 2010;24(4):627Y628. 11. Chang JP, Wu CC, Su KP. A case of venlafaxine-induced bruxism alleviated by duloxetine substitution. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):307. 12. Albayrak Y, Ekinci O. Duloxetine-induced nocturnal bruxism resolved by buspirone:
* 2014 Lippincott Williams & Wilkins
case report. Clin Neuropharmacol. 2011;34(4):137Y138. 13. Ellison JM, Stanziani P. SSRI-associated nocturnal bruxism in four patients. J Clin Psychiatry. 1993;54(11):432Y434. 14. Bostwick JM, Jaffee MS. Buspirone as an antidote to SSRI-induced bruxism in 4 cases. J Clin Psychiatry. 1999;60(12): 857Y860. 15. Romanelli F, Adler DA, Bungay KM. Possible paroxetine-induced bruxism. Ann Pharmacother. 1996;30(11):1246Y1248. 16. Kishi Y. Paroxetine-induced bruxism effectively treated with tandospirone. J Neuropsychiatry Clin Neurosci. 2007;19(1):90Y91. 17. Milanlioglu A. Paroxetine-induced severe sleep bruxism successfully treated with buspirone. Clinics (Sao Paulo). 2012; 67(2):191Y192. 18. Sabuncuoglu O, Ekinci O, Berkem M. Fluoxetine-induced sleep bruxism in an adolescent treated with buspirone: a case report. Spec Care Dentist. 2009;29(5): 215Y217. 19. Miyaoka T, Yasukawa R, Mihara T, et al. Successful electroconvulsive therapy in major depression with fluvoxamine-induced bruxism. J ECT. 2003;19(3):170Y172. 20. Wise M. Citalopram-induced bruxism. Br J Psychiatry. 2001;178(2):182.
Sleepwalking Associated With Metoprolol A Case Report To the Editors: etoprolol is widely used for the treatment of various cardiovascular conditions. It is reported to have central nervous system (CNS) adverse effects, such as delirium, visual hallucinations, and nightmares.1Y3 However, sleepwalking-related reports are rare in the literature. In 1 case, Pardalier et al4 reported somnambulism recurrence with the administration of propranolol for treating migraine. Similarly, Hensel and Pillman5 reported a 66-year-old woman’s sleepwalking linked to metoprolol who experienced somnambulism in childhood. Here we present a case of a 79-year-old man with no history of somnambulism who experienced sleepwalking possibly associated with metoprolol. This case is remarkable as it supports that sleepwalking can be triggered by metoprolol and indicates that sleepwalking could be an adverse reaction of metoprolol. More importantly, it was discovered by a clinical pharmacist, which reflects the value of current pharmacy practice in China.
M
Letters to the Editors
Also, the situation of clinical pharmacy services in China is discussed.
CASE REPORT A 79-year-old man, who had myocardial infarction and stent implantation 1 month ago, was admitted to the cardiology ward for medication adjustment. His medical history included unstable angina, hypertension, hyperlipidemia, stomach ulcer (caused by aspirin), upper gastrointestinal bleeding (caused by clopidogrel), and prostate cancer. There was no personal and family psychiatric illness history. His regular medications included aspirin (100 mg daily), clopidogrel (75 mg daily), isosorbide mononitrate (30 mg daily), felodipine (5 mg daily), pravastatin (40 mg daily), esomeprazole (20 mg twice daily), and goserelin (3.6 mg implanted monthly). After adjustment, metoprolol (12.5 mg twice daily) was prescribed for the first time. Two days later, the patient developed unusual sleeping behavior. According to his care worker, about 30 minutes after falling asleep, he suddenly sat up, got dressed, left bed, walked around, and mumbled, sometimes moved things, and sometimes woke up his roommates. He failed falling asleep again when the care worker woke him up. The next morning, he could not remember anything happened and felt excited. At that time, metoprolol was taken 3 times, and the total dose was 37.5 mg. Two days later, he sleepwalked again, with the total dose of 87.5 mg after 7 doses. The doctor consulted the pharmacist about the situation. As metoprolol has many CNS adverse reactions and was first used by the patient, we considered it might be associated with metoprolol and suggested bisoprolol or carvedilol for replacement. As to atenolol, there is limited convincing evidence about the effectiveness in reducing mortality postYmyocardial infarction.6 The doctor accepted and chose carvedilol (6.25 mg twice daily). In the next days, the patient sleepwalked 4 times, and the symptoms did not completely disappear until 5 days later. In addition, the patient took diazepam (2.5 mg nightly) several times but with no relief. All in all, the patient sleepwalked 6 times in 9 days after the use of metoprolol, in which 4 times happened after the discontinuation.
