Rhabdomyolysis With Risperidone and Escitalopram Coadministration: A Case Report.

LETTERS TO THE EDITORS—CASE REPORTS

Pharmacokinetic Interaction Between Valproic Acid, Meropenem, and Risperidone To the Editors:

CASE REPORT Combining different drugs is a common clinical practice, also for treating somatic diseases in psychiatric patients. Pharmacodynamic or pharmacokinetic drug-drug interactions can thereby lead to desired effects, attenuated effects, undesired harmful effects or even to serious adverse reactions. Treatment with several drugs enhances the risk of adverse drug reactions and drug-drug interactions. The probability of interactions increases with the number of applied drugs. Even in complex clinical cases, valid interaction checks are still difficult, especially to assess whether an indicated potential interaction risk is clinically relevant or not. The addition of the β-lactam antibiotic meropenem (MER) for antimicrobial chemotherapy to an ongoing therapy with valproic acid (VPA) leads to a well-known decrease of VPA serum concentrations.1,2 Largely unknown is the influence of this pharmacokinetic interaction on a concurrent treatment with the second-generation antipsychotic risperidone (RIS). We therefore show a clinically complex case where the interaction between VPA, MER, and RIS led to unexpected effects.

Mr A is a 43-year-old inpatient diagnosed with a multiple drug use dependence syndrome (International Classification of Diseases-10: F19.2) and a paranoid schizophrenia (International Classification of Diseases-10: F20.0). He was treated successfully with a combination of VPA 1800 mg and RIS 4 mg per day with a stable psychopathology and no signs of acute psychosis in the sense of missing positive symptoms, such as hallucinations, delusions, or bizarre behavior. Because of multiple bilateral phlegmons of the forearms with bone involvement in the course of an ongoing intravenous drug abuse, he had to undergo plastic surgery with overlap surgery of both forearms. Meropenem was added at a daily dose of 3000 mg because of infections of the skin transplants. Therapeutic drug monitoring of VPA and RIS was performed as part of an individualized treatment optimization. Drug concentrations were measured once a week as trough levels under steadystate conditions. According to the metabolic ratio between RIS and its active metabolite 9-OH-RIS with much higher levels for RIS than for 9-OH-RIS (mean, RIS/9-OH-RIS ratio of 5.3; SD, 2.0; see Table 1), it was assumed that the patient was phenotypically a cytochrome P450 2D6 (CYP2D6) poor metabolizer (PM). Genotyping of cytochrome P450 2D6, 2C9, and 2C19 was performed to complete the clinical diagnostic. Because of the stable clinical conditions with regard to the psychosis and serum levels of the active moiety (RIS + 9-OH-RIS) reaching the upper value of the

therapeutic reference range (20–60 μg/L),3 the administered daily dose of RIS was reduced from 4 mg to 2 mg before the start of the antimicrobial chemotherapy with MER (see Table 1). The mean concentration-bydose ratio (C/D) for the active moiety (calculated as serum concentration divided by the applied dose) was 15.3 (SD, 5.2) during this first period. The daily dose of VPA remained unchanged. After starting the antimicrobial chemotherapy, VPA mean serum concentrations decreased dramatically ( 83%) from 37 μg/mL (SD, 6) to 6 μg/mL (SD, 0.6). Despite a reduction of the prescribed daily dose of RIS from 4 to 2 mg, the serum concentration of RIS decreased only by 31% after adding MER (mean serum concentration, 50 ng/mL; SD, 15 ng/mL before; 34 ng/mL; SD, 8 ng/mL after addition of MER). Mean serum concentrations of the metabolite 9-OH-RIS decreased in an expected range, namely, by 54% (12 ng/mL, SD 6 ng/mL; after adding MER, mean 5 ng/mL; SD, 2 ng/mL). Interestingly, serum levels of RIS and 9-OH-RIS changed differentially after the addition of MER: the C/D ratio (drug concentration divided by daily dose) for RIS increased from 12.4 to 17.1, indicating a lower clearance of RIS, whereas C/D for 9-OH-RIS slightly decreased (from 2.9 to 2.7). The C/D ratio for the active moiety increased from 15.3 to 20.0 (see Table 1 and Fig. 1). After termination of the antimicrobial chemotherapy, the C/D ratio for RIS and active moiety decreased again. The ratio RIS/9-OH-RIS temporarily increased

TABLE 1. Daily Doses of RIS and VPA, and Serum Levels of RIS, 9-OH-RIS and VPA Before, During, and After a Concomitant Treatment With MER Risperidone Week DD risperidone, mg RIS, ng/mL C/D (RIS), (ng/mL)/(mg/d) 9-OH-RIS, ng/mL C/D (9-OH-RIS), (ng/mL)/(mg/day) RIS + 9-OH-RIS, AM, ng/mL C/D AM, (ng/mL)/(mg/day) Ratio RIS/9-OH-RIS, ng/mL DD VPA, mg VPA, μg/mL

1 4 35.5 8.9 4.9 1.2 40.4 10.1 7.2 1800 30.1

2 4 47.4 11.9 14.1 3.5 61.5 15.4 3.7 1800 40.3

3 4 66.0 16.5 16.0 4.0 82 20.5 4.1 1800 40.5

Concomitant Treatment With MER

Risperidone

mean 4 5 6 7 8 mean 9 10 11 4 2 2 2 2 2 2 2 2 2 49.6 22.4 43.3 29.1 38.2 38.3 34.3 23.5 24.8 21.5 12.4 11.2 21.7 14.6 19.1 19.2 17.1 11.8 12.4 10.8 11.7 3.6 5.9 3.9 5.2 8.1 5.3 5.6 2.6 7.0 2.9 1.8 3.0 2.0 2.6 4.0 2.7 2.8 1.3 3.5 61.3 26 49.2 33 43.4 46.4 39.6 29.1 27.4 28.5 15.3 13 24.6 16.5 21.7 23.2 19.8 14.6 13.7 14.3 5.0 6.2 7.3 7.5 7.4 4.7 6.6 4.2 9.5 3.1 1800 1800 1800 1800 1800 1800 1800 1800 1800 1800 37.0 6.0 5.4 5.2 7.3 7.1 6.2 54.4 67.4 69.4

12 2 20.9 10.5 4.0 2.0 24.9 12.5 5.2 1800 89

mean 2 22.7 11.3 4.8 2.4 27.5 13.7 5.5 1800 70.1

DD indicates daily dose; AM, active moiety.

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Journal of Clinical Psychopharmacology • Volume 36, Number 1, February 2016


Letters to the Editors

serum concentrations, no changes in psychopathology were observable. VPAwas administered for affective control and against impulsivity but decreasing VPA levels did not lead to a reoccurrence of any of those symptoms. Finally, the present complex case of pharmacokinetic interaction between the 3 drugs, possibly also depending on the metabolic status of the patient, underscores the clinical usefulness of therapeutic drug monitoring for treatment optimization. Luckily, during the entire duration of the inpatient treatment, before, during, and after the antimicrobial treatment with meropenem and although the daily dose of RIS was halved, the clinical condition of the patient was stable, and no psychotic symptoms recurred.

FIGURE 1. Risperidone, 9-OH-RIS and VPA serum levels before, during, and after concomitant medication with meropenem. Serum levels of RIS and 9-OH-RIS in ng/mL, VPA serum-levels in μg/mL. Daily dose of RIS was reduced from 4 mg to 2 mg. Meropenem treatment started at week 4 and ended with week 9.

ACKNOWLEDGMENTS All individuals included as authors of the manuscript have contributed substantially to the scientific process leading up to the writing of this paper.

but also serum levels of the active moiety of RIS increased, an effect mostly driven by a higher C/D ratio for RIS despite a small decrease of 9-OH-RIS concentration by dose ratio, suggesting a reduced formation of 9-OH-RIS from RIS. Of note, although CYP2D6 is the main isoform responsible of RIS metabolism, a contribution of CYP3A to RIS metabolism has also been suggested by several interaction studies with CYP3A inducers,5,6 or inhibitors.7,8 We therefore hypothesize that the observed inhibition of RIS metabolism in a CYP2D6 PM is due to the blockade of secondary metabolic pathways, mediated by CYP3A and/or other isoforms. An increasing importance of CYP3A4 in the metabolism of clozapine, a drug mainly metabolized by CYP1A2, has thus been demonstrated in patients with blocked CYP1A2 activity.9 Concerning RIS, in CYP2D6 PMs, CYP3A could be important for the production of 9-OH-RIS10 and a case study suggested that CYP2D6 genotype may influence susceptibility to a clinically important interaction with carbamazepine, a CYP3A inducer.11 If true, a weaker inhibitory effect of MER on RIS pharmacokinetics would probably be observed in a CYP2D6 extensive metabolizer, if observed at all. We can however not exclude that the observed interaction is mediated by changes in VPA serum concentrations, in that case the mechanism remaining unclear. Luckily, because of the relatively short period of decreased VPA

AUTHOR DISCLOSURE INFORMATION Mr Kuzin and Dr Paulzen declare no conflict of interests. Dr Gründer has served as a consultant for AstraZeneca (London, UK), BristolMyers Squibb (New York, NY), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, Ind), Johnson & Johnson (Beerse, Belgium), and Otsuka (Rockville, MD). He has served on the speakers’ bureau of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Cilag, Otsuka, Pfizer, Servier (Paris, France), and Wyeth. He has received grant support from Alkermes, Bristol-Myers Squibb, Eli Lilly, and Johnson & Johnson. He is co-founder of Pharma-Image – Molecular Imaging Technologies GmbH (Düsseldorf, Germany). Dr Eap received research support from AstraZeneca, Eli Lily, Fujisawa, Janssen Cilag, Novartis, Roche Organ Transplantation Research Foundation, Sandoz, SmithKline Beecham, Bristol-Myers Squibb, Takeda and Wyeth. He received honoraria for conferences or teaching CME courses from Advisis, AstraZeneca, Bristol-Myers Squibb, Eli Lily, Essex Chemie, GlaxoSmithKline, Janssen-Cilag, Lundbeck, Merck Sharp & Dohme, Novo Nordisk, Organon, Otsuka, Sandoz, Servier, Vifor-Pharma. Dr Eap received research support from Takeda and from the Roche Organ Transplantation Research Foundation (#152358701) in the previous 3 years. He received honoraria for conferences or teaching CME courses from Advisis, AstraZeneca, Essex Chemie,

from 5.0 (SD, 1.92) to 6.6 (SD, 1.19) under MER comedication and decreased again to 5.5 (SD, 2.80) after ending the MER therapy. Cytochrome P450 genotyping showed a PM status (*4/*4) for CYP2D6, an extensive metabolizer status (*1/*1) for 2C9, and a rapid metabolizer status (*1/*17) for 2C19.

DISCUSSION Several mechanisms are hypothesized to explain the decrease of VPA after the addition of carbapenem antibiotics, such as meropenem. They include an effect at the intestinal absorption site, the liver site (decrease of the uridine 5′-diphospho-glucuronic acid level by carbapenem antibiotics, a direct activation of uridine 5′diphosphoglucuronosyltransferase by carbapenem antibiotics, or an inhibition of β-glucuronidase) and/or at the distribution site of VPA in blood (for more details, see Mori et al4). The metabolism of both VPA and meropenem is independent from CYP2D6 activity, whereas RIS is mainly metabolized via CYP2D6 to the active metabolite 9-OHRIS. This pharmacokinetic interaction between 3 drugs is complexed by the CYP2D6 PM status. Because homozygotes for the null alleles of CYP2D6, such as *4, do not have any functional CYP2D6 protein, it was not expected that the preexisting high ratio of RIS/9-OH-RIS, indicating a CYP2D6 PM status, was influenced by MER. However, after starting MER, not only VPA serum levels decreased

© 2015 Wolters Kluwer Health, Inc. All rights reserved.


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Janssen-Cilag, Lundbeck, Merck Sharp & Dohme, Sandoz, Servier, Takeda, ViforPharma in the previous 3 years. Michael Paulzen, MD Department of Psychiatry Psychotherapy and Psychosomatics RWTH Aachen University; and Jülich Aachen Research Alliance-Translational Brain Medicine Aachen, Germany [email protected]

Chin-Bin Eap, PhD Unit of Pharmacogenetics and Clinical Psychopharmacology Centre for Psychiatric Neuroscience Department of Psychiatry and School of Pharmaceutical Sciences University of Geneva, University of Lausanne Geneva, Switzerland

Gerhard Gründer, MD Maxim Kuzin, MD Department of Psychiatry Psychotherapy and Psychosomatics RWTH Aachen University; and Jülich Aachen Research Alliance-Translational Brain Medicine Aachen, Germany

REFERENCES 1. Vélez Díaz-Pallarés M, Delgado Silveira E, Alvarez Díaz AM, et al. Analysis of the valproic acid-meropenem interaction in hospitalised patients. Neurologia. 2012;27: 34–38. 2. Park MK, Lim KS, Kim TE, et al. Reduced valproic acid serum concentrations due to drug interactions with carbapenem antibiotics: overview of 6 cases. Ther Drug Monit. 2012;34: 599–603. 3. Hiemke C, Baumann P, Bergemann N, et al. AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry. 2011;44:195–235. 4. Mori H, Takahashi K, Mizutani T. Interaction between valproic acid and carbapenem antibiotics. Drug Metab Rev. 2007;39: 647–657. 5. Spina E, Avenoso A, Facciolà G, et al. Plasma concentrations of risperidone and 9-hydroxyrisperidone: effect of comedication with carbamazepine or valproate. Ther Drug Monit. 2000;22:481–485. 6. Ono S, Mihara K, Suzuki A, et al. Significant pharmacokinetic interaction between risperidone and carbamazepine: its relationship with CYP2D6 genotypes. Psychopharmacology (Berl). 2002;162:50–54. 7. Jung SM, Kim KA, Cho HK, et al. Cytochrome P450 3A inhibitor itraconazole affects plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients. Clin Pharmacol Ther. 2005;78: 520–528. 8. Mahatthanatrakul W, Sriwiriyajan S, Ridtitid W, et al. Effect of cytochrome P450 3A4

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inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers. J Clin Pharm Ther. 2012;37:221–225. 9. Jaquenoud Sirot E, Knezevic B, Morena GP, et al. ABCB1 and cytochrome P450 polymorphisms: clinical pharmacogenetics of clozapine. J Clin Psychopharmacol. 2009;29: 319–326. 10. DeVane CL, Nemeroff CB. An evaluation of risperidone drug interactions. J Clin Psychopharmacol. 2001;21: 408–416. 11. Spina E, Scordo MG, Avenoso A, et al. Adverse drug interaction between risperidone and carbamazepine in a patient with chronic schizophrenia and deficient CYP2D6 activity. J Clin Psychopharmacol. 2001;21: 108–109.

