Journal of Clinical Psychopharmacology
&
Volume 34, Number 2, April 2014
interval (peaked at 565 milliseconds).9 A 41-year-old man who had ingested 270 mg of RIS and benzodiazepines showed sinus bradycardia and a prolonged QTc interval (peaked at 520 milliseconds).10 Therefore, in RIS overdose cases, fatal arrhythmia is the most common cause of death, which is consistent with the findings of the present case and those of previous cases.4 Considering the fatal toxic threshold, information regarding both the ingested dose and blood concentration of RIS is of great value. Furthermore, when the data on clinical characteristics and blood levels are accumulated, measurement of the blood concentration may provide useful information for initial management or prediction of patient outcome. A few reports have shown the blood concentration of RIS in victims who had taken high doses.1,3,11 Among the fatal cases, only the present case revealed both the ingested dose (82 mg) and blood concentration (447.4 ng/mL) by LC-MS analysis. The detected value was well in accordance with a nonfatal poisoning case in which a 45-year-old woman ingested 90 mg of RIS and revealed a maximum plasma concentration of 325 ng/mL by LCYtandem MS.1 In addition, 1.83 mg/mL of ethanol was detected in the blood of the present patient. Although the detailed mechanism and clinical characteristics of the interaction between RIS and alcohol have not been fully investigated, the metabolism of RIS by cytochrome P450 2D6 may be somewhat inhibited under the influence of alcohol, which is also metabolized by cytochrome P450. Therefore, the present case suggests that even if 82 mg of RIS is ingested under the influence of alcohol, the victim may suffer a fatal outcome if untreated. Routine alcohol checkups are also recommended for patients with RIS overdose. The RIS concentrations in our patient and the previously mentioned 45year-old patient differ from those in 2 previous reports in which the blood concentrations were higher and were mea sured by high-performance LC.1,3,11 With LC-MS or LCYtandem MS, specific ions originating from RIS can be detected; however, with high-performance LC, part of the structure of RIS can be detected by UV absorption. Further reports will clarify the differences in these values by specific measurement methods. All atypical antipsychotic agents have significant adverse effects if taken in excess. Therefore, special care is warranted in all cases of atypical antipsychotic overdose, including rigorous monitoring and highintensity clinical setting to manage respiratory compromise or cardiac difficulty. A prolonged QTc interval and wide QRS * 2014 Lippincott Williams & Wilkins
complex have been reported in some cases of RIS overdose, and some cases have ended in death, possibly because of asystole preceded by a QTc interval of 520 or 565 milliseconds.3,9,11 ACKNOWLEDGMENTS The authors thank Mr Takumi Kobayashi of Jansen Pharmaceutical Companies for his scientific suggestion. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Masahito Hitosugi, MD, PhD Department of Legal Medicine Dokkyo Medical University School of Medicine Tochigi, Japan [email protected]
Chie Tsukada, BSc Shinobu Yamauchi, PhD Toshiaki Nagai, PhD Department of Legal Medicine Dokkyo Medical University School of Medicine Tochigi, Japan
REFERENCES 1. Nishikage H, Nakanishi T, Takamitsu Y, et al. sequential changes in the plasma concentration of risperidone following intentional overdose. Clin Neuropharmacol. 2002;25:307Y309. 2. Keegan D. Risperidone: neurochemical pharmacologic and clinical properties of new antipsychotic drug. Can J Psychiatry. 1994;39(suppl 2):46Y52. 3. Springfield AC, Bodiford Ed. An overdose of risperidone. J Anal Toxicol. 1996;20:202Y203. 4. Acri AA, Henretig FM. Effects of risperidone in overdose. Am J Emerg Med. 1998;16:498Y501. 5. Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects following atypical antipsychotic medication overdose. Am J Emerg Med. 2009;27:607Y616. 6. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360:225Y235. 7. Kuspis D, Dean B, Krenzelok EP. Risperidone overdose assessment. J Toxicol Clin Toxicol. 1995;33:552. 8. Heather GS, Vicas IMO. Risperidone overdose: a case series. Vet Hum Toxicol. 1994;36:371. 9. Brown K, Levy H, Brenner C, et al. Overdose of risperidone. Ann Emerg Med. 1993;22:1908Y1910. 10. Duenas-Latia A, Castro-villamor M, Martin-Escudero JC, et al. New clinical manifestations of acute risperidone poisoning. Clin Toxicol. 1999;37:893Y894.
Letters to the Editors
11. Sung LH, Hoon TS, Lydia A, et al. Serum and urine risperidone concentrations in an acute overdose. J Clin Psychopharmacol. 1997;17:325Y326.