DISCUSSION In this report, the patient had no history of psychosis or somnambulism. He experienced episodes of sleepwalking 2 days after the administration of metoprolol. Then the symptoms completely disappeared 5 days after withdrawal of metoprolol. Hensel also reported sleepwalking as an adverse reaction of metoprolol.5 According to the probability www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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scale of Naranjo et al,7 the causative relationship between sleepwalking and metoprolol is possible drug effect. The time correlation of metoprolol and sleepwalking may not be typical. The interval between the use of metoprolol and the onset of sleepwalking can be as short as a few days in this report or as long as 8 weeks in Hensel and Pillman’s5 report. The interval between the discontinuation of metoprolol and remission of sleepwalking is a few weeks in Hensel and Pillman’s5 report. In this case, it took 5 days for the symptoms to disappear after the discontinuation of metoprolol. This atypical correlation affects our judgment and is worth attention. Compared with the high lipid solubility of propranolol, the lipid solubility of metoprolol and carvedilol is moderate, while low for bisoprolol.8 Propranolol is a nonselective A-blocking agent. Metoprolol and bisoprolol are selective type A1 adrenergic receptor blockers. Carvedilol has blocking effects at >1, A1, and A2 receptors.9 The A1/ A2 selectivity in intact cells of A-blockers is 1/8.3, 2.3/1, 13.5/1, and 1/4.5 for propranolol, metoprolol, bisoprolol, and carvedilol separately.10 The selectivity of A2 receptors could be the reason for sleepwalking, which will be discussed later. Despite the higher selectivity of A2, carvedilol is 98% bound to protein, whereas metoprolol is only 12%.8 Propranolol is also highly protein bound.8 However, carvedilol has lower selectivity and lower lipid solubility than propranolol. As a result, metoprolol and propranolol are more likely to cause CNS adverse reactions. The elimination half-life of metoprolol is 3 to 4 hours, and it is not extensively bound to plasma protein.8 However, metoprolol is moderately lipid soluble, widely distributed throughout the body. As the content of adipose tissue varies with each individual, the accumulation of metoprolol differs from man to man. The diversity of interval is possibly because of the extensive tissue binding. For obese people, the interval between the use/discontinuation of metoprolol and the onset/remission of sleepwalking could be longer than that of others. In this case, the body mass index of the patient is 21.61 kg/m2. Unfortunately, there is no related material of other patients. Considering the slender body type of this patient, it is acceptable that the interval is relatively shorter. According to Hensel and Pillman,5 the mechanism of sleepwalking is controversial. However, we agree that A2 and/or 5-HT receptor occupancies are related to sleep disorders.5,11 The affinity of metoprolol for the central A2 receptor is lower than propranolol.11 According to Gleiter and Deckert,12 the affinity of propranolol for
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serotonin 1A receptors is positive, whereas the affinity of metoprolol is negative. However, the potency at serotonin 1A receptors is considered as the mechanism of treatment for migraine.12 The definite subtype of 5-HT receptor correlated with sleepwalking is still not clear. As a result, 5-HT receptor occupancy mechanism cannot be excluded. Personally, we think individuals with larger number of A2/5-HT receptors or higher sensitivity to metoprolol are more likely to experience episodes of sleepwalking. It is pointed out that clinicianpharmacist collaboration can significantly improve patient care.13 According to the survey about what clinicians expect of a pharmacist’s work, we can conclude that pharmacists are welcomed in a clinician-led team.14 As the position paper listed, the scope of pharmacy services is wide ranging.15 As clinical pharmacists, there are many efforts we can make to be a necessary part of the multidisciplinary team. We should fulfill our patient-centered role, more than the traditional dispensing one. In China, the education of clinical pharmacists began in 1990s.16 According to the survey on ‘‘pilot program of the clinical pharmacist system,’’ carried out by NHFPC (National Health and Family Planning Commission) in 44 pilot hospitals from 2008 to 2010, most clinical pharmacy activities, sorted by the position paper, are fundamental, although less desirable and optimal.15,17 According to the model of Hutchinson et al,18 Chinese current clinical pharmacy is at the second stage of retrospective input to drug therapy decision making. This case is an example of successful pharmaceutical care with an optimal level, in which the role of pharmacists is well carried out.
AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Yanhong Wei, MS Department of Pharmacy Peking University Shougang Hospital Beijing, China [email protected]
Yatong Zhang, MS Department of Clinical Pharmacy Beijing Hospital of Health Ministry Beijing, China
Zhanquan Lin, BS Department of Pharmacy Peking University Shougang Hospital Beijing, China
Suowei Wu, MS Medical Administration Department Beijing Hospital of Health Ministry Beijing, China
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REFERENCES 1. Fisher AA, Davis M, Jeffery I. Acute delirium induced by metoprolol. Cardiovasc Drugs Ther. 2002;16(2):161Y165. 2. Sirois FJ. Visual hallucinations and metoprolol. Psychosomatics. 2006;47(6):537Y538. 3. Zhao Y, Xu W, Qiu L, et al. Metoprolol-induced psychosis in a young patient. Gen Hosp Psychiatry. 2013;35(1):102.e1Ye2. 4. Pardalier A, Giroud M, Dry J. Somnambulism, migraine and propranolol. Headache. 1987;27(3):143Y145. 5. Hensel J, Pillmann F. Late-life somnambulism after therapy with metoprolol. Clin Neuropharmacol. 2008;31(4):248Y250. 6. Freemantle N, Urdahl H, Eastaugh J, et al. What is the place of beta-blockade in patients who have experienced a myocardial infarction with preserved left ventricular function? Evidence and (mis) interpretation. Prog Cardiovasc Dis. 2002;44(4):243Y250. 7. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239Y245. 8. Frishman WH, Alwarshetty M. beta-Adrenergic blockers in systemic hypertension: pharmacokinetic considerations related to the current guidelines. Clin Pharmacokinet. 2002;41(7):505Y516. 9. Stafylas PC, Sarafidis PA. Carvedilol in hypertension treatment. Vasc Health Risk Manag. 2008;4(1):23Y30. 10. Baker JG. The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. Br J Pharmacol. 2010;160(5):1048Y1061. 11. Yamada Y, Shibuya F, Hamada J, et al. Prediction of sleep disorders induced by beta-adrenergic receptor blocking agents based on receptor occupancy. J Pharmacokinet Biopharm. 1995;23(2):131Y145. 12. Gleiter CH, Deckert J. Adverse CNS-effects of beta-adrenoceptor blockers. Pharmacopsychiatry. 1996; 29(6):201Y211. 13. Gallagher RM, Gallagher HC. Improving the working relationship between doctors and pharmacists: is inter-professional education the answer? Adv Health Sci Educ Theory Pract. 2012;17(2):247Y257. 14. Matsumoto Y, Shimizu M, Fukuoka M. What doctors expect of a pharmacist’s workVhow a pharmacist is evaluated by doctors. Yakugaku Zasshi. 2003;123(3):173Y178. 15. Society of Critical Care Medicine and American College of Clinical Pharmacy. Position paper on critical care pharmacy services. Pharmacotherapy. 2000;20(11):1400Y1406. 16. Ryan M, Shao H, Yang L, et al. Clinical pharmacy education in China. Am J Pharm Educ. 2008;72(6):129.
* 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology
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17. Wei YH, Shao H, Nie XY, et al. Current status and analysis of Chinese clinical pharmacists. Chin J New Drugs. 2011;20(9):844Y848. 18. Hutchinson RA, Vogel DP, Witte KW. A model for inpatient clinical pharmacy practice and reimbursement. Drug Intell Clin Pharm. 1986;20(12):989Y992.
Continuation Versus Discontinuation of Lithium During Pregnancy A Retrospective Case Series To the Editors: iagnostic accuracy and early therapeutic intervention are crucial in bipolar disorder (BD). Lithium (Li) has unique benefits for BD patientsVit is effective in preventing mood episode recurrences and significantly reduces suicide risk.1,2 Because of its narrow therapeutic index, regular monitoring of Li serum levels and adverse reactions is recommended. Pregnancy adds further complexity to the treatment of BD. Clinical studies on the course of BD during pregnancy have shown contrasting results.3 Recently, Bergink et al4 confirmed the importance of Li prophylaxis during pregnancy in BD women not only to maintain mood stability during pregnancy but also to prevent postpartum episodes. The decision as to whether to maintain or stop Li treatment during pregnancy should also consider that suicide is the leading cause of death among mothers.5 Therapeutic decision making in pregnant BD patients is also complicated by risks for the fetus during pregnancy and for neonatal complications after delivery. Recent reviews suggest that Li teratogenicity was previously overestimated.6 According to current estimates, up to 1 in 1,000 live births among the children of women treated during early pregnancy presents the Ebstein anomaly,7 a cardiac malformation with an excellent long-term functional status after surgery.8 To early detect these malformations, Li is recommended to be used only under obstetric supervision.9 Conversely, alternative mood stabilizers, such as anticonvulsant agents, are associated with a greater risk of major malformations, including neural tube defects.3 Furthermore, BD itself, whether in pharmacological treatment or not, seems to be associated with increased risks of adverse pregnancy outcomes.10 Because of the ethical concerns regarding clinical trials during pregnancy, information from case series may be useful to assess whether the