Anti-Inflammatory Therapy and Immunotherapy Were Partially Effective in a Patient With Anti–N-MethylD-Aspartate Receptor Antibodies and a Special Subgroup of Treatment-Resistant Schizophrenia To the Editors: atients with anti N-methyl-D-aspartate receptor (NMDAR) encephalitis with or without tumor typically exhibit psychotic symptoms including psychosis, memory deficits, seizures, catatonic features, and autonomic and breathing instability.1 They are treated by tumor resection, corticosteroids, intravenous immunoglobulin, and/or plasma exchange given alone or in combination and respond quickly to treatment.2 Some patients are reported to have NMDAR antibodies at the initial diagnosis of schizophrenia.3,4 In our experience, immunotherapy was partially effective in a patient with immunoglobulin G (IgG) antibodies against the NR1 subunit of NMDAR in the cerebrospinal fluid (CSF) and a special subgroup of treatment-resistant schizophrenia without neurological symptoms and signs. A 31-year-old woman with no psychiatric history started to have psychotic symptoms. At the age of 33 years, she presented with extreme agitation and auditory and visual hallucinations and was hospitalized by the emergency unit of a psychiatric hospital. Treatment with 3 atypical antipsychotics, 30 mg/d of aripiprazole for 6 weeks, then 6 mg/d of risperidone for 6 weeks, or 20 mg/d of olanzapine for 6 weeks, was

P

not effective, and her Positive and Negative Syndrome Scale (PANSS) score was still 117 (positive: 29, negative: 30). She had also cognitive impairment and her Mini-Mental State Examination (MMSE) score was 21 (orientation 7/10 [date, day, and floor], attention and calculation [serial 7’s] 0/5, language [write a sentence] 0/1). Her brain magnetic resonance imaging (MRI), electroencephalography (EEG), and CSF findings were normal, but NR1 IgG antibodies in CSF were confirmed by a cell-based assay.3 No tumor or tumor markers (cytokeratin 19 fragment, carcinoembryonic antigen, α-fetoprotein, antigen CA-19-9, and neuron-specific enolase) were seen on enhanced whole-body computed tomography or pelvic MRI. An Easy Z score imaging system of technetium 99m ECD single-photon emission computed tomography showed that blood flow in the left frontal lobe was reduced to a Z score of 3.0 or 4.0. She showed hypothyroidism (free triiodothyronine 2.76 pg/mL [2.30– 4.00 pg/mL], free thyroxine 0.85 ng/dL [0.97–1.69 ng/dL], thyroid-stimulating hormone 7.34 μU/mL [0.33–4.05 μU/mL], and various thyroid autoantibodies including antithyroglobulin antibody 172.9 IU/mL [0– 13.6 IU/mL], antithyroperoxidase antibody 981.9 IU/mL [0–3.2 IU/mL], thyrotrophin receptor antibody 2.27 IU/L [0–2.00 IU/L]) and IgG index of 0.733. No other autoantibodies were identified. We administered 100 μg/d levothyroxine sodium hydrate. After 6 months’ hospitalization, she received two 3-day courses of intravenous methylprednisolone 1000 mg/d, which did not induce a quick response. Four days after the end of the second methylprednisolone course, she received a 5-day course of intravenous Kenketsu globenin-I (freeze-dried polyethylene glycol–treated human normal immunoglobulin) 20,000 mg/d. Three days after immunoglobulin administration, the NR1 antibody was no longer present in the CSF, and the reduction of blood flow in the left frontal lobe was reduced to a Z score of less than 2.0. Her PANSS score declined to 85 (positive: 20, negative: 24), and her MMSE improved to 25 (orientation 9/10 [date], attention and calculation [serial 7’s] 1/5). She also underwent two 3-day courses of intravenous methylprednisolone 1000 mg/d, 10 weeks after the first immunotherapy, but again it did not induce a quick response. Seven months after the first immunotherapy, her PANSS score was reduced to 75 (positive: 14, negative: 25), and her MMSE was 25 (attention and calculation [serial 7’s] 1/5, recall 2/3). She now functions as a housewife and has not experienced a recurrence (Table 1). Among 571 patients with the NR1 IgG antibody, 22 (4%) were reported to develop psychiatric symptoms.1 However, almost all




TABLE 1. Longitudinal Changes in Laboratory Data and Assessment Scores

Baseline 1 mo 7 mo

Temp

CRP

WBC

TGAb

TPOAb

TRAb

NMDAR

MMSE

PANSS-P

PANSS-N

PANSS-T

36.4°C 36.6°C N/A

0.11 0.09 N/A

7090 6520 N/A

172.9 159.4 N/A

981.9 559 N/A

2.27 2.08 N/A

+ — N/A

21 25 25

29 20 15

30 24 25

117 85 75

Temp indicates body temperature; CRP, C-reactive protein (in mg/dL); WBC, white blood cell count (in μL); TGAb, antithyroglobulin antibody (in IU/mL); TPOAb, antithyroperoxidase antibody (in IU/mL); TRAb, thyrotrophin receptor antibody (in IU/L); NMDAR, N-methyl-D-aspartate receptor antibody; PANSS-P, N, T, PANSS–Positive, Negative, Total; N/A, not applicable.

patients had a tumor or abnormal MRI, EEG, or CSF. There are only 2 case reports of the efficacy of anti-inflammatory therapy and immunotherapy in patients who initially received a diagnosis of schizophrenia without neurological findings.5,6 These cases were first episodes and were quickly administered methylprednisolone and plasma exchange or added immunoglobulin. On the other hand, our case showed severe symptoms and chronic lack of treatment progress meeting the criteria of treatmentresistant schizophrenia.7 Previous reports did not mention a loss of NMDAR antibodies after these therapies. If the symptoms, including our case, are induced by physical conditions, it should not be referred to as “schizophrenia” according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition or International Classification of Diseases, 10th Revision, or they may comprise a special subgroup of schizophrenia. The reduction in the MMSE score in our case might be a sign of “organic brain syndrome.” Because the NMDAR antibody titer in the CSF was related to the clinical course and relapse of NMDAR encephalitis,8 it may also be related to the clinical course in a special subgroup of schizophrenia with NR1 antibodies. We should also consider the possibility of comorbidity with Hashimoto encephalitis9 because she had various thyroid autoantibodies. The prevalence of anti-GluRɛ2 (a subunit of NMDAR) antibodies was reported in CSF of patients with antithyroid antibodies.10 A normal EEG and absence of neurological findings and seizure are not typical of Hashimoto encephalitis, which is a steroid-responsive disorder.9 In our case, corticosteroids did not induce a quick response, but might have induced a delayed response. Aggressive anti-inflammatory therapy and immunotherapy may improve the prognosis of patients with anti-NMDAR antibodies and a special subgroup of treatmentresistant schizophrenia. ACKNOWLEDGMENT This study is partly supported by a grant from Zikei Institute of Psychiatry.

AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Mayuko Senda, MD Department of Neuropsychiatry Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences Okayama, Japan

Kazunori Bessho, MD Department of Psychiatry Okayama Psychiatric Medical Center Okayama, Japan

Etsuko Oshima, MD, PhD Shinji Sakamoto, MD Department of Neuropsychiatry Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama, Japan

Keiko Tanaka, MD, PhD Department of Neurology Kanazawa Medical University Ishikawa, Japan

Ko Tsutsui, MD, PhD Takashi Kanbayashi, MD, PhD Department of Neuropsychiatry Akita University Akita, Japan

Manabu Takaki, MD, PhD Department of Neuropsychiatry Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama, Japan [email protected]

Bunta Yoshimura, MD Department of Neuropsychiatry Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Department of Psychiatry Okayama Psychiatric Medical Center Okayama, Japan

REFERENCES 1. Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti–N-methyl-D-aspartate receptor encephalitis. JAMA Neurol. 2013;70: 1133–1139. 2. Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory


investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74. 3. Tsutsui K, Kanbayashi T, Tanaka K, et al. Anti-NMDA-receptor antibody detected in encephalitis, schizophrenia, and narcolepsy with psychotic features. BMC Psychiatry. 2012;12:37. 4. Steiner J, Walter M, Glanz W, et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry. 2013;70:271–278. 5. Zandi MS, Irani SR, Lang B, et al. Disease-relevant autoantibodies in first episode schizophrenia. J Neurol. 2011;258:686–688. 6. Kuppuswamy PS, Takala CR, Sola CL. Management of psychiatric symptoms in anti-NMDAR encephalitis: a case series, literature review and future directions. Gen Hosp Psychiatry. 2014;36:388–391. 7. Kane JM, Honigfeld G, Singer J, et al. Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull. 1988;24:62–67. 8. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol. 2014;13:167–177. 9. Shaw PJ, Walls TJ, Newman PK, et al. Hashimoto’s encephalopathy: a steroid-responsive disorder associated with high anti-thyroid antibody titers—report of 5 cases. Neurology. 1991;41:228–233. 10. Chiba Y, Katsuse O, Takahashi Y, et al. Anti-glutamate receptor ɛ2 antibodies in psychiatric patients with anti-thyroid autoantibodies—a prevalence study in Japan. Neurosci Lett. 2013;534:217–222.

Systemic Inflammatory Response Syndrome Associated With Clozapine and Successful Rechallenge A Case Report To the Editors: lozapine, a second-generation antipsychotic, has been suggested by clinical

C


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trials to be the pharmacological treatment of choice for refractory psychosis1 and may reduce suicidality in psychotic illness.2 Despite this efficacy when compared with other antipsychotic medications,1,3 its widespread use is often limited by its significant adverse effects,4 notably agranulocytosis, myocarditis, severe constipation, reduced seizure threshold, orthostatic hypotension, and metabolic syndrome.5 It is also associated with a benign, self-limiting fever following initiation of the medication that remits without treatment.6 However, it is not a commonly reported phenomenon that clozapine is associated with a rapidly progressing syndrome that is not attributed to classic neuroleptic malignant syndrome (NMS), involving multiple organ systems and meeting criteria for systemic inflammatory response syndrome (SIRS): (≥2 of) temperature greater than 38°C or less than 36°C, white blood cells less than 4.9 103/μL or greater than 12.9 103/μL and/or 10% bands, pulse greater than 90 beats/min, respirations greater than 20 breaths/min, or PCO2 greater than 2 mm Hg.7 Furthermore, there are few reports suggesting after such an occurrence a rechallenge with clozapine can be attempted. We encountered a patient with refractory psychosis who had been initiated on clozapine for the first time and subsequently presented to the hospital with persistent fever and lethargy. He then rapidly progressed to a syndrome involving his lungs, liver, kidneys, and blood that met criteria for SIRS. It was only after discontinuation of clozapine that his symptoms stabilized. Upon discontinuation of clozapine, the patient’s psychosis returned, and he was transferred to the inpatient psychiatric unit for further treatment. After several months of multiple failed antipsychotic drug trials using both first- and second-generation drugs, the patient was rechallenged with clozapine amid close monitoring and tolerated the medication with a vast improvement in his psychosis.

