Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 Letters to the Editors  indicate that risperidone may aid in the should take note of this interaction an autistic child. J Child Adolesc Psychophar- treatment of depression by augmenting between these 2 agents that are common- macol. 2004;14(3):342–343. 12. Hamilton S, Malone K. Serotonin syndrome the activity of selective serotonin reup- ly used in the elderly population. 9 during treatment with paroxetine and risper- take inhibitors, including paroxetine. idone. J Clin Psychopharmacol. 2000;20(1): Risperidone and paroxetine interaction 103–105. can lead to weight gain,10 priapism,11 M. Obadah Al Chekakie, MD* 13. Paroxetine[packageinsert].ResearchTriangle and rarely to serotonin syndrome.12 Jeffrey M. Ketz, PharmD Park, NC: GlaxoSmithKline Pharmaceuti- y cals; January 2005. Paroxetine is a substrate and in- Christopher M. Whinney, MD 14. Spina E, D’Arrigo C, Migliardi G, et al. hibitor of CYP2D6. Metabolism by *Department of Cardiologyz Plasma concentrations of risperidone and 9- the CYP2D6 enzyme is saturable at Loyola University Medical Center hydroxyrisperidone during combined treat- usual doses of paroxetine in 90% of Maywood, IL; ment with paroxetine. Ther Drug Monit. 2004; 13 Department of Pharmacy 26(4):386–390. patients. Paroxetine is known to raise y 15. Galantamine [package insert]. Titusville, NJ: the plasma concentration of risperidone Cleveland Clinic Foundation Janssen Pharmaceutica; March 2005. and 9-OH risperidone. When paroxetine Cleveland, OH 16. Bentue-Ferrer D, Tribut O, Polard E, was added to risperidone therapy, Spina and Section of Hospital Medicine et al. Clinically significant drug interac- z tions with cholinesterase inhibitors: a guide et al14 observed a 45% increase in mean Department of General Internal Medicine Cleveland Clinic Foundation for neurologists. CNS Drugs. 2003;17(13): risperidone plus 9-OH risperidone (ris- 947–963. Cleveland, OH peridone active moiety) concentrations 17. Huang F, Lasseter KC, Janssens L, et al. [email protected] in 10 CYP2D6 extensive metabolizers. Pharmacokinetic and safety assessments of galantamine and risperidone after the Our patient was also receiving galant- two drugs are administered alone and amine, a competitive inhibitor of acetyl- together. J Clin Pharmacol. 2002;42(12): cholinesterase. Galantamine is metabolized REFERENCES 1341–1351. via CYP2D6 and CYP3A4 but it does not 18. Scott LJ, Goa KL. Galantamine: a review of 15,16 1. Yoder E. Disorders due to heat and cold. In: its use in Alzheimer’s disease. Drugs. 2000; inhibit those enzymes. Coadministra- William P, Arend MD, et al, eds. Cecil Text 60(5):1095–1122. tion of galantamine and risperidone does Book of Medicine, Vol 1. 5th ed. New York, 19. Bores GM, Huger FP, Petko W, not increase the serum concentration of NY: WB Saunders; 2004:626–628. et al. Pharmacological evaluation of novel risperidone active moiety.17 Paroxetine 2. Parris C, Mack JM, Cochiolo JA, et al. Alzheimer’s disease therapeutics: acetylcho- can raise galantamine levels by inhibit- Hypothermia in 2 patients treated with linesterase inhibitors related to galantha- ing CYP2D6 leading to a 40% increase atypical antipsychotic medication. J Clin mine. J Pharmacol Exp Ther.1996;277(2): 16,18 Psychiatry. 2001;62(1):61–63. 728–738. in its bioavailability. Galantamine 3. Schwaninger M, Weisbrod M, Schwab S, 20. Gordon CJ. Thermoregulatory aspects of has been reported to cause hypothermia et al. Hypothermia induced by atypical neu- environmental exposure to anticholinester- in animal models,19 but there are no roleptics. Clin Neuropharmacol. 1998;21(6): ase agents. Rev Environ Health. 1996; reported cases of galantamine-induced 344–346. 11(3):101–117. 4. Phan TG, Yu RY, Hersch MI. Hypothermia hypothermia in humans in the English induced by risperidone and olanzapine in a literature. In organophosphate poison- patient with Prader-Willi syndrome. Med J ing, which usually leads to irreversible Aust. 1998;169(4):230–231. inhibition of acetylcholinesterase, hu- 5. Brevik A, Farver D. Atypical antipsychotic Impact of Orally mans usually have a hyperthermic induced mild hypothermia. S D J Med. 2003; 56(2):67–70. response compared with the hypother- Disintegrating 20 6. Razaq M, Samma M. A case of risperidone- mic response noted in rodents. Galant- induced hypothermia. Am J Ther. 2004;11(3): Olanzapine on Use of amine potentially may have contributed 229–230. to this patient’s hypothermia because of 7. Leysen JE, Janssen PM, Megens AA, et al. Intramuscular the pharmacokinetic interaction of gal- Risperidone: a novel antipsychotic with bal- anced serotonin-dopamine antagonism, recep- Antipsychotics, antamine and paroxetine or to a possible tor occupancy profile, and pharmacologic pharmacodynamic interaction between activity. J Clin Psychiatry. 