D
* 2014 Lippincott Williams & Wilkins
disease burden is reduced sufficiently by pharmacotherapy to offset the risks of drug exposure for each single patient. In this context, we describe the effect of continuation or discontinuation of Li during pregnancy in BD course and maternal/neonatal outcome, with a retrospective evaluation of the first pregnancy after starting Li treatment of all women with a diagnosis of BD type 1 (BDI) and BD type 2 (BDII). We systematically reviewed the psychiatric records of all BDI and BDII (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) female outpatients treated in the Lithium Clinic of the Unit of Clinical Psychopharmacology in the Teaching Hospital affiliated with the University of Cagliari from February 1976 to September 2012. We elected to study the first completed pregnancy after starting Li treatment. Detailed demographic and clinical information were collected for each patient using all available sources, including reviews of clinical records of psychiatric visits (average on a monthly basis) with detailed information through which each episode of illness can be retrospectively verified. We used the Retrospective NIMHYLife Chart Method (Bethesda, MD)11 to evaluate the clinical course of BD, focusing particularly on pregnancies and postpartum periods (considered as the 6 months after delivery). Pregnancies were considered ‘‘on-Li’’ if the patient continued treatment with Li during the entire period of pregnancy. Because recent guidelines12 suggest stopping Li 24 to 48 hours before a scheduled cesarean delivery or at the onset of labor in the event of spontaneous delivery, this was not considered as treatment discontinuation. Pregnancies were considered ‘‘off-Li’’ if the patient discontinued therapy at any other time during pregnancy. We report severity and frequency of illness episodes during the pregnancies and postpartum periods observed, as well as maternal/ neonatal short-term complications. We identified 12 women who had at least 1 completed pregnancy after starting Li treatment, and we assigned them to a treatment group (off-Li or on-Li). Table 1 summarizes their demographic and clinical features. Despite the small sample size, patients in the 2 groups seem to be comparable except for the fact that off-Li patients had a shorter period of well-being before the pregnancy (16.00 T 21.94 months vs 40.43 T 44.29 months). As far as patient 2 (off-Li) and patient 6 (on-Li), pregnancy was an unintended consequence of hypersexuality manifested during a manic episode. Only 1 patient (patient 6) presented psychiatric comorbidity, specifically panic attack disorder and previous history of cannabis abuse. Patients 4 and 11 were
Letters to the Editors
affected by autoimmune thyroiditis treated with levothyroxine (T4), whereas the other patients displayed no comorbidities. Patients 3 and 6 used to smoke and quit while pregnant. None of the patients were using alcohol. None of the off-Li patients was taking concomitant medication (apart from patient 4 who was on T4) neither folic acid. In the on-Li group, 4 of 7 patients were taking other medication (patients 6 and 7: benzodiazepines; patient 9: haloperidol; patient 10: haloperidol, benzodiazepines, and T4); all but 2 (patients 7 and 9) were taking folic acid. None of the off-Li pregnancy was planned by the patients, compared with 4 of 7 pregnancies (patients 8, 9, 11, and 12) in the on-Li group. Patient who continued Li received a median dosage of 900 mg daily with serum levels of 0.45 mEq/L during the first trimester, 0.42 mEq/L during the second trimester, and 0.40 mEq/L during the third trimester. During pregnancy, 1 off-Li patient (patient 4) experienced a manic episode with 1 day of hospitalization, whereas none of the on-Li patients experienced any episode of illness. With regard to maternal complications during pregnancy, we observed 1 case of gestational diabetes in an on-Li patient (patient 9). During the postpartum period, in the off-Li group, 4 of 5 patients experienced an episode (patient 2, mania; patient 3, depression; patient 4, mixed episode; patient 5, depression with switch to mania after antidepressant treatment), none of which required hospitalization. In the on-Li group, 2 of 7 patients presented a postpartum manic episode; patient 11 was hospitalized for 9 days, whereas patient 12 had a mild episode, probably due to the restart of Li treatment after the delivery at a lower dosage (300 mg daily) and serum level (0.27 mEq/L) compared with those before and during pregnancy. No off-Li patient had medical complications during the postpartum period, whereas 1 on-Li patient (patient 10) had upper airways infection treated with non-steroidal anti-inflammatory drugs and antibiotics, after which she had an acquired hemophilia leading to admission in a medical ward for several weeks. With regard to neonatal outcomes, we found 1 case of clubfoot in a child born to an off-Li patient (patient 4); among on-Li children, we noted 1 case of bilateral hip dislocation (patient 8).