CASE REPORT The patient is a 30-year-old nonsmoking white man with a chronic history of schizoaffective disorder, bipolar type. He had not responded adequately to multiple trials of atypical antipsychotics and mood stabilizers and had been hospitalized several times since the onset of his illness in his late teens. He did not have any significant medical history or allergies and no prior suicide attempts. He presented to the hospital with chief complaint of lethargy and fever for the previous 3 days. The patient was febrile (39.4°C) and tachycardic (120s beats/min) on presentation with no reported abnormalities on imaging or laboratory values and no

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concerning signs on physical examination (no extrapyramidal symptoms). Mental status at presentation was unremarkable for signs of delirium or confusion; the patient was fully alert and oriented, with appropriate concentration and memory and no waxing/ waning quality to his consciousness. He did display some mild paranoia, but otherwise spoke of his psychotic symptoms in a past tense (ideas of reference, thought broadcasting, auditory hallucinations) and denied suicidality. The patient was prescribed clozapine 175 mg daily, olanzapine 10 mg daily, valproic acid 1500 mg daily, and lithium 600 mg daily at the time of admission and was taking all medications as prescribed; lithium and valproic acid levels were therapeutic. The patient’s outpatient psychiatrist revealed that the patient had been started on clozapine 2 weeks prior to admission because of persistent auditory hallucinations and poor functioning and was in the process of tapering off olanzapine and lithium. It was confirmed he had been maintained on lithium, valproic acid, and olanzapine for several months and had not had any adverse reactions to these medications. Upon admission to the hospital with diagnosis of SIRS to the medical service, lithium and olanzapine were discontinued, clozapine was maintained at 175 mg daily, and valproic acid maintained at 1500 mg daily in divided doses. By day 3, the patient developed dyspnea and required supplemental oxygen through nasal cannula, fever persisted (maximum temperature 40°C) despite treatment, and alanine aminotransferase trended up. By day 5, the patient began wheezing, alanine aminotransferase increased further (110 U/L), creatinine and creatine phosphokinase (CPK) trended upward (1.32 mg/dL and 400 μg/L), bicarbonate trended downward (15 mEq/L), and procalcitonin (0.86 μg/L), erythrocyte sedimentation rate (59 mm/h), and lactate dehydrogenase (255 U/L) were all elevated. The patient was transferred to the intensive care unit, and clozapine was decreased to 100 mg daily. Despite extensive workup to rule out infectious or autoimmune disease, the patient’s fever and wheezing persisted, and no etiology was identified. Computed tomography imaging showed bilateral pleural effusions, renal fluid, and hepatomegaly; liver function tests remained elevated, bicarbonate was low, creatinine trended upward (1.59), and CPK peaked (585 μg/L). White blood cells also later spiked on day 8 (13.89 103/μL), and the patient became delirious. Confusion persisted, and clozapine was stopped on day 9 with valproic acid discontinued the following day. Although after discontinuation the patient’s psychosis and agitation resurfaced, his

physical symptoms, delirium, and laboratory values rapidly returned to baseline, and 5 days after stopping clozapine, he was transferred to the inpatient psychiatric unit for further treatment, with no recurrence of physical symptoms. Upon transfer, the patient was taking haloperidol 20 mg daily in divided doses, and this was discontinued because of severe akathisia. Over the next several months, the patient underwent trials of perphenazine (maximum 64 mg daily), fluphenazine (maximum 20 mg daily), and risperidone (maximum 8 mg daily); all were ineffective in treating his psychosis. He was noted to be internally preoccupied, delusional, socially withdrawn, emotionally distressed, and agitated. Furthermore, despite having no history of suicidal ideation prior to admission, he attempted suicide via hanging while on the inpatient unit and had been contemplating it for several days prior. Although the team had been reluctant to restart clozapine given previous reaction and recommended electroconvulsive therapy for the patient, both patient and family were resistant to this idea and opted to rechallenge with clozapine before considering electroconvulsive therapy. The team agreed to this with stringent monitoring, especially given his recent serious suicide attempt and clozapine’s antisuicide properties.2 The patient was subsequently administered clozapine with testing every 48 hours (complete blood count, renal panel, liver panel, and electrocardiography to monitor corrected QT interval). Clozapine dose was increased daily by 25 mg, and the patient tolerated this trial without adverse effects or major laboratory abnormalities, reaching daily dose of 400 mg. After clozapine was maximized, he was subsequently administered divalproex sodium up to a daily dose of 1000 mg, also well tolerated. The patient improved dramatically, and according to his family, he returned to his baseline and was safe for discharge home. He was discharged to a partial hospital program and at the time of this writing continues to do well outside the hospital on this regimen.

DISCUSSION The beginnings of multisystem syndrome may be misdiagnosed as benign fever following initiation of clozapine until the patient shows more severe signs of illness requiring medical intervention. This presents a complicated problem, as patients in whom clozapine is initiated are often chronic mentally ill patients with multiple failed medication trials.1,3 Treatment teams may be reluctant to stop medications in this population and choose to continue despite fever because evidence suggests it is likely



to be benign and self-limiting6; this was the case with our patient as well. Although admitting diagnosis was SIRS, this fails to identify the etiology of his presentation, as SIRS is simply a collection of symptoms intended to establish severity rather than a specific illness. Prominent among the differentials for this patient’s condition is atypical NMS. Although this patient did not have the classic hallmarks of NMS (rigidity, CPK >4 times of upper limit) as per Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, he did have many other signs such as hyperthermia, mental status changes, autonomic instability, and tachycardia; recent expert consensus suggests that this is sufficient to make a diagnosis of NMS.8 Furthermore, it has been reported that NMS secondary to clozapine can often present atypically without extrapyramidal signs, and CPK elevation can be less pronounced.9 There are reports of liver, kidney, and respiratory failure in some cases as well. Using the Delphi scale, our patient scored a 73/ 100, suggesting he had atypical NMS.9 Also worth mentioning is that the patient was also on lithium prior to admission, which has been implicated in NMS as well.10 Another differential diagnosis to consider is valproate-induced hyperammonemic encephalopathy.10 Valproate-induced hyperammonemic encephalopathy is characterized by mental status changes, vomiting, headache, seizures, and focal neurological deficits that are potentially associated with hyperammonemia-induced encephalopathy. Despite a valproic acid level within normal limits and routine laboratory work showing no abnormalities, this condition can occur, and when valproic acid is ceased, patients experience a speedy recovery. Although our patient did meet some of the criteria for valproate-induced hyperammonemic encephalopathy as he was taking valproic acid and recovered quickly upon its cessation, the patient’s ammonia level was checked the day prior to cessation and was 51 μmol/L. The patient did not exhibit vomiting, headache, seizure activity, or focal neurological deficits on examination. Other considerations are unspecified viral illness that was time limited and remitted with supportive care and accounted for the multisystem organ involvement in our patient and an unspecified autoimmune reaction given the patient’s elevated erythrocyte sedimentation rate. The major question that this report raises is the need for guidelines for rechallenging clozapine after a patient experiences multisystem organ involvement. There are some reported cases of patients tolerating retrial following NMS,11 but no evidencebased suggestions from controlled studies

for the time course between symptoms and restart, guidelines on monitoring during rechallenge, or potential contraindications. Our patient had a 4- to 5-month gap between discontinuing his clozapine and initiating rechallenge, with tight monitoring. Given clozapine’s efficacy as an antipsychotic in treatment-refractory psychosis as well as its protective qualities against suicidality, this issue must be clarified amid growing evidence that a rechallenge is possible. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Ravi Sivaperumal Ramasamy, MD Department of Psychiatry SUNY Stony Brook University Hospital Stony Brook, NY [email protected] Brian Bronson, MD Consult and Liaison Psychiatry SUNY Stony Brook University Hospital Stony Brook, NY Mark Lerman, DO Department of Psychiatry SUNY Stony Brook University Hospital Stony Brook, NY

REFERENCES 1. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600–610. 2. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidality in schizophrenia: international suicide prevention trial. Arch Gen Psychiatry. 2003;60:82–91. 3. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–796. 4. Baldessarini RJ, Frankenburg FR. Clozapine: a novel antipsychotic agent. N Engl J Med. 1991; 324:746–754. 5. Miller DD. Review and management of clozapine side effects. J Clin Psychiatry. 2000;61:14–17. 6. Lowe CM, Grube RR, Scates AC. Characterization and clinical management of clozapine-induced fever. Ann Pharmacother. 2007;41:1700–1704. 7. Klein Klouwenberg P, Ong D, Bonten M, et al. Classification of sepsis, severe sepsis, and septic shock: the impact of minor variations in data capture and definition of SIRS criteria. Intensive Care Med. 2012;38:811–819. 8. Gurrera RJ, Caroff SN, Cohen A, et al. An international consensus study of neuroleptic malignant syndrome diagnostic criteria using


Letters to the Editors the Delphi method. J Clin Psychiatry. 2011;72: 1222–1228. 9. Sachdev P, Kruk J, Kneebone M, et al. Clozapine-induced neuroleptic malignant syndrome: review and report of new cases. J Clin Psychopharmacol. 1995;15:365–371. 10. Verma R, Kori P. Valproate-induced encephalopathy with predominant pancerebellar syndrome. Indian J Pharmacol. 2012;44:129–130. 11. Manu P, Sarpal D, Muir O, et al. When can patients with potentially life-threatening adverse effects be rechallenged with clozapine? A systematic review of the published literature. Schizophr Res. 2012;134:180–186.

Three Cases of Late Onset Angioedema in Nursing Home Human Immunodeficiency Virus Patients on Ritonavir and Risperidone To the Editors: ngioedema is defined as “a localized edematous reaction of the deep dermis or subcutaneous or submucosal tissues appearing as giant wheals.”1 Extravasation of fluid from intravascular to extravascular compartments in response to an inflammatory agent underlies the basic mechanism of angioedema, which is thought to be a type 1 hypersensitivity reaction (IgE-mediated). The starling equation accounts for the movement of fluid between compartments (net filtration = Kc [change in hydraulic pressure − change in oncotic pressure]), explaining the edema, because there is a decrease in capillary cell adhesions upon exposure to an insulting agent (filtration coefficient, Kc) and permeation of fluid out of the blood vessels.2 Many drugs have been discussed in scientific literature as causes of angioedema, including, perhaps most famously, ACE inhibitors. One of the lesser-known medications that has been linked with angioedema is the atypical antipsychotic risperidone, and a number of case reports have been published regarding this association.3–5 Risperidone, commonly used to treat manic episodes of bipolar disorder and schizophrenia among other mental illnesses, is a transient dopamine D2 receptor and serotonin 5-HT3 antagonist.6 It is metabolized by the liver via the “formation of 9-hydroxyrisperidone,” an active metabolite, which is the most important metabolic pathway of risperidone in humans.7 Specifically, as Feng describes in Naunyn-Schmiedeberg's Archives

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of Pharmacology, “the enzymes CYPs 2D6, 3A4, and 3A5 were found to be the ones capable of metabolizing risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4, and 0.2 pmol, pmol(−1), CYP min(−1), respectively.7 Thus, CYP2D6 is a major contributor in eliminating risperidone from the human body. Another drug, ritonavir, a protease inhibitor commonly used in the treatment of human immunodeficiency virus (HIV) as part of highly active antiretroviral treatment to decrease the burden of HIV, has been described in using the CYP2D6 pathway in its metabolism. In an article published in the Journal of Pharmacology and Experimental Therapeutics, Kumar et al. state that “the HIV-1 protease inhibitor ritonavir (ABT-538) undergoes cytochrome P450-mediated biotransformation in human liver microsomes.”8 The article goes on to add that “ritonavir was (also) found to be an inhibitor of the reactions mediated by CYP2D6.”8 Presumably, in a patient utilizing both risperidone and ritonavir, drug-drug interaction would then be expected and should be monitored. Here we present 3 cases of patients residing in a nursing home setting, diagnosed with HIV/acquired immune deficiency syndrome and comorbid psychiatric illnesses, who were prescribed both risperidone and ritonavir. We aim to bring awareness to the possible complications of using these (or similarly acting) medications together to avoid negative outcomes in patients (Table 1).

CASE REPORTS C.P. is a 63-year-old woman with a history of HIV, hypertension, schizoaffective disorder, and polysubstance use in remission. She was transferred from an inpatient medical unit to the nursing home facility for long term care. She was diagnosed with HIV during her admission on the medical floor and was started on emtricitabine and tenovir, ritonvir, darunavir, escitalopram and continued on amlodipine. During her stay at the facility, she exhibited symptoms of mania and agitation for which she was started

TABLE 1. Antipsychotics Associated With Causing Angioedema Risperidone Lurasidone Olanzapine Iloperidone Ziprasidone

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Haloperidol Droperidol Clozapine Chlorpromazine Trifluoperazine


on risperidone 1 mg twice per day then increased to 2 mg twice per day. After 5 months of stabilization and improvement of her symptoms, she started to develop severe swelling of face and feet. Complete laboratory blood work were found to be within normal limits. All her medications were reviewed, and because risperidone was the only new medication added to the regimen, it was discontinued, after which the swelling resolved completely. She was then started on another antipsychotic, and no further swelling was observed. T.J. is a 42-year-old man with history of HIV, seizure disorder, hypertension, bilateral retinitis with retinal necrosis, history of alcohol use, and psychosis. He was referred to a nursing home facility for long-term care. On admission, his medications were risperidone 0.5 mg twice per day, emtricitabine and tenovir, lopinavir + ritonavir, thiamine, metoprolol and amlodipine. Risperidone was gradually increased to 2 mg twice a day, to control symptoms of psychosis, aggression and confusion, after all medical causes of delirium were ruled out. Patient did show improvement in symptoms of aggression. However, the team started to notice, after 6 months, generalized swelling of the body, more so of the face and both arms. Basic laboratory blood tests were normal, and after medication review, risperidone was decreased to 1 mg twice per day slowly and then eventually discontinued. Swelling resolved completely after several days. Patient was then switched and maintained on haloperidol. A.B. is a 50-year-old man with a history of HIV and schizophrenia. He was referred to a nursing home facility from his community provider due to being unable to take care of activities of daily living, recurrent falls, declining cognitive functioning, and history of medication noncompliance. His medications on admission were baclofen, darunavir, ritonavir, emtricitabine, and tenovir. He was started on risperidone 0.5 mg twice per day for symptoms of paranoia, which was increased gradually to 3 mg twice per day within a year. His psychiatric symptoms improved but swelling of the face, and the arms were observed after 15 months of having been on risperidone. Risperidone was then discontinued, and he was started on aripiprazole. Swelling slowly disappeared after discontinuation of risperidone.