Paliperidone-Related Peripheral Edema A Case Report and Review of the Literature To the Editors: eripheral edema as an infrequent adverse drug reaction to an antipsychotic medication has been reported to occur in 1% to 3% of patients taking antipsychotic drugs.1 A MEDLINE search from January 1950 to December 2012 using the MeSH terms ‘‘antipsychotic agents’’ and ‘‘edema’’ yielded only 28 relevant studies. Among them, risperidone (7 case studies and 2 clinical trials) and olanzapine (7 case studies) were the most frequently reported antipsychotic drugs associated with peripheral edema. They were followed by quetiapine (5 case studies), haloperidol (2 case studies), chlorpromazine (1 case study and 1 clinical trial), and other antipsychotics (1 case study each), including clozapine, ziprasidone, and amisulpride. Although the published information about antipsychotic-related peripheral edema is sparse, this adverse effect has been known to lead to discontinuation of the antipsychotic treatment in patients.2,3 To the best of our knowledge, paliperidone, a benzisoxazole drug that antagonizes the dopamine type 2 receptors and serotonin (5-HT) type 2A receptors, has not been reported to induce peripheral edema.4 Herein, we report a case of peripheral edema occurring in a patient being treated with paliperidone alone.
P
CASE REPORT In January 2010, a 50-year-old man with a 30-year history of paranoid schizophrenia and on a maintenance dosage of haloperidol (10 mg/d) was admitted to our psychiatric ward because of worsening persecutory delusions and auditory hallucinations. His medical history was unremarkable. Upon examination, he exhibited fearfulness, suspiciousness, and self-talking. He also had mild tremor and rigidity. Results of laboratory studies, chest radiograph, electrocardiography, and electroencephalography were all normal. We replaced the haloperidol with paliperidone. The dosage was increased from 6 to 9 mg/d over 2 weeks. By the end of this 2-week period, although his psychotic symptoms improved, a 3+ pitting edema developed dorsally in both of the patient’s feet, causing enough pain to interfere with his daily www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
269
Journal of Clinical Psychopharmacology
Letters to the Editors
&
Volume 34, Number 2, April 2014
TABLE 1. Clinical and Demographic Characteristics of 18 Reported Cases With Peripheral Edema Related by Antipsychotic Drug
Age Sex
Dose (mg)
Diagnosis
Time to Onset
Comedication Comorbidity
Site
Chlorpromazine6 Olanzapine2 Olanzapine7 Olanzapine8 Olanzapine9
45 34 58 34 50
F F M F F
Schizophrenia Bipolar disorder Bipolar disorder Bipolar disorder Bipolar disorder
400 Unknown 10 10 days 10 2 months 10 3 months 2.5 2 days
Unknown Yes Yes Yes Yes
None None Yes None None
Olanzapine10
37
M
Alcohol withdrawal
7.5
Unknown
None
Olanzapine10 Quetiapine11
30 55
M M
15 800
Unknown Yes
Quetiapine3 Quetiapine3 Quetiapine3
59 44 38
F F F
150 50 200
8 days 4 days 1 day
Quetiapine12 Risperidone13
73 8
F F
100 0.5
Risperidone14
16
M
Schizophrenia Schizoaffective disorder Bipolar disorder Depression Psychosis and agitation Bipolar disorder Adjustment disorder Autism, epilepsy
1.5 months 2 months 5 weeks
Bilateral Bilateral Bilateral Bilateral Bilateral limbs Bilateral
2
Risperidone15 Risperidone16
41 40
F F
Risperidone17
51
F
Schizophrenia Schizoaffective disorder Schizophrenia
Risperidone18
80
F
Depression
life. The edema tended to worsen when he stood for long periods and improve after lying down or wearing compression stockings for a few hours. Repeated laboratory workups, which included complete blood count, electrolytes, kidney/liver/ thyroid function tests, protein, albumin, C3, C4, IgE/IgM/IgG, urinalysis, and erythrocyte sedimentation rate, provided no explanation for the edema. Follow-up chest radiograph and electrocardiography remained normal. At 3 weeks, a nephrologist and endocrinologist jointly evaluated the patient’s reports and started to add diuretics (amiloride, 5 mg/d; and hydrochlorothiazide, 50 mg/d) to his regimen. Despite the diuretic treatment, which caused polyuria, the edema persisted for another 2 weeks. Because the patient was only taking paliperidone and diuretics, we suspected his edema might have been due to paliperidone. At 5 weeks, we lowered the dosage of paliperidone to 6 mg/d for 3 days, and the edema began decreasing. We further discontinued the paliperidone, and the edema completely subsided within 1 week. Over the following 3 weeks, we gradually reintroduced haloperidol (15 mg/d) without diuretics. Although his edema
270
www.psychopharmacology.com
Naranjo Score
lower limbs lower limbs lower limbs lower limbs upper/lower
8 9 7 9 10
lower limbs
7
None Yes
Bilateral lower limbs Bilateral lower limbs
7 8
Yes Yes Yes
None Yes Yes
Bilateral lower limbs Bilateral lower limbs Bilateral lower limbs
9 7 8
7 days 3 days
Yes None
None None
Bilateral lower limbs Bilateral lower limbs
7 7
Yes
None
Right lower limb
7
1 10
Few weeks 3 days 2 months
None Yes
None None
lower limbs upper/lower
7 8
2
4 days
None
None
upper/lower
10
2
20 days
Yes
None
Bilateral Bilateral limbs Bilateral limbs Bilateral limbs
upper/lower
9
did not recur, some of his psychotic symptoms did.