1994;55(suppl): Seclusion, and galantamine and risperidone. However, 5–12. accumulated clinical data in humans do 8. Heykants J, Huang ML, Mannens G, et al. The Restraint in an Acute not support this hypothesis. The de- pharmacokinetics of risperidone in humans: Inpatient Psychiatric crease in oral intake might be a result of asummary.JClinPsychiatry.1994;55(suppl): hypothermia and not the cause of it, 13–17. 9. Ostroff RB, Nelson JC. Risperidone augmen- Setting especially since the patient had no tation of selective serotonin reuptake inhibi- clinical signs of dehydration. tors in major depression. J Clin Psychiatry. To our knowledge, this is the sixth 1999;60(4):256–259. To the Editors: reported case of risperidone-induced hy- 10. Fukui H, Murai T. Severe weight gain Intramuscular (IM) conventional pothermia. The drug interaction between induced by combination treatment with antipsychotics have long been used to risperidone and paroxetine. Clin Neurophar- paroxetine and risperidone may also have macol. 2002;25(5):269–271. manage agitation and aggression in the 1 been a factor in the development of 11. Yang P, Tsai JH. Occurrence of priapism psychiatric inpatient setting. Although hypothermia in this patient. Clinicians with risperidone-paroxetine combination in generally effective, these preparations n 2006 Lippincott Williams & Wilkins 333

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Letters to the Editors Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006  have multiple drawbacks, both in terms in the 6 months after its introduction substance use disorders (excluding sub- of side effects2–6 and as a consequence (the ‘‘POST’’ group). The PICU is a stance-induced psychotic disorder), and of their route of administration. In locked, 12-bed psychiatric ‘‘crisis’’ unit (6) all other diagnoses.11 addition to these factors, treatment for the most acutely ill psychiatric invoking the principle of the ‘‘least patients treated at the West Los Angeles Administration of restrictive environment or intervention’’ VA. The study protocol was approved Intramuscular and Oral has become generally accepted in the by the West Los Angeles VAMC Antipsychotics for Acute psychiatric community.7 This ethical Institutional Review Board. An exemp- Agitation standpoint serves as a compromise tion to the requirement for informed The data regarding the number of between individual rights and severely consent was obtained by excluding administrations of emergent IM con- mentally ill patients’ need for treatment, identifying data and by other security ventional antipsychotics for both study particularly in cases in which impaired measures to protect confidential patient groups and of olanzapine Zydis in the reality testing or impulse control may information. POST group are shown in Table 1. be associated with potentially danger- There were no significant differences between the 2 groups. ous behavior. From this perspective, it Patient Demographics is important to reduce the use of both and Diagnoses Seclusion and Restraint invasive routes of medication adminis- The demographic and diagnostic In the PRE group, 16 patients tration and seclusion and restraint. information for the 2 groups are pre- (8.8%) were placed in seclusion, and 13 Finally, a reduction in the number of sented in Table 1. For purposes of (7.2%) were placed in restraints. In the violent outbursts and episodes of seclu- analysis, diagnoses assigned at the time POST group, 16 patients (9.4%) were sion and restraint may improve patient placed in seclusion, and 12 (7.0%) were 8,9 of discharge or transfer were divided into and staff morale. 