DISCUSSION At the end of 2010, an estimated 1.1 million persons aged 13 years or older were living with HIV infection in the United States.9 The ongoing development of treatment for

HIV and acquired immune deficiency syndrome is such that HIV is no longer an acute, progressive, and fatal syndrome, but instead is now a long-term, chronic illness with high incidence of comorbidities, such as psychiatric and neuropsychiatric manifestations occurring as a result of the primary HIV disease. Antiretroviral therapy may even precipitate or worsen psychiatric disorders for some of these patients.10 Angioedema (which can present within 1 to 2 hours of exposure to an acute allergen) can also present days or months after first taking these medications, or as a result of interaction of 2 or more medications. It is most commonly observed affecting the lips and eyes (periorbital area). Other commonly involved areas may include the face, hands, feet, and genitalia. However, this is not always visually evident, as in cases involving the gastrointestinal tract. Ritonavir is a very potent inhibitor of CYP3A and CYP2D6, and affects CYP2C9/10 to a lesser extent. Its inhibitory potency depends on the presence of both the 5-thiazolyl and 2-(1-methylethyl) thiazolyl groups. It has been proposed that it is oxidized by CYP3A to a chemically reactive fragment containing the 2-(1-methylethyl) thiazolyl group that causes enzyme inactivation.11 The extent to which an inhibitor (such as ritonivir) affects the metabolism of a drug depends upon factors, such as the dose and the ability of the inhibitor to bind to the enzyme.12 We postulate that the inhibited drug (ie, risperidone) may then accumulate, increasing its serum levels and leading to a significant potential for frequent pharmacological interactions and more side effects. All 3 patients taking ritonovir and risperidone had no documented evidence of edema before the incident. Risperidone serum level was not performed in these cases. However, the Naranjo Adverse Drug Reaction Probability Scale was calculated, and all 3 cases scored 6, 7, and 7, respectively, indicating probable association. After carefully reviewing the side effect profile of all medications provided, we attributed this late-onset presentation to the possibility of drug interaction with ritonivir via CPY2D6 inhibition on risperidone. We observed that despite different dosage regimens of risperidone, they all developed edema after several months of receiving both medications. All patients continued to be on ritonovir, and no further evidence of edema was observed.

AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest.



Luisa S. Gonzalez, MD Department of Psychiatry Albert Einstein College Of Medicine - Bronx Lebanon Hospital Center Bronx, NY [email protected]

Kavita Kothari, MD David A. Kasle, BA Department of Psychiatry Albert Einstein College Of Medicine - Bronx Lebanon Hospital Center Bronx, NY

REFERENCES 1. Dorland W. Dorland's illustrated medical dictionary. (32nd ed). Philadelphia, PA: Saunders; 2012:82. 2. Taylor AE. Capillary fluid filtration. Starling forces and lymph flow. Circ Res. 1981; 49:557–575. 3. Soumya R. Angioneurotic edema with risperidone: a case report and review of literature. Gen Hosp Psychiatry. 2010;32:646. e1–646.e3. 4. Kores Plesnicar B, Vitorovic S, Zalar B, et al. Three challenges and a rechallenge episode of angio-oedema occurring in treatment with risperidone. Eur Psychiatry. 2001;16: 506–507. 5. Cooney C, Nagy A. Angio-oedema associated with risperidone. BMJ. 1995; 311:1204. 6. Horacek J. Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia. CNS Drugs. 2006;20: 389–409. 7. Fang J, Bourin M, Baker GB. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4. Naunyn Schmiedebergs Arch Pharmacol. 1999;359: 147–151. 8. Kumar G, Rodrigues AD, Buko AM, et al. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther. 1996;277:423–431. 9. CDC. HIV/AIDS. Basic statistics: how many people are living with HIV in the United States? Atlanta, GA: US Department of Health and Human Services, CDC; 2014. 10. Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral agents. AIDS. 2002;16: 1201–1215. 11. Montellano P. Cytochrome P450 structure, mechanism, and biochemistry. 3rd ed. New York: Kluwer Academic/Plenum; 2005:450. 12. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76: 391–396.

Rhabdomyolysis With Risperidone and Escitalopram Coadministration A Case Report To the Editors: habdomyolysis is a potentially lifethreatening disease that is characterized by the damage of skeletal muscle cell membranes and the release of toxic intracellular contents. It can vary from relatively asymptomatic elevations in creatine phosphokinase (CK) to acute renal failure, shock, and death. The causes of rhabdomyolysis are varied and include hereditary genetic mutations, trauma, intense exercise, electrolyte abnormalities, metabolic disorders, infections, toxins, and medications.1 Antipsychotics have been implicated in rhabdomyolysis, both in association with neuroleptic malignant syndrome (NMS) and independent of it.2 We report a unique case of rhabdomyolysis in an adult patient taking risperidone and escitalopram without features of NMS or the presence of other causative agents.

R

CASE REPORT Mr B is a 25-year-old African American man with no significant psychiatric or medical history who was admitted to an inpatient psychiatric hospital for depression with suicidal ideation and thought disorganization. He denied the use of alcohol or other substances, was not taking any medications or herbal supplements, and reported no allergies. He had no family history of psychiatric or medical illnesses, including congenital muscle diseases. Mr B had started psychotherapy approximately 2 months before presentation but had not been prescribed any psychotropic agents. Vital signs, physical examination, and blood and urine studies, including urine toxicology, were within normal limits. Mr B was initially started on escitalopram 10 mg daily for neurovegetative symptoms and suicidality and mirtazapine 15 mg QHS to improve sleep and appetite. Mirtazapine was discontinued after 3 days because of dizziness. One week after starting escitalopram, risperidone was initiated at 0.5 mg QHS and, after 1 dose, titrated up to 1 mg. Mr B tolerated escitalopram and risperidone well, with no signs of sedation, myalgias, abdominal pain, extrapyramidal symptoms, akathisia, headache, seizurelike activity, or changes in mental status. All laboratory studies remained within normal limits. Ten days after starting escitalopram and 4 days after starting risperidone, Mr B complained of intermittent palpitations and



episodes of substernal chest pressure that spontaneously resolved after a few minutes. He denied muscle stiffness, calf tenderness, muscle aches, fevers, urinary symptoms, recent immobility, strenuous exercise, nausea, and vomiting. He also denied using illicit substances, and repeat toxicology screen continued to be negative for opiates, amphetamines, and cocaine. Vital signs were within normal limits (blood pressure was 126/80, and temperature was 98.4°F), and he had no rigidity of extremities, myoclonus, focal neurological deficits, rash, or changes in mental status. An acute coronary syndrome work-up was initiated, revealing a normal electrocardiogram and negative troponins but a CK of 11,589 U/L (normal, 10–160 U/L). Other laboratory studies were within normal limits (blood urea nitrogen was 10 mg/dL, creatinine level was 0.9 mg/dL, potassium was 4.2 mmol/L, sodium was 141 mmol/L, and CK-MB isoenzyme was 0.5 ng/mL) except for aspartate aminotransferase, which was 208 (normal, 8–38) U/L, and alanine aminotransferase, which was 101 (normal, 10–35) U/L. All psychiatric medications were discontinued, and Mr B received aggressive intravenous hydration. His CK progressively improved until his discharge 2 days later when it was 1624 U/L. Medical work-up did not reveal evidence of thyroid dysfunction, infection, or renal failure. His mood and thought organization continued to improve without treatment, and he was discharged to his outpatient psychiatrist for further management. Subsequent treatment and symptoms are unknown because the patient did not receive additional care at our hospital.

DISCUSSION Mr B had no previous medical illness, was not taking any medications or using illicit substances, and had no laboratory abnormalities upon admission. Shortly after initiating psychiatric medications, he developed rhabdomyolysis with a CK of 11,589 U/L. The resolution of rhabdomyolysis after drug discontinuation, as well as the lack of evidence for an inflammatory myopathy, infection, recent trauma, strenuous exercise, thyroid disease, NMS, seizure, or an acute coronary syndrome, suggests a causal relationship between Mr B's use of psychotropic agents and the development of rhabdomyolysis. Mr B's rhabdomyolysis was likely caused by either risperidone alone or by the additive effect of risperidone and escitalopram. Although the association between rhabdomyolysis and antipsychotic use has been shown in several case reports, risperidoneassociated rhabdomyolysis has been seen www.psychopharmacology.com

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only in the setting of NMS or in conjunction with other agents that independently cause rhabdomyolysis, such as statins, mirtazapine, or antipsychotic polypharmacy.3–5 The only cases of rhabdomyolysis in patients on risperidone monotherapy in the absence of NMS come from a study of children and adolescents in which onset occurred within 2 months of treatment and was preceded by muscle and abdominal pain.6 The incidence of rhabdomyolysis among antipsychotic users is significantly higher than in the general population, with 1 review finding that 10.5% of patients diagnosed with rhabdomyolysis were concomitantly taking an antipsychotic.3 A study of 475 hospitalized adults and children similarly found that 11% of rhabdomyolysis cases in the absence of NMS were caused by medications, most frequently first- and secondgeneration antipsychotics.7 The exact mechanism of antipsychoticrelated rhabdomyolysis is unknown. One hypothesis suggests that blockade of the serotonin 5-hydroxytryptamine 2A receptor in the skeletal muscle undermines glucose uptake and causes changes in the sarcolemma that increase permeability to CK.8,9 Antipsychotic-related rhabdomyolysis may also be caused by dopaminergic blockade of the nigrostriatal pathway, leading to involuntary movements, such as rigidity, stiffness, parkinsonism, and akathisia, that result in CK elevations.9 The use of antipsychotics with behavioral controls, such as restraints and manual holds, or electroshock therapy may also increase the incidence of rhabdomyolysis through intense, isometric movements. Unlike statins, there does not seem to be a dose-dependent relationship between antipsychotic use and the development of rhabdomyolysis.10 In this case, a serotonergic mechanism seems most likely, given the absence of behavioral controls or witnessed neuromuscular events. In contrast to risperidone, escitalopram and mirtazapine are unlikely to be individually responsible for Mr B's condition, as reports of rhabdomyolysis with antidepressant use are rare and usually occur in the setting of overdose, serotonin syndrome, or coadministration with a statin.11,12 To date, there has been only 1 report of rhabdomyolysis in a patient on escitalopram monotherapy in the absence of other risk factors.13 Mirtazapine, which was discontinued after 3 days, has only been linked to rhabdomyolysis in the setting of serotonin syndrome, which was not evident in this case. Mr B's rhabdomyolysis may have been caused by the interaction between risperidone and escitalopram. Risperidone is metabolized by the CYP2D6 enzyme, which is moderately inhibited by escitalopram. Therefore,

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coadministration may increase levels of risperidone.14 Escitalopram, when used in conjunction with risperidone, has also been shown to significantly enhance both cortical dopamine output and cortical N-methyl-D-aspartate receptor-mediated transmission,15 which could theoretically contribute to higher rates of neuromuscular events. In addition, up to 7% of African Americans are reported to have reduced activity of the CYP2D6 enzyme, potentially leading to elevated risperidone levels.16 Mr B developed rhabdomyolysis shortly after the initiation of psychotropic agents. The absence of other causes of rhabdomyolysis, as well as its resolution upon drug withdrawal, suggests a causal relationship between risperidone, possibly in conjunction with escitalopram, and rhabdomyolysis. Although there are currently no guidelines for rhabdomyolysis monitoring in patients who are starting antipsychotic therapy, close observation for clinical or laboratory evidence of rhabdomyolysis is recommended to prevent potentially lifethreatening events. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Alanna Chait Mermelstein, MD Department of Psychiatry New York Presbyterian/Weill Cornell Medical College New York, NY [email protected]

Joseph Mermelstein, MD Department of Internal Medicine Mount Sinai Beth Israel/Icahn School of Medicine New York, NY

REFERENCES 1. Giannoglou GD, Yiannis SC, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med. 2007;18: 90–100. 2. Aggarwal R, Guanci N, Marambage K, et al. A patient with multiple episodes of rhabdomyolysis induced by different neuroleptics. Psychosomatics. 2014;55:404–408. 3. Packard K, Price P, Hanson A. Antipsychotic use and the risk of rhabdomyolysis. J Pharm Pract. 2014;27:501–512. 4. Raitasuo V, Vataja R, Elomaa E. Risperidone-induced neuroleptic malignant syndrome in young patient. Lancet. 1994; 344:1705. 5. Levin GM, Lazowick AL, Powell HS. Neuroleptic malignant syndrome with risperidone. J Clin Psychopharmacol. 1996;16:192–193.

6. Star K, Iessa N, Almandil NB, et al. Rhabdomyolysis reported for children and adolescents treated with antipsychotic medicines: a case series analysis. J Child Adolesc Psychopharmacol. 2012;22:440–451. 7. Melli G, Chaudhry V, Cornblath DR. Rhabdomyolysis: an evaluation of 475 hospitalized patients. Medicine (Baltimore). 2005;84:377–385. 8. Bishara D, Taylor D. Upcoming agents for the treatment of schizophrenia: mechanism of action, efficacy and tolerability. Drugs. 2008; 68:2269–2292. 9. Devarajan S, Dursun SM. Antipsychotic drugs, serum creatine kinase (CPK) and possible mechanisms. Psychopharmacology (Berl). 2000;152:122. 10. Cooper JM, Jones AL. Neuroleptic malignant syndrome or a statin drug reaction? A case report. Clin Neuropharmacol. 2009;32: 348–349. 11. Huska MT, Catalano G, Catalano MC. Serotonin syndrome associated with the use of escitalopram. CNS Spectr. 2007;12: 270–274. 12. Gareri P, Segura-García C, De Fazio P, et al. Sertraline-induced rhabdomyolysis in an elderly patient with dementia and comorbidities. Ann Pharmacother. 2009;43:1354–1359. 13. Lewien A, Kranaster L, Hoyer C, et al. Escitalopram-related rhabdomyolysis. J Clin Psychopharmacol. 2011;31:251–253. 14. Rao P, Bhagat N, Shah B, et al. Interaction between escitalopram and risperidone. Indian J Psychiatry. 2005;47:65. 15. Marcus EL, Vass A, Zislin J. Marked elevation of serum creatine kinase associated with olanzapine therapy. Ann Pharmacother. 1999;33:697–700. 16. Cai WM, Nikoloff DM, Pan RM, et al. CYP2D6 genetic variation in healthy adults and psychiatric African-American subjects: implications for clinical practice and genetic testing. Pharmacogenomics J. 2006;6: 343–350.

