Journal of Clinical Psychopharmacology • Volume 36, Number 1, February 2016
Letters to the Editors
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
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
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
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Journal of Clinical Psychopharmacology • Volume 36, Number 1, February 2016
Letters to the Editors
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
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 36, Number 1, February 2016
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
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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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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
© 2015 Wolters Kluwer Health, Inc. All rights reserved.
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
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Journal of Clinical Psychopharmacology • Volume 36, Number 1, February 2016
Letters to the Editors
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
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 36, Number 1, February 2016
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
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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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