6categories:(1)primarypsychoticdis- placed in restraints. There were no signif- Recently, literature has emerged orders (ie, schizophrenia and schizoaffec- icant differences between the 2 groups. showing that, in patients willing to take tive disorder), (2) substance-induced them, oral atypical antipsychotics are as psychotic disorder and psychotic disorder DISCUSSION effective as IM conventional antipsy- not otherwise specified, (3) type I bipolar The results of this study do not sup- chotics in treating acute psychotic disorder, (4) dementia or delirium, (5) port our hypothesis that the availability of agitation.10 We report on the use of a rapidly dissolving oral formulation of TABLE 1. Patient Demographics, Diagnoses, and Use of p.r.n. Antipsychotics an atypical antipsychotic (olanzapine; Zyprexa, Eli Lilly and Co, Indianapolis, PRE Group POST Group IN; Zydis, Cardinal Health Pharmaceu- (n = 181) (n = 171) tical Technologies and Services, Som- Age, mean ± SD, y 46.6 ± 8.5 47.5 ± 9.2 erset, NJ) on a high-intensity acute Male, n (%) 166 (92) 161 (94) inpatient ward. Length of stay, mean ± SD, d 7.4 ± 8.7 8.2 ± 10.2 In November 2002, the psychiat- Caucasian, n (%) 78 (43) 69 (40) ric intensive care unit (PICU) at the West Los Angeles Veterans’ Affairs African American, n (%) 75 (41) 87 (51) Medical Center (VAMC) replaced 5 mg Hispanic, n (%) 20 (11) 13 (8) oral haloperidol with 10 mg olanzapine Other, n (%) 8 (4) 2 (1) Zydis (an oral, rapidly disintegrating Primary psychotic disorder, n (%) 44 (24.3) 46 (26.9) ‘‘wafer’’ formulation) as the ‘‘as need- Substance-induced psychosis/psychosis 19 (10.5) 15 (8.8) ed’’ oral antipsychotic of choice for not otherwise specified, n (%) agitation. We hypothesized that the Bipolar disorder, n (%) 22 (12.2) 15 (8.8) availability of oral olanzapine Zydis Dementia/delirium, n (%) 7 (3.9) 7 (4.1) would reduce the use of IM antipsy- Substance use disorder, n (%) 62 (34.3) 66 (38.6) chotics in this setting. We also exam- All emergent IM conventional 27 (14.9) 26 (15.2) ined the impact of olanzapine Zydis on antipsychotics, n (%) the use of seclusion and restraint. ‘‘First-line’’ emergent IM N/A 20 (11.7) In a retrospective chart review, conventional antipsychotics, n (%) we collected data on the use of p.r.n. ‘‘Second-line’’ emergent IM N/A 9 (5.3) IM antipsychotics, seclusion, and re- conventional antipsychotics, n (%) straint for all patients admitted to the Emergent oral olanzapine Zydis, n (%) N/A 37 (21.6) PICU at the VAMC in West Los PRE indicates patients admitted in 6-month period before addition of olanzapine Zydis to the ward Angeles in the 6 months before the formulary; POST, patients admitted in six-month period after addition of olanzapine Zydis to the ward introduction of olanzapine Zydis to the formulary; N/A, not applicable; first-line, before administration of olanzapine Zydis; second-line, after ward formulary (the ‘‘PRE’’ group) and administration of olanzapine Zydis (for a given episode of agitation).

334 n 2006 Lippincott Williams & Wilkins

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology Volume 26, Number 3, June 2006 Letters to the Editors  a rapidly disintegrating formulation of medication. Thus, there may have been Los Angeles, CA an atypical antipsychotic for emergent a tradeoff between use of benzodiaze- [email protected] use would reduce the use of IM anti- pines and olanzapine Zydis after the psychotics or of seclusion or restraint in introduction of the latter. A study in an acute inpatient psychiatric setting. In which only antipsychotics were used comparison with a similar patient popu- might provide a more definitive com- REFERENCES lation admitted before the addition of parison of the utility of oral atypical 1. Buckley PF. The role of typical and atypical olanzapine Zydis to the ward formulary, antipsychotics versus IM medications in antipsychotic medications in the management the study group demonstrated no change controlling severe agitation. of agitation and aggression. J Clin Psychiatry. in use of IM antipsychotics, seclusion, 1999;60(suppl 10):52–60. It should also be remembered that 2. Ayd FJ Jr. A survey of drug-induced ex- or restraint. While this may suggest that although olanzapine Zydis dissolves tra pyramidal reactions. JAMA. 1961;175: the introduction of olanzapine Zydis to rapidly in the mouth, its absorption 1054–1060. the ward formulary did not reduce the occurs via the gastric mucosa. There- 3. Van Putten T, Marder SR. Behavioral toxicity use of more restrictive interventions, the fore, its onset of action is equivalent to of antipsychotic drugs. J Clin Psychiatry. lack of a quantitative measurement of the tablet form.12 This relatively slow 1987;48(suppl 9):13–19. illness severity (eg, a Global Assessment onset of action (peak plasma level at 6 4. Keck PE Jr, Pope HG Jr, Cohen BM, et al. of Functioning score at the time of Risk factors for neuroleptic malignant syn- hours after administration) may in part drome: a case-control study. Arch Gen admission) precludes drawing any firm explain the lack of effect seen for conclusions regarding the impact or lack Psychiatry. 