Addiction to Armodafinil and Modafinil Presenting With Paranoia To the Editors:

CASE REPORT Armodafinil, the R-enantiomer of modafinil, was FDA-approved for the treatment of excessive daytime sleepiness associated with shift work, obstructive sleep apnea, and narcolepsy in 2007. Modafinil and armodafinil have been touted as safe and effective for the treatment of negative symptoms of



schizophrenia.1 Modafinil has also been investigated as a potential treatment for cocaine dependence2 and amphetamine dependence.3 The exact mechanism of action of both modafinil and armodafinil remains unclear, but evidence supports the involvement of the dopaminergic system.4 There are only a couple of studies in humans that suggest addictive potential with modafinil, but no similar studies regarding armodafinil were available at the time of writing this article.5,6 The authors present a case of apparent addiction to modafinil and armodafinil presenting with paranoid delusions. Mr P was a 54 year old with a selfreported history of stimulant misuse (modafinil, crack cocaine, and mixed amphetamine salts) who presented to the emergency department (ED) complaining of anxiety that he attributed to his not having taken benzodiazepines for 4 or 5 days. He had reportedly presented to the same emergency room several times during the previous month requesting clonazepam refills and had ultimately been referred to his primary care physician but did not make it to the appointment that had been scheduled for him. He had previously been fired by his primary care physician for abuse of medications. He also reported feeling “paranoid” at times—stating that he did not like his neighbor and was having “difficulty” with her. His substance use history was significant for having taken 1200 mg of armodafinil daily, despite only being prescribed 250 mg per day. Armodafinil had first been prescribed to him one week prior to this ED visit. He had previously abused modafinil for 2 years (obtained via the internet) because “It made ya feel good—like you are smoking crack cocaine.” He claimed that he had switched to modafinil after several years of abusing mixed amphetamine salts and crack cocaine. A comprehensive metabolic panel obtained in the ED was significant for hyponatremia (Na = 127 mmol/L) and a 7-panel urine drug test was negative for PCP, benzodiazepines, cocaine, amphetamines, cannabinoids, opiates, and barbiturates. A review of the state's automated prescription reporting system over the preceding year indicated that he had received only clonazepam throughout that time and during the week before admission had received 2 prescriptions totaling 30 tablets of armodafinil 250 mg. The ED physician diagnosed him with psychosis, anxiety, paranoia, and hyponatremia and admitted him to a medical unit for further psychiatric and neurological work-up. That night, he had a witnessed seizure and was administered lorazepam. He reported a history of seizures that he claimed were related to prior episodes of benzodiazepine withdrawal.

Psychiatric consultation the next day reported manic behavior (flight of ideas, inappropriate sexual comments to female staff, pressured speech, and incessant talking) and delusions regarding his neighbor (“she's in my head all the time… lack of privacy, looking in my window…telling me to get to work…getting mail from others that used to live there”). He was started on clonazepam 2 mg by mouth (PO) 3 times per day (TID), gabapentin 300 mg PO TID, and olanzapine 5 mg PO 2 times per day. Repeat CMP revealed that his sodium level had normalized (Na = 136 mmol/L). The following day, clonazepam was decreased to 1 mg 2 times per day and olanzapine changed to 10 mg PO at bedtime. He told the psychiatric nurse practitioner that he felt like he was “ready to die.” He then explained his feelings by stating that he was a long-time stimulant user and that, without them, he feels extremely drowsy. He subsequently asked: “You don't have any Adderall do you?” On hospital day 4, he was medically cleared and transferred to an inpatient detoxification unit as the consulting psychiatrist felt that his psychosis had resolved by the time of transfer. On the detoxification unit, he stated that he was convinced that his neighbor was listening in on his conversations but, at times, questioned the validity of his thoughts. He denied on multiple occasions that he had ever heard the voice of his neighbor or anyone else when they were not physically present. When a psychiatry resident suggested his family be contacted by the treatment team, he responded in a paranoid fashion, “How do you know my brother?” The following day, his anxiety increased, and he was later noted to be anxious with restlessness and “abrupt movements.” He reported “panic, racing thoughts, and I can't shut up.” He further stated “When I was about 12 years old I told my mother I had racing thoughts, they went 'round and 'round in my mind and wouldn't quit. She gave me a Valium and I began to take them and steal them from her. I was taking them all the way through junior high and high school and I have been taking them ever since. I buy them from India and all over the place.” On his last day on the detox unit, he complained of insomnia: “But this is nothing new. I think I am just anxious to get out of here by tomorrow.” He later began pushing on the locked doors leading out of the unit, demanding loudly: “I want to leave right now. I want to run a marathon. My dad's office is across the street and I will go see him.” His judgment was felt to be impaired, putting him at risk for self-harm, and he was therefore transferred to a locked



psychiatric unit on an involuntary basis. His psychiatric condition stabilized, and there was no further incident throughout that night. He was discharged home the next day on the following medications: gabapentin, 300 mg every 8 hours; thiamine, 100 mg TID; folic acid, 1 mg daily; and a 14-mg nicotine patch.

DISCUSSION This is the first case report of an individual with a prior history of a stimulant use disorder who characterized the use of high-dose modafinil as being similar to that of smoking crack cocaine. Human studies looking at the addictive potential of modafinil have reported that 800 mg of modafinil was similar to 90 mg of methylphenidate in terms of a “like the drug” response on a Drug Rating Questionnaire5 and that it was also similar to D-amphetamine in terms of “liking.”6 Modafinil has also been shown to have reinforcing qualities in humans under conditions of behavioral demand.7 There is also considerable evidence from animal studies that suggests that modafinil has addictive potential.8,9 Although modafinil and armodafinil have exhibited activity at several different receptor subtypes,10,11 it is their ability to bind to the dopamine transporter and thereby block reuptake of dopamine (DA) that has raised concerns about potential abuse liability. Both drugs bind to the dopamine transporter, though less potently than cocaine, and elevate DA levels in the shell of the nucleus accumbens—a characteristic common to drugs of abuse.12 Additionally, both drugs substituted for cocaine in mice trained to discriminate cocaine from saline, but they were less potent than cocaine.12 A few animal studies refute the addictive potential of modafinil.13–15 Also, an extensive review of the preclinical, clinical, and postmarketing data suggested that the abuse liability of modafinil is limited.16 The psychosis associated with this case is not unexpected, nor unusual, given the stimulant action of modafinil and armodafinil.17,18 Though the psychosis exhibited by this patient could have been secondary to benzodiazepine withdrawal, the absence of perceptual disturbances, clouded sensorium, or autonomic hyperactivity seems to suggest another etiology. Given that the patient had a well-documented seizure during his hospital stay; it is possible that his delusions may have been representative of interictal psychosis. The patient also exhibited manic symptoms during his hospital stay that initially resolved within 24 hours, but may have reappeared toward the very end of his stay on the detox unit. www.psychopharmacology.com

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This case should heighten awareness regarding the potential abuse liability of modafinil and armodafinil and call into question the notion that either medication may be a safer alternative to amphetaminelike stimulants in patients with known histories of addiction. This case also illustrates that, as has been reported previously with modafinil, armodafinil can induce psychosis.

AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Jason M. Jerry, MD, FAPA Alcohol and Drug Recovery Center Department of Psychiatry and Psychology The Cleveland Clinic and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland, OH [email protected] Nicole Shirvani, MD Department of Psychiatry and Psychology The Cleveland Clinic and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland, OH Roman Dale, MD Department of Psychiatry and Psychology The Cleveland Clinic and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland, OH

REFERENCES 1. Andrade C, Kisely S, Monteiro I, et al. Antipsychotic augmentation with modafinil or armodafinil for negative symptoms of schizophrenia: systematic review and meta-analysis of randomized controlled trials. J Psychiatr Res. 2015; 60:14–21. 2. Karila L, Gorelick D, Weinstein A, et al. New treatments for cocaine dependence: a focused review. Int J Neuropsychopharmacol. 2008;11: 425–438. 3. Pérez-Mañá C, Castells X, Torrens M, et al. Efficacy of psychostimulant drugs for amphetamine abuse or dependence. Cochrane Database Syst Rev. 2013;9: CD009695. 4. Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA. 2009;301: 1148–1154. 5. Jasinski DR. An evaluation of the abuse potential of modafinil using methylphenidate as a reference. J Psychopharmacol. 2000; 14:53–60.

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Journal of Clinical Psychopharmacology • Volume 36, Number 1, February 2016 6. Makris AP, Rush CR, Frederich RC, et al. Behavioral and subjective effects of D-amphetamine and modafinil in healthy adults. Exp Clin Psychopharmacol. 2007;15: 123–133. 7. Stoops WW, Lile JA, Fillmore MT, et al. Reinforcing effects of modafinil: influence of dose and behavioral demands following drug administration. Psychopharmacology (Berl). 2005;182:186–193. 8. Shuman T, Cai DJ, Sage JR, et al. Interactions between modafinil and cocaine during the induction of conditioned place preference and locomotor sensitization in mice: implications for addiction. Behav Brain Res. 2012;235: 105–112. 9. Andersen ML, Kessler E, Murnane KS, et al. Dopamine transporter-related effects of modafinil in rhesus monkeys. Psychopharmacology (Berl). 2010;210: 439–448. 10. Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry. 2006;67:554–566. 11. Gerrard P, Malcolm R. Mechanisms of modafinil: A review of current research. Neuropsychiatr Dis Treat. 2007;3:349–364. 12. Loland CJ, Mereu M, Okunola OM, et al. R-modafinil (armodafinil): a unique dopamine uptake inhibitor and potential medication for psychostimulant abuse. Biol Psychiatry. 2012; 72:405–413. 13. Deroche-Gamonet V, Darnaudéry M, Bruins-Slot L, et al. Study of the addictive potential of modafinil in naive and cocaine-experienced rats. Psychopharmacology (Berl). 2002;161:387–395. 14. Tahsili-Fahadan P, Carr GV, Harris GC, et al. Modafinil blocks reinstatement of extinguished opiate-seeking in rats: mediation by a glutamate mechanism. Neuropsychopharmacology. 2010; 35:2203–2210. 15. Paterson NE, Fedolak A, Olivier B, et al. Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents. Pharmacol Biochem Behav. 2010;95:449–456. 16. Myrick H, Malcolm R, Taylor B, et al. Modafinil: preclinical, clinical, and post-marketing surveillance—a review of abuse liability issues. Ann Clin Psychiatry. 2004;16: 101–109. 17. Prado E, Paholpak P, Ngo M, et al. Agitation and psychosis associated with dementia with Lewy bodies exacerbated by modafinil use. Am J Alzheimers Dis Other Demen. 2012;27: 468–473. 18. Rudhran V, Manjunatha N, John JP. High-dose, self-administered modafinil-related psychosis: is it the pedal in the prodrome of psychosis? J Clin Psychopharmacol. 2013; 33:576–577.

Nalmefene Mistakenly Prescribed to Reduce Alcohol Consumption in Patients Under Buprenorphine Substitution Therapy Resulting in Acute Opioid Withdrawal Management in an Emergency Setting To the Editors: any patients go to emergency departments (EDs) because of acute complications of substance use disorders. Drug interactions between opioid antagonists and opioid maintenance treatment in opioid users have already been described as case reports1,2 or case series3 focusing on naltrexone as an opiate antagonist. Nalmefene, a μ- and δ-opioid receptor antagonist and a partial κ-opioid receptor agonist, has been approved by the European Medicines Agency for the reduction of alcohol consumption in alcohol-dependent patients who have a high drinking-risk level without physical withdrawal symptoms and who do not require immediate detoxification.4 Nalmefene must not be used in patients receiving opioid maintenance therapy. We are unaware of any previous reports of an accidental association of nalmefene and buprenorphine (BUP) precipitating opioid withdrawal (OW). We present 2 patients on stable opioid maintenance with BUP who were inadvertently prescribed nalmefene to reduce alcohol consumption.