DISCUSSION This case patient developed peripheral edema when he was administered paliperidone but not haloperidol. We found no apparent alternative medical cause that could better account for the development of edema in this patient. The course of events and manner of resolution suggested that there had been an adverse reaction after the paliperidone treatment. The edema in this case scored 8 on the Naranjo Scale, an algorithm that evaluates the association between an adverse reaction and a suspected drug, suggesting that this adverse event was probably related to paliperidone.5 Because there is a lack of a systematic review investigating the demographic and clinical characteristics of patients who have antipsychotic-related peripheral edema, we performed a simple descriptive analysis of relevant articles (25 case studies) identified by MEDLINE search. Using the Naranjo Scale to verify the validity of previous reports on edema secondary to antipsychotic drug, we found large variability in establishing the causality of those
drugs because their estimated Naranjo probability scores ranged from 2 to 10. Among the 25 studies, only 15 studies (18 reported cases) showed higher likelihood that an antipsychotic produced the edema (Naranjo probability scores Q7; Table 1).2,3,6Y18 These reported cases are more likely to be female (72.2%) and have bipolar disorder (33.3%) or schizophrenia (22.2%). Their mean age was 44.1 years old. Most of them were reported in the context of concomitant medications (66.7%) but no concurrent medical illness (77.8%). Risperidone and olanzapine (both 33.3%) were the most likely drugs to have related peripheral edema, followed by quetiapine (27.8%) and chlorpromazine (5.6%). The time of edema onset after beginning antipsychotic treatment varied (standard deviation, 28.5 days), although the mean time was 25.8 days. The mechanism underlying the development of peripheral edema after antipsychotic use remains unclear. By reviewing the literature, we found 3 hypotheses that might explain this adverse effect: (1) a peripheral vasodilation possibly mediated by antipsychotic antagonism to >-receptors and/or 5-HT2 receptors,12,14 (2) an indirect * 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology
&
Volume 34, Number 2, April 2014
increase in water retention through activating the hormone system (eg, renin and aldosterone),6 and (3) a type I and/or type IV allergic response to antipsychotic.3 The hypothesis of an antipsychotic-related vasodilation seemed to be more plausible because a recent cross-sectional study has shown a significant change in vascular compliance in 63 psychiatric patients on risperidone or quetiapine compared to a control group composed of 111 nonpsychiatric subjects who did not take any antipsychotic.19 Given that paliperidone is the 9hydroxy metabolite of risperidone, it is likely that these 2 drugs share common pathogenic pathways causing the edema.4 One possibility is that the compounds they share induce the edematous event. These compounds include the paliperidone itself and its associated metabolites resulting from a benzisoxazole scission or N-dealkylation metabolic pathway, and the common inactive ingredients that make up risperidone and paliperidone, such as titanium dioxide, propylene glycol, and ionic compounds containing sodium.20 It would be interesting to study the pathogenic role of these compounds because some of them are not well studied and some are categorized as drug additives that have been used to formulate several other antipsychotics (eg, olanzapine and quetiapine) that have been known to induce peripheral edema. In summary, this report alerts physicians to the potential development of peripheral edema in patients being prescribed paliperidone. Several patient characteristics and many other antipsychotics may be linked to this adverse effect. Therefore, close monitoring might be needed when initiating antipsychotic treatment. A multicenter study using a central database, including follow-up data, should be performed to systematically study peripheral edema in patients treated with antipsychotics. ACKNOWLEDGMENTS No financial support was received for this work. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Hung-Jen Chen, MD Department of Psychiatry Kaohsiung Kai-Syuan Psychiatric Hospital Kaohsiung, Taiwan
Shuai-Ting Lin, MD Department of Psychiatry Kaohsiung Kai-Syuan Psychiatric Hospital Kaohsiung, Taiwan [email protected] * 2014 Lippincott Williams & Wilkins
Heng-Chia Hsu, MD Kai-Da Cheng, MD Hin-Yeung Tsang, MRCPsych, PhD Department of Psychiatry Kaohsiung Kai-Syuan Psychiatric Hospital Kaohsiung, Taiwan
REFERENCES
Letters to the Editors
learning disability and autism. Autism. 2006;10:308Y310. 15. Ravasia S. Risperidone-induced edema. Can J Psychiatry. 2001;46:453Y454. 16. Sanders RD, Lehrer DS. Edema associated with addition of risperidone to valproate treatment. J Clin Psychiatry. 1998;59:689Y690.
1. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Gillman AG, Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics. 6th ed. New York, NY: Macmillan; 1980:397.
17. Yang HN, Cheng YM. Peripheral edema associated with risperidone oral solution: a case report and a review of the literature. J Clin Psychopharmacol. 2012; 32:128Y130.
2. Christensen RC. Olanzapine-associated bilateral pedal edema. J Clin Psychiatry. 2003;64:972.
18. Hosseini SH, Ahmadi A. Peripheral edema occurring during treatment with risperidone combined with citalopram. Case Rep Med. 2012;2012:540732.
3. Koleva HK, Erickson MA, Vanderlip ER, et al. 3 case reports of edema associated with quetiapine. Ann Clin Psychiatry. 2009; 21:77Y80.
19. Koola MM, Brown WV, Qualls C. Reduced arterial compliance in patients with psychiatric diagnoses. Schizophr Res. 2012;137:251Y253.
4. Chwieduk CM, Keating GM. Paliperidone extended release: a review of its use in the management of schizophrenia. Drugs. 2010;70:1295Y1317.
20. Mannens G, Huang ML, Meuldermans W. Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos. 1993;21:1134Y1141.
5. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239Y245. 6. Witz L, Shapiro MS, Shenkman L. Chlorpromazine induced fluid retention masquerading as idiopathic oedema. Br Med J (Clin Res Ed). 1987;294:807Y808. 7. Yovtcheva SP, Yazel JJ. Olanzapine-induced bilateral pedal edema: a case report. Gen Hosp Psychiatry. 2000;22:290Y291. 8. Yalu? I, Ozten E, Evren Tufan A, et al. Bilateral pedal edema associated with olanzapine use in manic episode of bipolar disorder: report of two cases. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1541Y1542. 9. Deshauer D, Erwin L, Karagianis J. Case report: edema related to olanzapine therapy. Can Fam Physician. 2006;52:620Y621. 10. Nayak V, Chogtu B, Devaramane V, et al. Pedal edema with olanzapine. Indian J Pharmacol. 2009;41:49Y50. 11. Chen HK, Liao HY, Huang CC. Concurrent pedal edema and sinus bradycardia associated with quetiapine. Psychiatry Clin Neurosci. 2011;65:537Y538. 12. Chen CY, Yeh YW, Kuo SC, et al. Pedal edema associated with addition of low-dose quetiapine to valproate treatment in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1551Y1552. 13. Akdag ST, Fettahoglu EC, Ozatalay E. Pedal edema induced by low-dose risperidone monotherapy in a child. J Child Adolesc Psychopharmacol. 2009; 19:481Y482. 14. Feroz-Nainar C, Selvaraj P, Roy M. Risperidone induced oedema in a child with
Risperidone and Quetiapine-Related Arthralgia To the Editors: isperidone and quetiapine are atypical antipsychotics with serotonin 5-HT2 and dopamine D2 antagonistic properties and are widely used in the treatment of psychotic disorders. We report a case of arthralgic adverse effects after risperidone and quetiapine treatment. Mr A, a 44-year-old male, visited our outpatient clinic because of anxiety, depressed mood, and poor sleep in the past 6 months because he had the feeling that he was being followed by an unknown stalker who may harm him. Under the diagnosis of persecutory delusional disorder, treatment with quetiapine (12.5 mg/d) was initiated. Because of his poor medication compliance, the medication was shifted to risperidone long-acting injection (12.5 mg/injection) with a 2-week interval, and the dosage was titrated to 37.5 mg/injection 1 month later. At the same time, he was also treated with fludiazepam for anxiety and with flunitrazepam for insomnia. Initially, he only had pain in his right knee after the quetiapine treatment. He had a history of previous trauma with his right knee, so he did not pay much attention to the pain. However, right after the risperidone injection treatment began, the joint pain progressed to his whole body without localized erythematous change, heat, or swelling. He had no history of
R
www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
271
&
Volume 34, Number 2, April 2014