DISCUSSION We described 12 cases of BD patients (followed-up for a mean of 15.54 T 11.81 years) who had at least 1 completed pregnancy after starting Li treatment. We observed a different relapse rate across pregnancy and postpartum among Li continuers and discontinuers. Among the 5 patients www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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AUTHOR DISCLOSURE INFORMATION Dr Michele Raja is on the speaker’s bureau of Lundbeck and Chiesi Farmaceutici. Dr Silvia Raja declares no conflict of interest. Michele Raja, MD Centro ‘‘Gaetano Perusini’’ Rome, Italy [email protected] [email protected]
Silvia Raja, MD Universita` degli Studi di Roma ‘‘La Sapienza’’ Rome, Italy
REFERENCES 1. De la Hoz-Aizpurua J-L, Dı´az-Alonso E, LaTouche-Arbizu R, et al. Sleep bruxism. Conceptual review and update. Med Oral Patol Oral Cir Bucal. 2011;16(2):e231Ye238. 2. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep. 1994;17(8):739Y743. 3. Hublin C, Kaprio J, Partinen M, et al. Sleep bruxism based on self-report in a nationwide twin cohort. J Sleep Res. 1998;7(1):61Y67. 4. Lavigne GJ, Rompre´ PH, Guitard F, et al. Lower number of K-complexes and K-alphas in sleep bruxism: a controlled quantitative study. Clin Neurophysiol. 2002;113(5):686Y693. 5. Schneider C, Schaefer R, Ommerborn MA, et al. Maladaptive coping strategies in patients with bruxism compared to non-bruxing controls. Int J Behav Med. 2007;14(4):257Y261. 6. Feu D, Catharino F, Quinta˜o CC, et al. A systematic review of etiological and risk factors associated with bruxism. J Orthod. 2013;40(2):163Y171. 7. Micheli F, Fernandez Pardal M, Gatto M, et al. Bruxism secondary to chronic antidopaminergic exposure. Clin Neuropharmacol. 1993;16(4):315Y323. 8. Brown ES, Hong SC. Antidepressant-induced bruxism successfully treated with gabapentin. J Am Dent Assoc. 1999;130(10):1467Y1469. 9. Jaffee MS, Bostwick JM. Buspirone as an antidote to venlafaxine-induce bruxism. Psychosomatics. 2000;41(6):535Y536. 10. Kuloglu M, Ekinci O, Caykoylu A. Venlafaxine-associated nocturnal bruxism in a depressive patient successfully treated with buspirone. J Psychopharmacol. 2010;24(4):627Y628. 11. Chang JP, Wu CC, Su KP. A case of venlafaxine-induced bruxism alleviated by duloxetine substitution. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35(1):307. 12. Albayrak Y, Ekinci O. Duloxetine-induced nocturnal bruxism resolved by buspirone:
* 2014 Lippincott Williams & Wilkins
case report. Clin Neuropharmacol. 2011;34(4):137Y138. 13. Ellison JM, Stanziani P. SSRI-associated nocturnal bruxism in four patients. J Clin Psychiatry. 1993;54(11):432Y434. 14. Bostwick JM, Jaffee MS. Buspirone as an antidote to SSRI-induced bruxism in 4 cases. J Clin Psychiatry. 1999;60(12): 857Y860. 15. Romanelli F, Adler DA, Bungay KM. Possible paroxetine-induced bruxism. Ann Pharmacother. 1996;30(11):1246Y1248. 16. Kishi Y. Paroxetine-induced bruxism effectively treated with tandospirone. J Neuropsychiatry Clin Neurosci. 2007;19(1):90Y91. 17. Milanlioglu A. Paroxetine-induced severe sleep bruxism successfully treated with buspirone. Clinics (Sao Paulo). 2012; 67(2):191Y192. 18. Sabuncuoglu O, Ekinci O, Berkem M. Fluoxetine-induced sleep bruxism in an adolescent treated with buspirone: a case report. Spec Care Dentist. 2009;29(5): 215Y217. 19. Miyaoka T, Yasukawa R, Mihara T, et al. Successful electroconvulsive therapy in major depression with fluvoxamine-induced bruxism. J ECT. 2003;19(3):170Y172. 20. Wise M. Citalopram-induced bruxism. Br J Psychiatry. 2001;178(2):182.
Sleepwalking Associated With Metoprolol A Case Report To the Editors: etoprolol is widely used for the treatment of various cardiovascular conditions. It is reported to have central nervous system (CNS) adverse effects, such as delirium, visual hallucinations, and nightmares.1Y3 However, sleepwalking-related reports are rare in the literature. In 1 case, Pardalier et al4 reported somnambulism recurrence with the administration of propranolol for treating migraine. Similarly, Hensel and Pillman5 reported a 66-year-old woman’s sleepwalking linked to metoprolol who experienced somnambulism in childhood. Here we present a case of a 79-year-old man with no history of somnambulism who experienced sleepwalking possibly associated with metoprolol. This case is remarkable as it supports that sleepwalking can be triggered by metoprolol and indicates that sleepwalking could be an adverse reaction of metoprolol. More importantly, it was discovered by a clinical pharmacist, which reflects the value of current pharmacy practice in China.
M
Letters to the Editors
Also, the situation of clinical pharmacy services in China is discussed.
CASE REPORT A 79-year-old man, who had myocardial infarction and stent implantation 1 month ago, was admitted to the cardiology ward for medication adjustment. His medical history included unstable angina, hypertension, hyperlipidemia, stomach ulcer (caused by aspirin), upper gastrointestinal bleeding (caused by clopidogrel), and prostate cancer. There was no personal and family psychiatric illness history. His regular medications included aspirin (100 mg daily), clopidogrel (75 mg daily), isosorbide mononitrate (30 mg daily), felodipine (5 mg daily), pravastatin (40 mg daily), esomeprazole (20 mg twice daily), and goserelin (3.6 mg implanted monthly). After adjustment, metoprolol (12.5 mg twice daily) was prescribed for the first time. Two days later, the patient developed unusual sleeping behavior. According to his care worker, about 30 minutes after falling asleep, he suddenly sat up, got dressed, left bed, walked around, and mumbled, sometimes moved things, and sometimes woke up his roommates. He failed falling asleep again when the care worker woke him up. The next morning, he could not remember anything happened and felt excited. At that time, metoprolol was taken 3 times, and the total dose was 37.5 mg. Two days later, he sleepwalked again, with the total dose of 87.5 mg after 7 doses. The doctor consulted the pharmacist about the situation. As metoprolol has many CNS adverse reactions and was first used by the patient, we considered it might be associated with metoprolol and suggested bisoprolol or carvedilol for replacement. As to atenolol, there is limited convincing evidence about the effectiveness in reducing mortality postYmyocardial infarction.6 The doctor accepted and chose carvedilol (6.25 mg twice daily). In the next days, the patient sleepwalked 4 times, and the symptoms did not completely disappear until 5 days later. In addition, the patient took diazepam (2.5 mg nightly) several times but with no relief. All in all, the patient sleepwalked 6 times in 9 days after the use of metoprolol, in which 4 times happened after the discontinuation.