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CASE REPORTS Patient 1 A 47-year-old woman presented to the ED with acute OW 4 hours after she took a single oral dose of 18 mg nalmefene (Selincro; Lundbeck, Valby, Denmark), prescribed by her general practitioner. She had decided to decrease her alcohol consumption because the social services had been notified by a schoolteacher that she had been drunk when she had picked up her young son. She had been receiving BUP (8 mg/d) for several years because of a history of heroin use. She complained of nausea, dizziness, abdominal pain, rhinorrhea, myalgia, and acute agitation, which started within 30 minutes of nalmefene intake. She had already experienced OW, so she self-administered 36 mg of bromazepam with alcohol to alleviate her symptoms before attending the ED. Because she had observed a



temporal relationship between the overall onset of abdominal pain, gastrointestinal stress, and nalmefene intake, she believed that drinking alcohol would decrease these symptoms. At admission, physical examination showed elevated blood pressure (168/87 mm Hg); pulse, 110 beats per minute; normal temperature; and Glasgow Coma Scale, 13. Electrolytes and liver enzymes were normal, as was an electrocardiogram. Toxicology blood screen showed a blood alcohol concentration of 1.86 g/L and was positive for benzodiazepines. Urinary drug screen (Rapid Diagnostics; MP Biomedicals) was positive for benzodiazepines and BUP. The patient was admitted to the detoxification unit and reported taking BUP every morning at about 9:00 A.M. She was a regular smoker. She met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria for severe alcohol use disorder (AUD). She was given a polyionic perfusion solution, 100 mg of thiamine, and an oral dose of 20 mg diazepam with an additional 10 mg after 2 hours. Despite the treatment, symptoms worsened, and she became more agitated, complaining of abdominal pain and emesis. She was not confused, and neurological examination was unremarkable, so a computed tomography scan was not performed. Diazepam and cyamemazine were given to reduce agitation. Metopimazine, antispasmodics, and paracetamol were added to reduce abdominal pain. No opioid medication was delivered. Clinical signs of withdrawal syndrome persisted for approximately 10 hours before resolving. She was then referred to the addiction team and discharged on her original dose of BUP and bromazepam.

Patient 2 A 25-year-old man with antisocial personality disorder and a 4-year history of alcohol dependence had taken 7 mg BUP daily at 8:00 A.M. for many years. He went to the ED with a 2-hour history of agitation, tremor, nausea, and sweating. He reported that symptoms had started within 20 minutes after taking a single oral nalmefene dose of 18 mg, prescribed by his general practitioner (18 mg/d). Upon admission, the patient received 50 mg of oxazepam, with an additional 50 mg after 1 hour, associated with 100 mg of thiamine. He was also given cyamemazine 50 mg and additional 50 mg “as needed.” Toxicological tests showed a blood alcohol concentration of 0.66 g/L and were positive for benzodiazepines. Electrolytes, liver enzymes, and full blood count were normal, as was an electrocardiogram. Urinary drug

screen was positive for benzodiazepines and BUP (Rapid Diagnostics, MP Biomedicals). The patient was admitted to the detoxification unit where he received intravenous fluids and loading doses of oxazepam. His medical history, including AUD, past heroin abuse and current tobacco use, was reported by his brother. He had been treated with baclofen several months previously, but had discontinued the treatment without medical advice because he considered that it was not effective. His private general practitioner replaced baclofen with nalmefene to increase treatment adherence. The patient spent the night in observation and was discharged in the morning after being given his original dose of BUP. Follow-up was programmed with the substance misuse team. He met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria for severe AUD.

DISCUSSION Nalmefene, a selective opioid receptor ligand with antagonist activity at the μ and δ receptors and partial agonist activity at the κ receptor, is well known to emergency physicians (EPs) and has been used for years to reverse opioid overdose in the emergency setting.5 Given intravenously, nalmefene is useful because its action starts within 2 min of administration, and its antagonist effects are evident for more than 8 hours.6 In addition to its use in opioid overdose, nalmefene has been shown to be of interest in reducing alcohol consumption. It has now been licensed in this indication, given “as needed.”7 Accidental or intentional ingestion of an opioid antagonist in opioid-dependent patients will result in an acute OW reaction, as described with naltrexone in heroin users.1,2,8–10 The EPs asked for the specialized mobile addiction team to help in patient management. The questions raised by the EPs were: how long should the patient be observed? Is there a risk of acute worsening? Should the patient be observed in the detoxification unit where resuscitation can be performed? Should BUP be given at admission or as usual? What BUP dose should be given? From a pharmacological viewpoint, nalmefene is structurally similar to naltrexone but possesses a longer duration of action. Nalmefene is rapidly absorbed after oral administration and peak plasma level is reached within 90 minutes after ingestion. Its elimination half-life is 13.4 hours after a single dose and occupancy of μ-opioid receptors varies between 87.2% and 100% 3 hours after intake and persists up to 74 hours.11



The management of nalmefeneaccelerated OW should not differ from that of other acute OW. Titrated doses of opioids could aid in improving the withdrawal symptoms but is still debated. Some authors consider that methadone, BUP, and opioid agents are not appropriate in this emergency context,2,8 whereas others in a case of severe OW precipitated by nalmefene administered titrated doses of a short-acting opioid.12 It is important to underline the differences between our patients and those studied by Donnerstag et al,12 who were dependent on codeine or methadone. Because our patients were receiving BUP maintenance treatment, we believe that opioids were not indicated, first due to the antagonist potency of nalmefene and the difficulty in matching the pharmacokinetics of the agonist and antagonist, and second due to its high affinity to μ receptors requiring greater doses of opioids, with an increased risk of over-sedation and possible overdose. Moreover, it is known that BUP produces milder acute withdrawal than other full μ-opioid agonists at higher doses13 because of its “ceiling effect.” Given the high μ-receptor affinity and long-acting kinetics of BUP, we assume that there is very little risk in administering a full advance dose of BUP in the ED setting to suppress nalmefene-precipitated withdrawal. Several reasons could explain why the EPs did not give BUP. The EPs still have strong reservations about the routine use of such a medication in this setting due to the possibility of encouraging opioid-seeking persons to present to EDs claiming to have precipitated OW, although Berg et al14 observed that patients who received BUP were not more likely to return to the ED within 30 days for a drug-related visit. The EPs gave loading doses of benzodiazepines and cyamemazine for their sedative effects in treating agitation and to manage alcohol withdrawal, even if they should have suggested diagnoses other than acute alcohol withdrawal because both patients had reported taking alcohol and benzodiazepines before being admitted. Alcohol withdrawal should be systematically considered, especially in the ED, in every case of unexplained confusion and agitation in patients with a history of AUD. However, the association of nonspecific symptoms relating to different systems (psychological, motor, and somatic) can lead to misdiagnosis between alcohol withdrawal and OW syndromes. Generally, agitated patients admitted to the ED are totally unknown by the medical staff and require adequate sedation. No real consensus on the treatment of agitated patients exists, and there is no evidence that benzodiazepines are more effective than neuroleptics, which explains why both drugs are www.psychopharmacology.com

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prescribed in emergency wards.15 Nonetheless, benzodiazepines are the only approved medications to treat alcohol withdrawal and should have been preferred in this context where alcohol withdrawal was suspected, given the high risk of catatonia in this situation of GABAergic depletion.16 Cyamemazine and neuroleptics, whatever the class, including new antipsychotics, are less safe and may increase the risk of respiratory depression particularly in associated alcohol and OW syndromes. Moreover, they enhance the risk of dysrhythmia due to the hyperadrenergic states in withdrawal syndromes. Our patients met the criteria for severe AUD as a comorbid association with opioid dependence. Both substances, alcohol and opioids, are known to share close interrelations in the ventral tegmental area and nucleus accumbens. Alcohol consumption stimulates the endogenous release of opioids, which binds to μ and δ receptors. It thereby increases the release of dopamine in the nucleus accumbens, which induces reward and positive reinforcement effects. Alcohol intake is decreased by blocking opioid receptors, which explains the development of drugs acting as μ-receptor antagonists, such as naltrexone and more recently nalmefene. Buprenorphine, increasingly used in the treatment of opioid dependence, may be of value in AUD because of its antagonist effect on the μ receptor. This hypothesis has been put forward as BUP may be effective in reducing both opioid and alcohol use in patients with co-occurring AUD. Currently, there is no clear evidence concerning the effect of opioid maintenance therapy on alcohol consumption, as described by Soyka17 in a recent review. It is still debated whether adjusting the daily dose of BUP may decrease alcohol intake in patients with AUD. Nonetheless, the US Substance Abuse and Mental Health Services Administration concluded as follows in their clinical guidelines for the use of BUP in the treatment of opioid addiction: “Pharmacotherapy with buprenorphine for opioid addiction will not necessarily have a beneficial effect on an individual's use of other drugs. It is essential that patients be referred to treatment of addiction to other types of drugs when indicated… In addition, care must be exercised in the prescribing of buprenorphine for patients who abuse alcohol… because of the documented potential for fatal interactions.”17 In clinical practice, regarding the severity of alcohol use associated with benzodiazepines in both patients, we can assume that the daily dose of BUP should be increased to attempt to decrease other substance abuse. A recent study observed that alcohol craving was less with BUP than with methadone,18 but the BUP dose was higher than

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that prescribed to our patients. Given that both patients continued substance abuse despite opioid maintenance treatment, but due to the low dose of BUP prescribed, we can assume that treatment with BUP should be adjusted and daily dose increased. Then, after the dose of BUP has been optimized, first-line alcohol treatments (with the exception of μ-antagonist receptors) should be considered for patients who continue to drink. The incidence of comorbid AUD in patients with opioid addiction is increasing, and primary care clinicians and EPs need first to be familiar with significant drug-drug interactions, particularly when new agents are licensed for AUD. Second, these physicians require improved knowledge on substitution through more exhaustive continuing medical education programs. When their own abilities to treat are overwhelmed (eg, complex comorbid cases), they can refer patients toward specialized centers of care. Links between specialists and general practitioners must be reinforced by means of network structures, with intervision and supervision meetings, as it is known that many general practitioners and EPs believe they have neither the skills nor the expertise to deal with comorbid substance use disorders. We are aware of the limitations of our description, focusing only on clinical appreciation of 2 cases, but it actually reflects daily practice in an ED. Moreover, it allows for the collection of objective data and adds a novel contribution to the literature.

AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest.

Fanny Pélissier, MD Poisons and Substance Abuse Treatment Centre Toulouse-Purpan University Hospital Toulouse, France

Marie-Eve Rougé Bugat, MD, PhD Department of Primary Care Toulouse University Hospital University of Toulouse III and INSERM U 1027 Toulouse, France

Philippe Nubukpo, MD, PhD Department of Addiction Medicine Esquirol Hospital Limoges, France

Nicolas Franchitto, MD, PhD Poisons and Substance Abuse Treatment Centre Toulouse-Purpan University Hospital University of Toulouse III INSERM U 1027 Toulouse, France

and Department of Addiction Medicine Toulouse-Purpan University Hospital Toulouse, France [email protected]

REFERENCES 1. Singh SM, Sharma B. Unintentional rapid opioid detoxification: case report. Psychiatr Danub. 2009;21:65–67. 2. Yeo M, Campbell V, Bonomo Y, et al. Acute opioid withdrawal on accidental injection of naltrexone. J Paediatr Child Health. 2003;39: 315–317. 3. Hassanian-Moghaddam H, Afzali S, Pooya A. Withdrawal syndrome caused by naltrexone in opioid abusers. Hum Exp Toxicol. 2013;33: 561–567. 4. François C, Laramée P, Rahhali N, et al. A predictive microsimulation model to estimate the clinical relevance of reducing alcohol consumption in alcohol dependence. Eur Addict Res. 2014;20:269–284. 5. Kaplan JL, Marx JA. Effectiveness and safety of intravenous nalmefene for emergency department patients with suspected narcotic overdose: a pilot study. Ann Emerg Med. 1993;22:187–190. 6. Gal TJ, DiFazio CA. Prolonged antagonism of opioid action with intravenous nalmefene in man. Anesthesiology. 1986;64:175–180. 7. Paille F, Martini H. Nalmefene: a new approach to the treatment of alcohol dependence. Subst Abuse Rehabil. 2014;5:87–94. 8. Boyce SH, Armstrong PA, Stevenson J. Effect of innappropriate naltrexone use in a heroin misuser. Emerg Med J. 2003;20: 381–382. 9. Bristow K, Meek R, Clark N. Acute opioid withdrawal in the emergency department: inadvertent naltrexone abuse? Emerg Med. 2001;13:359–363. 10. Quigley MA, Boyce SH. Unintentional rapid opioid detoxification. Emerg Med J. 2001;18: 494–495. 11. Ingman K, Hagelberg N, Aalto S, et al. Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology. 2005;30: 2245–2253. 12. Donnerstag N, Schneider T, Lüthi A, et al. Severe opioid withdrawal syndrome after a single dose of nalmefene. Eur J Clin Pharmacol. 2015;71:1025–1026. 13. Walsh SL, Preston KL, Stitzer ML, et al. Clinical pharmacology of buprenorphine: ceiling effects at high doses. Clin Pharmacol Ther. 1994;55:569–580. 14. Berg ML, Idrees U, Ding R, et al. Evaluation of the use of buprenorphine for opioid withdrawal in an emergency department. Drug Alcohol Depend. 2007;86:239–244. 15. Rund DA, Ewing JD, Mitzel K, et al. The use of intramuscular benzodiazepines


Journal of Clinical Psychopharmacology • Volume 36, Number 1, February 2016 and antipsychotic agents in the treatment of acute agitation or violence in the emergency department. J Emerg Med. 2006;31:317–324. 16. Geoffroy PA, Rolland B, Cottencin O. Catatonia and alcohol withdrawal: a complex and underestimated syndrome. Alcohol Alcohol. 2012;47:288–290. 17. Soyka M. Alcohol use disorders in opioid maintenance therapy: prevalence, clinical correlates and treatment. Eur Addict Res. 2015;21:78–87. 18. Arias AJ, Kranzler HR. Treatment of co-occurring alcohol and other drug use disorders. Alcohol Res Health. 2008;31: 155–167.