interval (peaked at 565 milliseconds).9 A 41-year-old man who had ingested 270 mg of RIS and benzodiazepines showed sinus bradycardia and a prolonged QTc interval (peaked at 520 milliseconds).10 Therefore, in RIS overdose cases, fatal arrhythmia is the most common cause of death, which is consistent with the findings of the present case and those of previous cases.4 Considering the fatal toxic threshold, information regarding both the ingested dose and blood concentration of RIS is of great value. Furthermore, when the data on clinical characteristics and blood levels are accumulated, measurement of the blood concentration may provide useful information for initial management or prediction of patient outcome. A few reports have shown the blood concentration of RIS in victims who had taken high doses.1,3,11 Among the fatal cases, only the present case revealed both the ingested dose (82 mg) and blood concentration (447.4 ng/mL) by LC-MS analysis. The detected value was well in accordance with a nonfatal poisoning case in which a 45-year-old woman ingested 90 mg of RIS and revealed a maximum plasma concentration of 325 ng/mL by LCYtandem MS.1 In addition, 1.83 mg/mL of ethanol was detected in the blood of the present patient. Although the detailed mechanism and clinical characteristics of the interaction between RIS and alcohol have not been fully investigated, the metabolism of RIS by cytochrome P450 2D6 may be somewhat inhibited under the influence of alcohol, which is also metabolized by cytochrome P450. Therefore, the present case suggests that even if 82 mg of RIS is ingested under the influence of alcohol, the victim may suffer a fatal outcome if untreated. Routine alcohol checkups are also recommended for patients with RIS overdose. The RIS concentrations in our patient and the previously mentioned 45year-old patient differ from those in 2 previous reports in which the blood concentrations were higher and were mea sured by high-performance LC.1,3,11 With LC-MS or LCYtandem MS, specific ions originating from RIS can be detected; however, with high-performance LC, part of the structure of RIS can be detected by UV absorption. Further reports will clarify the differences in these values by specific measurement methods. All atypical antipsychotic agents have significant adverse effects if taken in excess. Therefore, special care is warranted in all cases of atypical antipsychotic overdose, including rigorous monitoring and highintensity clinical setting to manage respiratory compromise or cardiac difficulty. A prolonged QTc interval and wide QRS * 2014 Lippincott Williams & Wilkins
complex have been reported in some cases of RIS overdose, and some cases have ended in death, possibly because of asystole preceded by a QTc interval of 520 or 565 milliseconds.3,9,11 ACKNOWLEDGMENTS The authors thank Mr Takumi Kobayashi of Jansen Pharmaceutical Companies for his scientific suggestion. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Masahito Hitosugi, MD, PhD Department of Legal Medicine Dokkyo Medical University School of Medicine Tochigi, Japan [email protected]
Chie Tsukada, BSc Shinobu Yamauchi, PhD Toshiaki Nagai, PhD Department of Legal Medicine Dokkyo Medical University School of Medicine Tochigi, Japan
REFERENCES 1. Nishikage H, Nakanishi T, Takamitsu Y, et al. sequential changes in the plasma concentration of risperidone following intentional overdose. Clin Neuropharmacol. 2002;25:307Y309. 2. Keegan D. Risperidone: neurochemical pharmacologic and clinical properties of new antipsychotic drug. Can J Psychiatry. 1994;39(suppl 2):46Y52. 3. Springfield AC, Bodiford Ed. An overdose of risperidone. J Anal Toxicol. 1996;20:202Y203. 4. Acri AA, Henretig FM. Effects of risperidone in overdose. Am J Emerg Med. 1998;16:498Y501. 5. Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects following atypical antipsychotic medication overdose. Am J Emerg Med. 2009;27:607Y616. 6. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360:225Y235. 7. Kuspis D, Dean B, Krenzelok EP. Risperidone overdose assessment. J Toxicol Clin Toxicol. 1995;33:552. 8. Heather GS, Vicas IMO. Risperidone overdose: a case series. Vet Hum Toxicol. 1994;36:371. 9. Brown K, Levy H, Brenner C, et al. Overdose of risperidone. Ann Emerg Med. 1993;22:1908Y1910. 10. Duenas-Latia A, Castro-villamor M, Martin-Escudero JC, et al. New clinical manifestations of acute risperidone poisoning. Clin Toxicol. 1999;37:893Y894.
Letters to the Editors
11. Sung LH, Hoon TS, Lydia A, et al. Serum and urine risperidone concentrations in an acute overdose. J Clin Psychopharmacol. 1997;17:325Y326.