DISCUSSION In this report, the patient had no history of psychosis or somnambulism. He experienced episodes of sleepwalking 2 days after the administration of metoprolol. Then the symptoms completely disappeared 5 days after withdrawal of metoprolol. Hensel also reported sleepwalking as an adverse reaction of metoprolol.5 According to the probability www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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scale of Naranjo et al,7 the causative relationship between sleepwalking and metoprolol is possible drug effect. The time correlation of metoprolol and sleepwalking may not be typical. The interval between the use of metoprolol and the onset of sleepwalking can be as short as a few days in this report or as long as 8 weeks in Hensel and Pillman’s5 report. The interval between the discontinuation of metoprolol and remission of sleepwalking is a few weeks in Hensel and Pillman’s5 report. In this case, it took 5 days for the symptoms to disappear after the discontinuation of metoprolol. This atypical correlation affects our judgment and is worth attention. Compared with the high lipid solubility of propranolol, the lipid solubility of metoprolol and carvedilol is moderate, while low for bisoprolol.8 Propranolol is a nonselective A-blocking agent. Metoprolol and bisoprolol are selective type A1 adrenergic receptor blockers. Carvedilol has blocking effects at >1, A1, and A2 receptors.9 The A1/ A2 selectivity in intact cells of A-blockers is 1/8.3, 2.3/1, 13.5/1, and 1/4.5 for propranolol, metoprolol, bisoprolol, and carvedilol separately.10 The selectivity of A2 receptors could be the reason for sleepwalking, which will be discussed later. Despite the higher selectivity of A2, carvedilol is 98% bound to protein, whereas metoprolol is only 12%.8 Propranolol is also highly protein bound.8 However, carvedilol has lower selectivity and lower lipid solubility than propranolol. As a result, metoprolol and propranolol are more likely to cause CNS adverse reactions. The elimination half-life of metoprolol is 3 to 4 hours, and it is not extensively bound to plasma protein.8 However, metoprolol is moderately lipid soluble, widely distributed throughout the body. As the content of adipose tissue varies with each individual, the accumulation of metoprolol differs from man to man. The diversity of interval is possibly because of the extensive tissue binding. For obese people, the interval between the use/discontinuation of metoprolol and the onset/remission of sleepwalking could be longer than that of others. In this case, the body mass index of the patient is 21.61 kg/m2. Unfortunately, there is no related material of other patients. Considering the slender body type of this patient, it is acceptable that the interval is relatively shorter. According to Hensel and Pillman,5 the mechanism of sleepwalking is controversial. However, we agree that A2 and/or 5-HT receptor occupancies are related to sleep disorders.5,11 The affinity of metoprolol for the central A2 receptor is lower than propranolol.11 According to Gleiter and Deckert,12 the affinity of propranolol for
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serotonin 1A receptors is positive, whereas the affinity of metoprolol is negative. However, the potency at serotonin 1A receptors is considered as the mechanism of treatment for migraine.12 The definite subtype of 5-HT receptor correlated with sleepwalking is still not clear. As a result, 5-HT receptor occupancy mechanism cannot be excluded. Personally, we think individuals with larger number of A2/5-HT receptors or higher sensitivity to metoprolol are more likely to experience episodes of sleepwalking. It is pointed out that clinicianpharmacist collaboration can significantly improve patient care.13 According to the survey about what clinicians expect of a pharmacist’s work, we can conclude that pharmacists are welcomed in a clinician-led team.14 As the position paper listed, the scope of pharmacy services is wide ranging.15 As clinical pharmacists, there are many efforts we can make to be a necessary part of the multidisciplinary team. We should fulfill our patient-centered role, more than the traditional dispensing one. In China, the education of clinical pharmacists began in 1990s.16 According to the survey on ‘‘pilot program of the clinical pharmacist system,’’ carried out by NHFPC (National Health and Family Planning Commission) in 44 pilot hospitals from 2008 to 2010, most clinical pharmacy activities, sorted by the position paper, are fundamental, although less desirable and optimal.15,17 According to the model of Hutchinson et al,18 Chinese current clinical pharmacy is at the second stage of retrospective input to drug therapy decision making. This case is an example of successful pharmaceutical care with an optimal level, in which the role of pharmacists is well carried out.
AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Yanhong Wei, MS Department of Pharmacy Peking University Shougang Hospital Beijing, China [email protected]
Yatong Zhang, MS Department of Clinical Pharmacy Beijing Hospital of Health Ministry Beijing, China
Zhanquan Lin, BS Department of Pharmacy Peking University Shougang Hospital Beijing, China
Suowei Wu, MS Medical Administration Department Beijing Hospital of Health Ministry Beijing, China
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REFERENCES 1. Fisher AA, Davis M, Jeffery I. Acute delirium induced by metoprolol. Cardiovasc Drugs Ther. 2002;16(2):161Y165. 2. Sirois FJ. Visual hallucinations and metoprolol. Psychosomatics. 2006;47(6):537Y538. 3. Zhao Y, Xu W, Qiu L, et al. Metoprolol-induced psychosis in a young patient. Gen Hosp Psychiatry. 2013;35(1):102.e1Ye2. 4. Pardalier A, Giroud M, Dry J. Somnambulism, migraine and propranolol. Headache. 1987;27(3):143Y145. 5. Hensel J, Pillmann F. Late-life somnambulism after therapy with metoprolol. Clin Neuropharmacol. 2008;31(4):248Y250. 6. Freemantle N, Urdahl H, Eastaugh J, et al. What is the place of beta-blockade in patients who have experienced a myocardial infarction with preserved left ventricular function? Evidence and (mis) interpretation. Prog Cardiovasc Dis. 2002;44(4):243Y250. 7. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239Y245. 8. Frishman WH, Alwarshetty M. beta-Adrenergic blockers in systemic hypertension: pharmacokinetic considerations related to the current guidelines. Clin Pharmacokinet. 2002;41(7):505Y516. 9. Stafylas PC, Sarafidis PA. Carvedilol in hypertension treatment. Vasc Health Risk Manag. 2008;4(1):23Y30. 10. Baker JG. The selectivity of beta-adrenoceptor agonists at human beta1-, beta2- and beta3-adrenoceptors. Br J Pharmacol. 2010;160(5):1048Y1061. 11. Yamada Y, Shibuya F, Hamada J, et al. Prediction of sleep disorders induced by beta-adrenergic receptor blocking agents based on receptor occupancy. J Pharmacokinet Biopharm. 1995;23(2):131Y145. 12. Gleiter CH, Deckert J. Adverse CNS-effects of beta-adrenoceptor blockers. Pharmacopsychiatry. 1996; 29(6):201Y211. 13. Gallagher RM, Gallagher HC. Improving the working relationship between doctors and pharmacists: is inter-professional education the answer? Adv Health Sci Educ Theory Pract. 2012;17(2):247Y257. 14. Matsumoto Y, Shimizu M, Fukuoka M. What doctors expect of a pharmacist’s workVhow a pharmacist is evaluated by doctors. Yakugaku Zasshi. 2003;123(3):173Y178. 15. Society of Critical Care Medicine and American College of Clinical Pharmacy. Position paper on critical care pharmacy services. Pharmacotherapy. 2000;20(11):1400Y1406. 16. Ryan M, Shao H, Yang L, et al. Clinical pharmacy education in China. Am J Pharm Educ. 2008;72(6):129.
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17. Wei YH, Shao H, Nie XY, et al. Current status and analysis of Chinese clinical pharmacists. Chin J New Drugs. 2011;20(9):844Y848. 18. Hutchinson RA, Vogel DP, Witte KW. A model for inpatient clinical pharmacy practice and reimbursement. Drug Intell Clin Pharm. 1986;20(12):989Y992.