Effectiveness of Nalmefene in Binge Eating Disorder A Case Report To the Editors: inge eating disorder (BED) is a common eating disorder (ED), affecting between 1.5% and 3.0% of women, characterized by binge eating without purging that often, but not necessarily, is associated with obesity (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition). Although no guidelines for the treatment of BED are available, the literature supports the use of antidepressants, anticonvulsants, antiobesity agents, and cognitive-behavioral therapy, all with a modest efficacy.1,2 Therefore, other drugs, specifically sibutramine and topiramate, have been recently shown to significantly reduce binge eating behavior and body weight in obese patients with BED.3,4 Further, the pharmacotherapy of BED is now focusing on other compounds, such as opiate blockers and modulators of peptide hormones.5 The present study reports the positive response of a patient with BED treated with nalmefene, an opioid receptor modulator recently approved by the European Medicine Agency for the treatment of alcoholism in adults with high drinking risk.6 The patient was a 40-year-old lawyer, married with 2 children, with no personality disorders nor a positive family history for psychiatric disorders. She had been suffering from BED since her adolescence but had hidden the disorder until the marriage, when she revealed the problem to her husband. He convinced her to consult a psychiatrist who prescribed fluoxetine (up to 60 mg/d) that was effective but was stopped after 6 months. Because she soon relapsed, she consulted other psychiatrists

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who prescribed sertraline and valproate as well as different psychotherapies, all ineffective, so that she was admitted to a psychiatric ward for a depressive episode characterized by depressed mood, loss of energy, drowsiness, decreased interest in daily activities, reduced concentration, and feelings of hopelessness and treated with clomipramine (75 mg/d). After a short period of relative well-being, she suffered from another similar depressive episode and consulted us 3 years ago. On that occasion, she showed a normal body mass index, a score of 33 on the Binge Eating Scale, and of 25 on the Hamilton Rating Scale for Depression. She referred to having 3 binge episodes a day, especially after dinner, and was strongly convinced that she could not recover any more. She was given bupropion (300 mg/d) and topiramate (up to 400 mg/d), which led to a significant improvement in 5 weeks so that she could resume work full time. However, 1 year later, when her father had a severe medical problem, she relapsed. We then added trazodone (300 md/d) and agomelatine (25 md/d) with a subsequent improvement lasting another year. Unfortunately, she stopped the treatment against our advice and soon relapsed. The previous treatment was no more effective, and therefore, we prescribed nalmefene (18 mg/d) after obtaining her informed consent. After 2 weeks, the binge episodes had totally disappeared, and she indicated that for the first time since the onset of the disorder, she felt no urge to eat. After 1 year, the patient is still well, with no significant side effect (just a mild nausea at the beginning of the treatment that had disappeared after 1 month). This case report highlights the potential use of nalmefene in the treatment of BED. Nalmefene is a new compound combining μ and δ receptor (MOR and DOR) antagonism and κ receptor (KOR) partial agonism. The direct involvement of the opioid system in the rewarding effect of alcohol and the indirect modulation of dopaminergic transmission in the mesolimbic areas are considered the main mechanisms of action of nalmefene to reduce alcohol intake.7 In animal models, nalmefene resulted in being more effective than naltrexone, another opioid modulator shown to be effective in BED.8 However, naltrexone, despite showing a similar affinity for MOR, behaves as an antagonist of MOR, DOR, and KOR.9 Available evidence suggests that such mechanisms may be involved also in food craving.10 Therefore, we would suggest with caution that a MOR/DOR antagonism coupled with KOR partial agonism, typical of nalmefene, might be particularly useful in food craving, such as that typical of BED.



In conclusion, our case report underlines that nalmefene might represent a new pharmacological paradigm in terms of therapeutic target (reduction of food consumption) in BED and other food craving conditions. Further, it suggests that nalmefene may be prescribed also daily and not only when needed, to improve food addiction. Future studies should explore the possibility that nalmefene should be useful not only to reduce alcohol consumption,11 but also to treat specifically different types of addictions.

AUTHOR DISCLOSURE INFORMATION All authors have reviewed and approved the manuscript before submission and accepted the responsibility for the information contained in the submission. The authors declare no conflicts of interest.

Donatella Marazziti, MD Dipartimento di Medicina Clinica e Sperimentale Sezione di Psichiatria University of Pisa Pisa, Italy [email protected]

Armando Piccinni, MD Stefano Baroni, Dr BiolSci Liliana Dell'Osso, MD Dipartimento di Medicina Clinica e Sperimentale Section of Psychiatry University of Pisa Pisa, Italy

REFERENCES 1. Appolinario JC, McElroy SL. Pharmacological approaches in the treatment of binge eating disorder. Curr Drug Targets. 2004;3:301–307. 2. Brambilla F, Samek L, Company M, et al. Multivariate therapeutic approach to binge-eating disorder: combined nutritional, psychological and pharmacological treatment. Int Clin Psychopharmacol. 2009;6:312–317. 3. McElroy SL, Guerdjikova AI, Mori N, et al. Pharmacological management of binge eating disorder: current and emerging treatment options. Ther Clin Risk Manag. 2012;8: 219–241. 4. Tata AL, Kockler DR. Topiramate for binge-eating disorder associated with obesity. Ann Pharmacother. 2006;11:1993–1997. 5. Marazziti D, Rossi L, Baroni S, et al. Novel treatment options of binge eating disorder. Curr Med Chem. 2011;18:5159–5164.


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Letters to the Editors 6. Keating GM. Nalmefene: a review of its use in the treatment of alcohol dependence. CNS Drugs. 2013;27:761–772. 7. Spanagel R. Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev. 2009;89: 649–705. 8. Nealey KA, Smith AW, Davis SM, et al. κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats. Neuropharmacology. 2011;61:35–42. 9. Katsuura Y, Heckmann JA, Taha SA. mu-Opioid receptor stimulation in the nucleus accumbens elevates fatty tastant intake by increasing palatability and suppressing satiety signals. Am J Physiol Regul Integr Comp Physiol. 2011;301: 244–254. 10. Gosnell BA, Levine AS. Reward systems and food intake: role of opioids. Int J Obes (Lond). 2009;33:S54–S58. 11. Soyka M. Nalmefene a treatment of alcohol dependence: a current update. Int J Neuropsychopharmacol. 2013;18:1–10.

Recurrent Catatonia in Parkinson Disease To the Editors: atatonia is a motor dysregulation syndrome that occurs in various medical conditions.1 However, few reports have described catatonia in patients with Parkinson disease (PD).2,3 We present an elderly patient with PD, who developed recurrent episodes of catatonia for a period of 3 years, and discuss the challenges of managing catatonia in this clinical setting.

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CASE REPORT An 80-year-old woman, who had been diagnosed with idiopathic PD 12 years ago, presented to our emergency department with stupor, mutism, and immobility with minimal response to painful stimuli. According to her family, during the previous week, she had been severely agitated and had visual hallucinations. She also became suspicious of her children and believed that her food was poisoned. Therefore, they sought help in an emergency unit of a psychiatric hospital. However, she became increasingly unresponsive afterward and refused food and fluids for the last few days. The patient had been on stable doses of levodopa/benserazide 200/50 mg 4 times daily and pramipexol 2 mg twice daily (BID) in the preceding year, with fairly well controlled motor symptoms. Her daughter also had PD with age of onset at 40 years.

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She had a medical history significant for hypertension, coronary artery disease, asthma, and hypothyroidism. Further information revealed a history of hospitalization at another center 1 and a half years ago, because of a similar episode of immobility and mutism preceded by a short period of agitation and visual hallucinations. She had been continuously treated with sertraline 50 mg and quetiapine 50 mg once daily afterward. At our initial examination, patient's eyes and mouth were firmly closed and she had gegenhalten rigidity at her neck and extremities. She had no focal neurological signs or meningeal irritation and was afebrile with normal vital signs. A physical examination revealed findings of dehydration. An initial complete blood count and blood chemistry including a serum creatinine phosphokinase level were in the normal range, except for moderate hypernatremia (150 mEq/L) and hypoglycemia (45 mg/dL). Further laboratory analyses revealed a normal thyroid profile, serum vitamin B12/ folic acid levels, and negative serum VDRL/rapid plasma reagin tests. A cranial magnetic resonance imaging showed a moderately severe global cortical atrophy and several small periventricular T2 hyperintensities. After admission, patient's dehydration and hypoglycemia were managed with intravenous fluids. Afterward, a therapeutic trial of diazepam 5 mg intramuscularly followed by lorazepam 1 mg orally was given. This brought about a marked response within 2 to 3 hours; the patient could walk, albeit slowly, sat on a chair, and asked whether the police were after her. However, the response did not persist, and consequently, the dose of lorazepam was gradually increased up to 5 mg/d by the third day. In the following days, she was persistently stuporous, negativistic, and uncooperative and had no oral intake. Electroconvulsive therapy (ECT) was then considered; however, it was deferred because of an acute exacerbation of patient's asthma and concurrent clinical findings of aspiration pneumonia with a moderate degree of hypoxia, which required treatment with a parenteral antibiotic, inhaled bronchodilators, and nasal oxygen. At the tenth day, while the patient was still stuporous, an electroencephalogram revealed generalized low-amplitude theta activity, vertex waves, and positive occipital sharp transients of sleep. Hence, an iatrogenic toxic encephalopathy secondary to lorazepam was suspected, and this agent was discontinued. In the following days, the patient was slightly more responsive; she could open her eyes shortly and occasionally follow simple commands. At the 15th day, on the grounds of resistant catatonic

symptoms and a deferred ECT due to clinical instability, memantine at 5 mg daily dose was initiated by enteral route. At the 16th to 18th days, her negativism and immobility resolved markedly, and she began oral intake of food and fluids. At this stage, her mental examination revealed a general mental confusion and incoherence, but no active psychotic symptoms. At the 21st day, with near complete resolution of the initial symptoms, she was discharged. On an outpatient visit a month later, she was better off with memantine 10 mg BID. Her mental examination revealed moderate dementia with a mini–mental state examination score of 18/30. Five months later, the family reported that the patient had suspiciousness and insomnia and also exhibited a waxing and waning overactivity, which involved some home activities such as cleaning and tidying. The patient was then on a stable antiparkinson regimen arranged at another center 3 months earlier, and it consisted of levodopa/benserazide 50/12.5 mg BID, sustained release levodopa/benserazide 100/ 25 mg BID, levodopa/carbidopa/entacapone 100/25/200 mg and 150/37.5/200 mg BID, and pramipexol 2 mg BID. She also received memantine 10 mg BID. Soon afterward, she had a loss of interest in daily activities for a period of 3 weeks and became preoccupied with vague abdominal complaints and constipation. According to the family, she was irritable and paranoid and was reluctant to take her medications. At the interview, she was unwilling to respond to questions and had little eye contact. She also demonstrated psychomotor retardation with frequent thought blocking. Her mental examination revealed some depressed mood and anhedonia; thus, duloxetine 30 mg/d and lamotrigine 25 mg/d were prescribed. Two weeks later, however, she had to be hospitalized for recurrence of catatonic stupor with fairly similar symptoms at previous hospitalizations. On admission, her physical neurological examination was unremarkable except for a generalized rigidity, and an extensive biochemical workup of plasma and urine revealed normal results. A standard paraneoplastic panel and a test for anti-N-methylD-aspartate receptor antibodies were also negative. Because of the anticipated medical risks related to immobility and lack of oral intake, modified ECT treatment was started promptly with family's consent on hospital day 3. Electroconvulsive therapy was repeated on the 2 consecutive days and continued biweekly thereafter. Meanwhile, levodopa/benserazide 100/25 mg 6 times a day, pramipexol 1 mg BID, and memantine 10 mg BID were administered by nasogastric tubing. A mild to moderate



response to ECT appeared after the fourth session (on day 10) as demonstrated by spontaneous opening of eyes, after some simple commands and the rare “yes/no” answers. During this period, on several occasions, she had horrifying complex visual and auditory hallucinations, which were accompanied by persecutory delusions (“thieves coming up” and “bombs exploding outside”). Therefore, quetiapine 25 mg at bedtime was started, whereas pramipexol was gradually discontinued and total daily dose of L-dopa was increased up to 900 mg in 5 days. A significantly greater improvement of patient's negativism was observed after the sixth and the final ECT session (15th day). Nevertheless, at this point, the patient appeared severely apathetic and exhibited prolonged immobility when left unattended. She did not initiate any motor acts by herself, ask for food or fluids, or change position in bed, yet she tended to follow most commands without any hesitation (symptoms of severe passivity). Furthermore, her speech was nonspontaneous, perseverative, and incoherent with occasional echolalia. Consequently on day 22, a therapeutic trial with oral amantadine (started at 50 mg and titrated in 50 mg daily increments) was initiated. A mild resolution of the residual catatonic symptoms was noted by the 24th day with this treatment, and a major improvement followed on day 27 at a daily dose of 200-mg amantadine. At that time, her mini–mental state examination score was 22/30. She was discharged on day 30.