Paliperidone-Related Peripheral Edema A Case Report and Review of the Literature To the Editors: eripheral edema as an infrequent adverse drug reaction to an antipsychotic medication has been reported to occur in 1% to 3% of patients taking antipsychotic drugs.1 A MEDLINE search from January 1950 to December 2012 using the MeSH terms ‘‘antipsychotic agents’’ and ‘‘edema’’ yielded only 28 relevant studies. Among them, risperidone (7 case studies and 2 clinical trials) and olanzapine (7 case studies) were the most frequently reported antipsychotic drugs associated with peripheral edema. They were followed by quetiapine (5 case studies), haloperidol (2 case studies), chlorpromazine (1 case study and 1 clinical trial), and other antipsychotics (1 case study each), including clozapine, ziprasidone, and amisulpride. Although the published information about antipsychotic-related peripheral edema is sparse, this adverse effect has been known to lead to discontinuation of the antipsychotic treatment in patients.2,3 To the best of our knowledge, paliperidone, a benzisoxazole drug that antagonizes the dopamine type 2 receptors and serotonin (5-HT) type 2A receptors, has not been reported to induce peripheral edema.4 Herein, we report a case of peripheral edema occurring in a patient being treated with paliperidone alone.
P
CASE REPORT In January 2010, a 50-year-old man with a 30-year history of paranoid schizophrenia and on a maintenance dosage of haloperidol (10 mg/d) was admitted to our psychiatric ward because of worsening persecutory delusions and auditory hallucinations. His medical history was unremarkable. Upon examination, he exhibited fearfulness, suspiciousness, and self-talking. He also had mild tremor and rigidity. Results of laboratory studies, chest radiograph, electrocardiography, and electroencephalography were all normal. We replaced the haloperidol with paliperidone. The dosage was increased from 6 to 9 mg/d over 2 weeks. By the end of this 2-week period, although his psychotic symptoms improved, a 3+ pitting edema developed dorsally in both of the patient’s feet, causing enough pain to interfere with his daily www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
269
Journal of Clinical Psychopharmacology
Letters to the Editors
&
Volume 34, Number 2, April 2014
TABLE 1. Clinical and Demographic Characteristics of 18 Reported Cases With Peripheral Edema Related by Antipsychotic Drug
Age Sex
Dose (mg)
Diagnosis
Time to Onset
Comedication Comorbidity
Site
Chlorpromazine6 Olanzapine2 Olanzapine7 Olanzapine8 Olanzapine9
45 34 58 34 50
F F M F F
Schizophrenia Bipolar disorder Bipolar disorder Bipolar disorder Bipolar disorder
400 Unknown 10 10 days 10 2 months 10 3 months 2.5 2 days
Unknown Yes Yes Yes Yes
None None Yes None None
Olanzapine10
37
M
Alcohol withdrawal
7.5
Unknown
None
Olanzapine10 Quetiapine11
30 55
M M
15 800
Unknown Yes
Quetiapine3 Quetiapine3 Quetiapine3
59 44 38
F F F
150 50 200
8 days 4 days 1 day
Quetiapine12 Risperidone13
73 8
F F
100 0.5
Risperidone14
16
M
Schizophrenia Schizoaffective disorder Bipolar disorder Depression Psychosis and agitation Bipolar disorder Adjustment disorder Autism, epilepsy
1.5 months 2 months 5 weeks
Bilateral Bilateral Bilateral Bilateral Bilateral limbs Bilateral
2
Risperidone15 Risperidone16
41 40
F F
Risperidone17
51
F
Schizophrenia Schizoaffective disorder Schizophrenia
Risperidone18
80
F
Depression
life. The edema tended to worsen when he stood for long periods and improve after lying down or wearing compression stockings for a few hours. Repeated laboratory workups, which included complete blood count, electrolytes, kidney/liver/ thyroid function tests, protein, albumin, C3, C4, IgE/IgM/IgG, urinalysis, and erythrocyte sedimentation rate, provided no explanation for the edema. Follow-up chest radiograph and electrocardiography remained normal. At 3 weeks, a nephrologist and endocrinologist jointly evaluated the patient’s reports and started to add diuretics (amiloride, 5 mg/d; and hydrochlorothiazide, 50 mg/d) to his regimen. Despite the diuretic treatment, which caused polyuria, the edema persisted for another 2 weeks. Because the patient was only taking paliperidone and diuretics, we suspected his edema might have been due to paliperidone. At 5 weeks, we lowered the dosage of paliperidone to 6 mg/d for 3 days, and the edema began decreasing. We further discontinued the paliperidone, and the edema completely subsided within 1 week. Over the following 3 weeks, we gradually reintroduced haloperidol (15 mg/d) without diuretics. Although his edema
270
www.psychopharmacology.com
Naranjo Score
lower limbs lower limbs lower limbs lower limbs upper/lower
8 9 7 9 10
lower limbs
7
None Yes
Bilateral lower limbs Bilateral lower limbs
7 8
Yes Yes Yes
None Yes Yes
Bilateral lower limbs Bilateral lower limbs Bilateral lower limbs
9 7 8
7 days 3 days
Yes None
None None
Bilateral lower limbs Bilateral lower limbs
7 7
Yes
None
Right lower limb
7
1 10
Few weeks 3 days 2 months
None Yes
None None
lower limbs upper/lower
7 8
2
4 days
None
None
upper/lower
10
2
20 days
Yes
None
Bilateral Bilateral limbs Bilateral limbs Bilateral limbs
upper/lower
9
did not recur, some of his psychotic symptoms did.