1989;46:914–918. olanzapine Zydis in reducing emergent 5. Casey DE. Motor and mental aspects of of impact of the availability of p.r.n. IM use and seclusion and restraint in the extrapyramidal syndromes. Int Clin Psycho- olanzapine Zydis on these outcome present study. It is possible that IM pharmacol. 1995;10(suppl 3):105–114. measures. In other words, it is possible antipsychotics, seclusion, or restraint 6. Czekalla J, Beasley CM Jr, Dellva MA, et al. that a difference in overall illness se- was used before the onset of the clinical Analysis of the QTc interval during olanza- verity between the 2 groups may have effect of olanzapine Zydis. pine treatment of patients with schizophrenia obscured any potential benefits such as The use of IM atypical antipsy- and related psychosis. J Clin Psychiatry. reduced use of IM antipsychotics, seclu- 2001;62:191–198. chotics, such as olanzapine and ziprasi- sion, or restraint. However, this possible 7. Munetz MR, Geller JL. The least re- done, both of which have been recently explanation seems less likely when strictive alternative in the postinstitutional approved for acute use in the United era. Hosp Community Psychiatry. 1993;44: considering the lack of any known States, would avoid this pharmacokinetic 967–973. changes in the VA population accessing 8. Brennan W. We don’t have to take this: services during the 12 months of the disadvantage of oral olanzapine while maintaining atypical antipsychotic effica- dealing with violence at work. Nurs Stand. study and the similar demographics and 2000;14(suppl 28):3–17. distribution of diagnoses in the 2 groups. cy. These agents greatly reduce the fre- 9. Chengappa KNR, Levine J, Ulrich R, et al. This study has several limitations. quency of many of the adverse reactions Impact of risperidone on seclusion and Patients must agree, if only by assent, to seen with conventional antipsychotics, restraint at a state psychiatric hospital. Can take any oral medication. Patients who but obviously not those consequent to the J Psychiatry. 2000;45:827–832. IM route of administration. Neverthe- 10. Currier GW, Simpson GM. Risperidone are extremely ill or acutely agitated may liquid concentrate and oral lorazepam refuse oral medications, precluding this less, these agents may address the acute treatment needs of patients too agitated versus intramuscular haloperidol and intra- treatment option and necessitating IM muscular lorazepam for treatment of psy- medication when agitation requires to benefit from an oral agent. chotic agitation. J Clin Psychiatry. 2001;62: emergent medication. We did not assess 153–157. the role of patient refusal in the 11. American Psychiatric Association. Diagnos- ACKNOWLEDGMENT tic and Statistical Manual of Mental Dis- selection of interventions for emergent orders. Fourth Edition, Text Revision. agitation. Similarly, we did not address The authors thank George Bartzokis, Washington, DC; American Psychiatric As- the role of nursing staff’s clinical MD, for his help with data analysis and sociation; 2000. judgment regarding these interventions. interpretation. 12. Zyprexa Zydis Product Information. Indian- Another limitation of the study is apolis, IN: Eli Lilly and Co; June 2005. its naturalistic design. We did not Joseph R. Simpson Jr, MD, PhD* address variables such as standing Christopher R. Thompson, MD Altered Expression of antipsychotic or mood-stabilizing med- Mace Beckson, MD y ication orders or the use of p.r.n. oral *University of Southern California Keckzx Myeloperoxidase benzodiazepines. In fact, in the acute School of Medicine, Institute of Psychiatry, inpatient setting studied here, oral Law and Behavioral Science, Precursor, Myeloid Cell benzodiazepines, primarily lorazepam, University of California, Los Angeles Nuclear Differentiation are used frequently on a p.r.n. basis for y Neuropsychiatric Institute, anxiety and agitation. It is possible that University of California and Antigen, Fms-related those who did not respond to benzodia- Psychiatricz Intensive Care Unit Tyrosine Kinase 3 zepines had a more severe level of Departmentx of Veterans’ Affairs agitation more likely to require IM Greater Los Angeles Healthcare System Ligand, and Antigen n 2006 Lippincott Williams & Wilkins 335

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