Continuation Versus Discontinuation of Lithium During Pregnancy A Retrospective Case Series To the Editors: iagnostic accuracy and early therapeutic intervention are crucial in bipolar disorder (BD). Lithium (Li) has unique benefits for BD patientsVit is effective in preventing mood episode recurrences and significantly reduces suicide risk.1,2 Because of its narrow therapeutic index, regular monitoring of Li serum levels and adverse reactions is recommended. Pregnancy adds further complexity to the treatment of BD. Clinical studies on the course of BD during pregnancy have shown contrasting results.3 Recently, Bergink et al4 confirmed the importance of Li prophylaxis during pregnancy in BD women not only to maintain mood stability during pregnancy but also to prevent postpartum episodes. The decision as to whether to maintain or stop Li treatment during pregnancy should also consider that suicide is the leading cause of death among mothers.5 Therapeutic decision making in pregnant BD patients is also complicated by risks for the fetus during pregnancy and for neonatal complications after delivery. Recent reviews suggest that Li teratogenicity was previously overestimated.6 According to current estimates, up to 1 in 1,000 live births among the children of women treated during early pregnancy presents the Ebstein anomaly,7 a cardiac malformation with an excellent long-term functional status after surgery.8 To early detect these malformations, Li is recommended to be used only under obstetric supervision.9 Conversely, alternative mood stabilizers, such as anticonvulsant agents, are associated with a greater risk of major malformations, including neural tube defects.3 Furthermore, BD itself, whether in pharmacological treatment or not, seems to be associated with increased risks of adverse pregnancy outcomes.10 Because of the ethical concerns regarding clinical trials during pregnancy, information from case series may be useful to assess whether the
D
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disease burden is reduced sufficiently by pharmacotherapy to offset the risks of drug exposure for each single patient. In this context, we describe the effect of continuation or discontinuation of Li during pregnancy in BD course and maternal/neonatal outcome, with a retrospective evaluation of the first pregnancy after starting Li treatment of all women with a diagnosis of BD type 1 (BDI) and BD type 2 (BDII). We systematically reviewed the psychiatric records of all BDI and BDII (according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) female outpatients treated in the Lithium Clinic of the Unit of Clinical Psychopharmacology in the Teaching Hospital affiliated with the University of Cagliari from February 1976 to September 2012. We elected to study the first completed pregnancy after starting Li treatment. Detailed demographic and clinical information were collected for each patient using all available sources, including reviews of clinical records of psychiatric visits (average on a monthly basis) with detailed information through which each episode of illness can be retrospectively verified. We used the Retrospective NIMHYLife Chart Method (Bethesda, MD)11 to evaluate the clinical course of BD, focusing particularly on pregnancies and postpartum periods (considered as the 6 months after delivery). Pregnancies were considered ‘‘on-Li’’ if the patient continued treatment with Li during the entire period of pregnancy. Because recent guidelines12 suggest stopping Li 24 to 48 hours before a scheduled cesarean delivery or at the onset of labor in the event of spontaneous delivery, this was not considered as treatment discontinuation. Pregnancies were considered ‘‘off-Li’’ if the patient discontinued therapy at any other time during pregnancy. We report severity and frequency of illness episodes during the pregnancies and postpartum periods observed, as well as maternal/ neonatal short-term complications. We identified 12 women who had at least 1 completed pregnancy after starting Li treatment, and we assigned them to a treatment group (off-Li or on-Li). Table 1 summarizes their demographic and clinical features. Despite the small sample size, patients in the 2 groups seem to be comparable except for the fact that off-Li patients had a shorter period of well-being before the pregnancy (16.00 T 21.94 months vs 40.43 T 44.29 months). As far as patient 2 (off-Li) and patient 6 (on-Li), pregnancy was an unintended consequence of hypersexuality manifested during a manic episode. Only 1 patient (patient 6) presented psychiatric comorbidity, specifically panic attack disorder and previous history of cannabis abuse. Patients 4 and 11 were
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affected by autoimmune thyroiditis treated with levothyroxine (T4), whereas the other patients displayed no comorbidities. Patients 3 and 6 used to smoke and quit while pregnant. None of the patients were using alcohol. None of the off-Li patients was taking concomitant medication (apart from patient 4 who was on T4) neither folic acid. In the on-Li group, 4 of 7 patients were taking other medication (patients 6 and 7: benzodiazepines; patient 9: haloperidol; patient 10: haloperidol, benzodiazepines, and T4); all but 2 (patients 7 and 9) were taking folic acid. None of the off-Li pregnancy was planned by the patients, compared with 4 of 7 pregnancies (patients 8, 9, 11, and 12) in the on-Li group. Patient who continued Li received a median dosage of 900 mg daily with serum levels of 0.45 mEq/L during the first trimester, 0.42 mEq/L during the second trimester, and 0.40 mEq/L during the third trimester. During pregnancy, 1 off-Li patient (patient 4) experienced a manic episode with 1 day of hospitalization, whereas none of the on-Li patients experienced any episode of illness. With regard to maternal complications during pregnancy, we observed 1 case of gestational diabetes in an on-Li patient (patient 9). During the postpartum period, in the off-Li group, 4 of 5 patients experienced an episode (patient 2, mania; patient 3, depression; patient 4, mixed episode; patient 5, depression with switch to mania after antidepressant treatment), none of which required hospitalization. In the on-Li group, 2 of 7 patients presented a postpartum manic episode; patient 11 was hospitalized for 9 days, whereas patient 12 had a mild episode, probably due to the restart of Li treatment after the delivery at a lower dosage (300 mg daily) and serum level (0.27 mEq/L) compared with those before and during pregnancy. No off-Li patient had medical complications during the postpartum period, whereas 1 on-Li patient (patient 10) had upper airways infection treated with non-steroidal anti-inflammatory drugs and antibiotics, after which she had an acquired hemophilia leading to admission in a medical ward for several weeks. With regard to neonatal outcomes, we found 1 case of clubfoot in a child born to an off-Li patient (patient 4); among on-Li children, we noted 1 case of bilateral hip dislocation (patient 8).
DISCUSSION We described 12 cases of BD patients (followed-up for a mean of 15.54 T 11.81 years) who had at least 1 completed pregnancy after starting Li treatment. We observed a different relapse rate across pregnancy and postpartum among Li continuers and discontinuers. Among the 5 patients www.psychopharmacology.com
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