DISCUSSION This case patient developed peripheral edema when he was administered paliperidone but not haloperidol. We found no apparent alternative medical cause that could better account for the development of edema in this patient. The course of events and manner of resolution suggested that there had been an adverse reaction after the paliperidone treatment. The edema in this case scored 8 on the Naranjo Scale, an algorithm that evaluates the association between an adverse reaction and a suspected drug, suggesting that this adverse event was probably related to paliperidone.5 Because there is a lack of a systematic review investigating the demographic and clinical characteristics of patients who have antipsychotic-related peripheral edema, we performed a simple descriptive analysis of relevant articles (25 case studies) identified by MEDLINE search. Using the Naranjo Scale to verify the validity of previous reports on edema secondary to antipsychotic drug, we found large variability in establishing the causality of those
drugs because their estimated Naranjo probability scores ranged from 2 to 10. Among the 25 studies, only 15 studies (18 reported cases) showed higher likelihood that an antipsychotic produced the edema (Naranjo probability scores Q7; Table 1).2,3,6Y18 These reported cases are more likely to be female (72.2%) and have bipolar disorder (33.3%) or schizophrenia (22.2%). Their mean age was 44.1 years old. Most of them were reported in the context of concomitant medications (66.7%) but no concurrent medical illness (77.8%). Risperidone and olanzapine (both 33.3%) were the most likely drugs to have related peripheral edema, followed by quetiapine (27.8%) and chlorpromazine (5.6%). The time of edema onset after beginning antipsychotic treatment varied (standard deviation, 28.5 days), although the mean time was 25.8 days. The mechanism underlying the development of peripheral edema after antipsychotic use remains unclear. By reviewing the literature, we found 3 hypotheses that might explain this adverse effect: (1) a peripheral vasodilation possibly mediated by antipsychotic antagonism to >-receptors and/or 5-HT2 receptors,12,14 (2) an indirect * 2014 Lippincott Williams & Wilkins
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Clinical Psychopharmacology
&
Volume 34, Number 2, April 2014
increase in water retention through activating the hormone system (eg, renin and aldosterone),6 and (3) a type I and/or type IV allergic response to antipsychotic.3 The hypothesis of an antipsychotic-related vasodilation seemed to be more plausible because a recent cross-sectional study has shown a significant change in vascular compliance in 63 psychiatric patients on risperidone or quetiapine compared to a control group composed of 111 nonpsychiatric subjects who did not take any antipsychotic.19 Given that paliperidone is the 9hydroxy metabolite of risperidone, it is likely that these 2 drugs share common pathogenic pathways causing the edema.4 One possibility is that the compounds they share induce the edematous event. These compounds include the paliperidone itself and its associated metabolites resulting from a benzisoxazole scission or N-dealkylation metabolic pathway, and the common inactive ingredients that make up risperidone and paliperidone, such as titanium dioxide, propylene glycol, and ionic compounds containing sodium.20 It would be interesting to study the pathogenic role of these compounds because some of them are not well studied and some are categorized as drug additives that have been used to formulate several other antipsychotics (eg, olanzapine and quetiapine) that have been known to induce peripheral edema. In summary, this report alerts physicians to the potential development of peripheral edema in patients being prescribed paliperidone. Several patient characteristics and many other antipsychotics may be linked to this adverse effect. Therefore, close monitoring might be needed when initiating antipsychotic treatment. A multicenter study using a central database, including follow-up data, should be performed to systematically study peripheral edema in patients treated with antipsychotics. ACKNOWLEDGMENTS No financial support was received for this work. AUTHOR DISCLOSURE INFORMATION The authors declare no conflicts of interest. Hung-Jen Chen, MD Department of Psychiatry Kaohsiung Kai-Syuan Psychiatric Hospital Kaohsiung, Taiwan
Shuai-Ting Lin, MD Department of Psychiatry Kaohsiung Kai-Syuan Psychiatric Hospital Kaohsiung, Taiwan [email protected] * 2014 Lippincott Williams & Wilkins
Heng-Chia Hsu, MD Kai-Da Cheng, MD Hin-Yeung Tsang, MRCPsych, PhD Department of Psychiatry Kaohsiung Kai-Syuan Psychiatric Hospital Kaohsiung, Taiwan
REFERENCES
Letters to the Editors
learning disability and autism. Autism. 2006;10:308Y310. 15. Ravasia S. Risperidone-induced edema. Can J Psychiatry. 2001;46:453Y454. 16. Sanders RD, Lehrer DS. Edema associated with addition of risperidone to valproate treatment. J Clin Psychiatry. 1998;59:689Y690.