DISCUSSION Catatonic stupor is a life-threatening medical emergency, which should be differentiated from other causes of general unresponsiveness and treated urgently to prevent associated complications.4 Nonetheless, catatonia remains to be a widely underrecognized phenomenon.5 Its diagnosis might be even more problematic in the elderly patients and in presence of neurodegenerative diseases, where catatonia-related symptoms can be easily ascribed to the primary neurological syndrome or some unrelated/secondary medical conditions. To our knowledge, only 2 case reports described catatonia in patients with PD. In 1 reported case, catatonic symptoms developed after a switch in the ongoing dopaminergic treatment (after withdrawal of pramipexol and talipexol due to hallucinations and delusions),2 and in the other, these followed a state, which resembled neuroleptic malignant syndrome.3 In our case, catatonia was recurrent and these episodes followed an acutely psychotic and agitated period. According to further information gathered from medical records and the family, patient's agitation

was treated with parenteral followed by oral olanzapine several days before the second episode, and an unknown parenteral sedative agent was administered before the first. On these 2 occasions, a neuroleptic malignant-like syndrome or acute akinesia in Parkinson disease was an important diagnostic alternative. However, this could be effectively ruled out by the absence of hypertermia, severe rigidity, autonomic symptoms, and serum creatinine phosphokinase elevation. In the last catatonic episode, where the patient was for a long time under our follow-up; symptoms emerged gradually for weeks without an intervening dopamine antagonist; hence, we had an initial impression that these were associated with an underlying major depressive disorder. However, further observation of the patient's mental state over the treatment course yielded no appreciable depressive symptoms, and visual hallucinations and persecutory delusions were predominant after resolution of the initially severe negativism. These together with the prodromal period of overactivity and punding-like phenomena indicate that the patient's catatonia might be a severe motor manifestation of psychosis and a late complication of PD, which were accentuated by the moderate cognitive impairment and excessive dopaminergic dosing. Nevertheless, it is possible that in the initial and the second episodes of catatonia, emergency administration of dopamine receptor antagonists might have also contributed. Catatonia is hypothesized to reflect a “top-down” (frontal) dysregulation of basal ganglia in severe psychiatric states and a GABAergic deficiency and/or an increased glutamergic activity have been suggested as underlying neurochemical dysfunction.6–8 Similarly, a severe blockade of dopamine at these brain regions has also been proposed.6,7 In our case, both top-down and “bottom-up” mechanisms of dysregulation of the frontal-basal ganglionic system might have played a role, as suggested by active psychotic symptoms and the presence of PD, which is primarily a disease of basal ganglia. N-methyl-D-aspartate receptor antagonists memantine and amantadine were found effective in alleviation of our patient's catatonic symptoms on the separate episodes. However, it is interesting that the third catatonic episode emerged despite the ongoing treatment with memantine. On this occasion, an ECT course was effective in reducing negativism and unresponsiveness, although amantadine was required eventually for recovery from the particularly severe amotivational state. Amantadine has a moderate dopaminergic affinity,9 and this might have brought about the additional clinical benefit. Both of these agents have been successfully used in treatment of



lorazepam-resistant catatonic symptoms, ECT unresponsive catatonia, and apathy associated with neurological insults.8,10–12 Our final observation was that lorazepam should be administered cautiously for catatonia in the elderly patients with neurodegenerative diseases such as PD, because higher doses might result in a severe encephalopathy or deep sedation, and it might be particularly challenging to distinguish this complication in presence of catatonic stupor. It should be recognized that a general recommendation of benzodiazepines for the treatment of catatonia was reached after reports largely from young patients with primary psychiatric disorders. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Written informed consent was obtained from patient's next-of-kin (her daughter) for publication of this case report. Burç Çağrı Poyraz, MD Department of Psychiatry Cerrahpaşa Faculty of Medicine University of Istanbul Istanbul, Turkey Cana Aksoy Poyraz, MD Department of Psychiatry Cerrahpaşa Faculty of Medicine University of Istanbul Istanbul, Turkey [email protected] Ahmet Yassa, MD Mehmet Kemal Arıkan, MD, PhD Department of Psychiatry Cerrahpaşa Faculty of Medicine University of Istanbul Istanbul, Turkey Ayşegül Gündüz, MD Güneş Kızıltan, MD Department of Neurology Cerrahpaşa Faculty of Medicine University of Istanbul Istanbul, Turkey

REFERENCES 1. Taylor MA, Fink M. Catatonia in psychiatric classification: a home of its own. Am J Psychiatry. 2003;160: 1233–1241. 2. Kamigaichi R, Kubo S, Ishikawa K, et al. Effective control of catatonia in Parkinson's disease by electroconvulsive therapy: a case report. Eur J Neurol. 2009;16:e6. 3. Suzuki K, Awata S. Catatonic stupor during the course of Parkinson's disease resolved with electroconvulsive therapy. Mov Disord. 2006; 21:123–124.


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Letters to the Editors 4. Swartz C, Galang RL. Adverse outcome with delay in identification of catatonia in elderly patients. Am J Geriatr Psychiatry. 2001;9:78–80. 5. Van der Heijden FM, Tuinier S, Arts NJ, et al. Catatonia: disappeared or under-diagnosed? Psychopathology. 2005;38:3–8. 6. Taylor MA. Catatonia: a review of the behavioral neurologic syndrome. Neuropsychiatry Neuropsychol Behav Neurol. 1990;3:48–72. 7. Fink M, Taylor MA. Catatonia: A Clinician's Guide to Diagnosis and Treatment. Cambridge UK: Cambridge University Press; 2003. 8. Carroll BT, Thomas C, Jayanti K, et al. Treating persistent catatonia when benzodiazepines fail. Curr Psychiatry. 2005;4:56–64. 9. Northoff G, Eckert J, Fritze J. Glutamatergic dysfunction in catatonia? Successful treatment of three acute akinetic catatonic patients with the NMDA antagonist amantadine. J Neurol Neurosurg Psychiatry. 1997;62:404–406. 10. Utumi Y, Iseki E, Arai H. Three patients with mood disorders showing catatonia and frontotemporal lobes atrophy. Psychogeriatrics. 2013;13:254–259. 11. Obregon DF, Velasco RM, Wuerz TP, et al. Memantine and catatonia: a case report and literature review. J Psychiatr Pract. 2011;17:292–299. 12. Links KA, Black SE, Graff-Guerrero A, et al. A case of apathy due to frontotemporal dementia responsive to memantine. Neurocase. 2013;19:256–261.


chest which were considered psychological in origin by a dermatologist and pediatrician. He had no known drug allergy but had a few episodes of skin eruptions possibly related to food. He was first started on sertraline 25 mg. He used this dosage for 3 months without any significant side effects. Then sertraline was increased to 50 mg/d. He generally tolerated it well except he developed itching and mild skin eruptions on his arms and upper chest. Sertraline was discontinued by the family for 1 month, during which time, there were no skin eruptions and itching. On the next visit, it was revealed he had some problems in his school due mainly due to attention problems. His recent episode of itching and mild and local skin eruptions were considered as stress related, and we decided to restart sertraline 50 mg and add MPH 27 mg/d. His anxiety and attention problems showed moderate to much improvement during 4 months of treatment. There were no significant side effects except some level of decreased appetite during the day and rebound increased appetite at nights without any significant weight change. His weight was 58 kg, and we decided to increase MPH to 54 mg/d. After 1 week of treatment, he developed nonpruritic maculopapular skin rash first on his face and chest and then the rash spread all over the body within 1 day (Fig. 1). We discontinued sertraline and MPH. He

received a short-term antihistaminic and steroid treatment. His skin rash resolved within 10 days of discontinuation. He denied using any other medication or unusual food. We obtained verbal consent from both the patient and his family to publish this report and to include his photograph.

DISCUSSION Methylphenidate has been the first-line psychopharmacological treatment in children and adolescents with attention-deficit hyperactivity disorder and results in significant improvement in 70% to 80% of affected children.7 Nausea, decreased appetite, weight loss, and sleep disturbances are among the most frequently reported adverse effects during MPH treatment.7 Besides these common adverse effects, MPH has also been reported to cause some unusual adverse effects, such as hallucinations,8,9 hypersexuality or inappropriate sexual behaviors,10,11 skin eruptions,1–6 obsessive-compulsive symptoms,12,13 gynecomastia,14 and painful muscle cramps.15 A review of the literature regarding MPH-related skin eruptions revealed that skin eruptions were usually local or included several parts (such as face, neck, arms, scrotum, chest, or trunk) of the body in these reports.1–5 Skin eruptions in these reports included pruritic maculopapular,1,4 pruritic raised edematous circular

Diffuse Maculopapular Rash With Increasing Dosage of Methylphenidate To the Editors: here have been several reports of methylphenidate hydrochloride (MPH)-related skin reactions in children and adolescents with attention-deficit hyperactivity disorder treated with this medication.1–6 Here we present an 11-year-old boy who developed diffuse nonpruritic maculopapular skin rash with increasing dosage of MPH.

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CASE E is an 11-year-old boy who has been followed up with diagnosis of social and generalized anxiety and attention deficit disorders for the last 2 years. His developmental history and intellectual capacity were within normal limits. He had no significant medical or neurological history but had several episodes of itching and mild and local skin eruptions on his arms and

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FIGURE 1. Diffuse maculopapuler rash after increasing dosage of OROS-methylphenidate. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


shaped,2 fixed drug eruption,3 exanthematous pustulosis,5 and exfoliative dermatitis.6 It may be interesting to note that, despite being a psychostimulant like MPH, we did not see any report of amphetaminerelated skin rash in the literature. The patient in our case developed nonpruritic diffuse rash including his face, neck, trunk, back, arms, and legs. As far as we can recognize, this is the first report of such a skin reaction related to MPH treatment. It may be important to note that MPH-related skin rash may have different characteristics, such as local versus general, pruritic versus nonpruritic, or maculopapular versus fixed versus pustular versus exfoliative. There are several methods for causality assessment of adverse drug reactions.16 In this case, we used the Naranjo causality scale which revealed a score of 7 showing probable causality.17 Drug formulation may also be important because 1 article reported that skin rash did not occur with immediate MPH, whereas it occurred with osmotic [controlled] release oral [delivery] system (OROS) MPH.1 The authors stated that OROS MPH capsules contain several substances (such as butylated hydroxytoluene, carnauba wax, cellulose acetate, hypromellose, phosphoric acid, poloxamer, polyethylene oxides, povidone, propylene glycol, sodium chloride stearic acid, succinic acid, synthetic iron oxides, titanium dioxide, and triacetin) not available in MPH tablets.1 Despite the statement “hypersensitivity to MPH or other components of product” included as a contraindication in the package insert of OROS MPH, there is no further information regarding which of those substances may cause allergic reactions or skin eruptions. Because MPH is increasingly used in pediatric populations, clinicians should be familiar with the possibility and nature of MPH-related skin rash. Although present reports are not of life-threatening severity, skin rash may be frightening for the patient and family and impairs treatment compliance.

AUTHOR DISCLOSURE INFORMATION The authors warrant that the article is original, is not for consideration by another journal, has not been previously published, and has been prepared according to the manuscript rules. The authors warrant that they have no conflict of interests in general or in connection with the submitted article and no financial relationships with any pharmaceutical company. Ilyas Kaya, MD Department of Child and Adolescent Psychiatry Istanbul Medical Faculty Istanbul, Turkey [email protected]

Murat Coskun, MD Department of Child and Adolescent Psychiatry Istanbul Medical Faculty Istanbul, Turkey

REFERENCES 1. Coskun M, Tutkunkardas MD, Zoroglu S. OROS methylphenidate-induced skin eruptions. J Child Adolesc Psychopharmacol. 2009;19:593–594. 2. Goyal R, Arroyave A, Malik S. Urticaria and angioedema secondary to methylphenidate exposure in a young child. J Child Adolesc Psychopharmacol. 2015;25:731–733. 3. Cohen HA, Ashkenazi A, Nussinovitch M, et al. Fixed drug eruption of the scrotum due to methylphenidate. Ann Pharmacother. 1992;26:1378–1379. 4. Confino-Cohen R, Goldberg A. Succesful desensitization of methylphenidate-induced rash. J Child Adolesc Psychopharmacol. 2005;15:703–705. 5. Heinzerling LM, Pichler W, Anliker MD. Acute generalized exanthematous pustulosis induced by methylphenidate: a new adverse effect. Arch Dermatol. 2011;147:872–873. 6. Weil AJ. Exfoliative dermatitis after medication with methylpheni-date HCl (ritalin). Ann Allergy. 1968;26:402–404. 7. Green WH. Sympathomimetic amines and central nervous system stimulants. In: Child


Letters to the Editors and Adolescent Clinical Psychopharmacology. 4th eds. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:55–90. 8. Ross RG. Psychotic and manic-like symptoms during stimulant treatment of attention deficit hyperactivity disorder. Am J Psychiatry. 2006;163:1149–1152. 9. Coskun M, Zoroglu S. Tactile and visual hallucinations in a child with methylphenidate and fluoxetine combination. J Clin Psychopharmacol. 2008;28:723–725. 10. Coskun M, Zoroglu S. A report of two cases of sexual side effects with OROS methylphenidate. J Child Adolesc Psychopharmacol. 2009;19: 477–479. 11. Bilgiç A, Gürkan K, Türkoğlu S. Excessive masturbation and hypersexual behavior associated with methylphenidate. J Am Acad Child Adolesc Psychiatry. 2007;46:789–790. 12. Kouris S. Methylphenidate-induced obsessive-compulsiveness. J Am Acad Child Adolesc Psychiatry. 1998;37:135. 13. Coskun M. Methylphenidate induced obsessive-compulsive symptoms treated with sertraline. Bull Clin Psychopharmacol. 2011;21:275–276. 14. Coskun M, Adak I, Akaltun I. Bilateral gynecomastia in a preadolescent boy while under treatment with methylphenidate and paroxetine. J Clin Psychopharmacol. 2014;34: 537–538. 15. Coskun M, Kaya I. Painful muscle cramps possibly associated with withdrawal from methylphenidate. J Child Adolesc Psychopharmacol. 2015. [Epub ahead of print]. 16. Agbabiaka TB, Savović J, Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug Saf. 2008;31:21–37. 17. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245.


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Acute rhabdomyolysis associated with coadministration of levofloxacin and simvastatin in a patient with normal renal function.

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Bilateral acute closed angle glaucoma associated with the discontinuation of escitalopram: a case report.

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