1. Baldessarini RJ. Drugs and the treatment of psychiatric disorders. In: Gillman AG, Goodman LS, Gilman A, eds. The Pharmacological Basis of Therapeutics. 6th ed. New York, NY: Macmillan; 1980:397.
17. Yang HN, Cheng YM. Peripheral edema associated with risperidone oral solution: a case report and a review of the literature. J Clin Psychopharmacol. 2012; 32:128Y130.
2. Christensen RC. Olanzapine-associated bilateral pedal edema. J Clin Psychiatry. 2003;64:972.
18. Hosseini SH, Ahmadi A. Peripheral edema occurring during treatment with risperidone combined with citalopram. Case Rep Med. 2012;2012:540732.
3. Koleva HK, Erickson MA, Vanderlip ER, et al. 3 case reports of edema associated with quetiapine. Ann Clin Psychiatry. 2009; 21:77Y80.
19. Koola MM, Brown WV, Qualls C. Reduced arterial compliance in patients with psychiatric diagnoses. Schizophr Res. 2012;137:251Y253.
4. Chwieduk CM, Keating GM. Paliperidone extended release: a review of its use in the management of schizophrenia. Drugs. 2010;70:1295Y1317.
20. Mannens G, Huang ML, Meuldermans W. Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos. 1993;21:1134Y1141.
5. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239Y245. 6. Witz L, Shapiro MS, Shenkman L. Chlorpromazine induced fluid retention masquerading as idiopathic oedema. Br Med J (Clin Res Ed). 1987;294:807Y808. 7. Yovtcheva SP, Yazel JJ. Olanzapine-induced bilateral pedal edema: a case report. Gen Hosp Psychiatry. 2000;22:290Y291. 8. Yalu? I, Ozten E, Evren Tufan A, et al. Bilateral pedal edema associated with olanzapine use in manic episode of bipolar disorder: report of two cases. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1541Y1542. 9. Deshauer D, Erwin L, Karagianis J. Case report: edema related to olanzapine therapy. Can Fam Physician. 2006;52:620Y621. 10. Nayak V, Chogtu B, Devaramane V, et al. Pedal edema with olanzapine. Indian J Pharmacol. 2009;41:49Y50. 11. Chen HK, Liao HY, Huang CC. Concurrent pedal edema and sinus bradycardia associated with quetiapine. Psychiatry Clin Neurosci. 2011;65:537Y538. 12. Chen CY, Yeh YW, Kuo SC, et al. Pedal edema associated with addition of low-dose quetiapine to valproate treatment in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:1551Y1552. 13. Akdag ST, Fettahoglu EC, Ozatalay E. Pedal edema induced by low-dose risperidone monotherapy in a child. J Child Adolesc Psychopharmacol. 2009; 19:481Y482. 14. Feroz-Nainar C, Selvaraj P, Roy M. Risperidone induced oedema in a child with
Risperidone and Quetiapine-Related Arthralgia To the Editors: isperidone and quetiapine are atypical antipsychotics with serotonin 5-HT2 and dopamine D2 antagonistic properties and are widely used in the treatment of psychotic disorders. We report a case of arthralgic adverse effects after risperidone and quetiapine treatment. Mr A, a 44-year-old male, visited our outpatient clinic because of anxiety, depressed mood, and poor sleep in the past 6 months because he had the feeling that he was being followed by an unknown stalker who may harm him. Under the diagnosis of persecutory delusional disorder, treatment with quetiapine (12.5 mg/d) was initiated. Because of his poor medication compliance, the medication was shifted to risperidone long-acting injection (12.5 mg/injection) with a 2-week interval, and the dosage was titrated to 37.5 mg/injection 1 month later. At the same time, he was also treated with fludiazepam for anxiety and with flunitrazepam for insomnia. Initially, he only had pain in his right knee after the quetiapine treatment. He had a history of previous trauma with his right knee, so he did not pay much attention to the pain. However, right after the risperidone injection treatment began, the joint pain progressed to his whole body without localized erythematous change, heat, or swelling. He had no history of
R
www.psychopharmacology.com
Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
271
