Emergency Treatment of Acute

Emergency Treatment of Acute Psychosis

James Randolph Hillard, M.D.

The author reviews the evolution of emergency psychiatric practice over the past 20 years—from the concept of high-dose medication to the more rational treatment approach for acute © Copyrightpsychosis made possible 1998 by modern pharmacodynamic insight Postgraduate and the availability of Press,new pharmaco- Inc. therapeutic agents. A decision tree for current practice in the rapid tranquilization of agitated, appar- ently psychotic patients is described. (J Clin 1998;59[suppl 1]:57–60)

major impetus for the founding of psychiatric emer- frequent practice at that time was to give repeated doses of A gency services 20 or 30 years ago was the concept antipsychotic every 30 minutes or even every 15 minutes of “rapid tranquilization.”1 The concept was that patients until the patient was tranquilized or asleep.3 would come in to an emergency service, acutely psychotic, would be given high doses of antipsychotic medication, TEN YEARS AGO and would be able to leave the emergencyOne personal room copywell may be printed enough compensated to avoid hospitalization. Over the Table 1 lists several synonyms which have been used to years, the limitations to this concept have become describe the acute treatment of psychotic episodes. Only increasingly apparent, but modern understanding of phar- one of these synonyms has withstood the test of time. Both macodynamics and the availability of new pharmaco- rapid neuroleptization and psychotolysis imply that these therapeutic agents now allow a more rational treatment psychoses are being rapidly made to vanish by treatment approach for acute psychosis. Unfortunately, many clini- with antipsychotic medications. In fact, clinical experi- cians are still using outdated approaches, such as high- ences have not proven this to be the case. Patients who are dose conventional , rather than more ratio- acutely tearing up an emergency room because they are nal treatment approaches. This paper will review the hearing voices will, after treatment with antipsychotic development of emergency psychiatric practice over the medications, usually become less agitated, less hostile, and last 20 years and will describe a decision tree for rational less suspicious, but will generally still describe hearing current practice. voices, although they will usually say the voices are less loud, less frightening, or easier to ignore.5 Rapid digitali- TWENTY YEARS AGO zation describes the attractive, but completely discredited, notion that antipsychotic medications can be dosed like Twenty years ago was the golden age for high-dose digitalis such that a high loading dose can be followed by a antipsychotics. Some studies used doses equivalent to lower maintenance dose, giving rise to a faster onset of ac- 1000 mg of .2 Doses of 100 mg were relatively tion. Unfortunately, studies have been very consistent in common in clinical practice.3 This was also a time when demonstrating that higher doses initially, in fact, do not many psychopharmacologists recommended against rou- lead to a more rapid response.6 Chemical restraint is prob- tine use of anticholinergic agents.4 Not surprisingly, this ably the least appropriate term to use for medicolegal as era led to an enormous number of dystonic reactions, and well as for clinical reasons. Court decisions about the ap- even today, it is frequent to meet patients who believe that propriate use of seclusion and restraint have been quite they are “allergic” to haloperidol because of the extreme variable in their exact stipulations, but have been remark- extrapyramidal reactions they may have had in the past. A ably consistent in mandating that chemicals be used for treatment, rather than restraint, of patients.7 The only term which has stood the test is the most modest, that is, rapid From the Department of Psychiatry, University of tranquilization, which implies giving patients medication Cincinnati, Cincinnati, Ohio. to make them less agitated and hostile. Presented at the closed symposium “Clinical Outcomes in Given this relatively modest definition of rapid tranqui- the Treatment of Schizophrenia,” April 12, 1996, held in New Orleans, Louisiana, and sponsored by an unrestricted lization, we are left with the questions of what drugs to educational grant from Janssen Phamaceutica, Inc. use, how much, by what route, and for how long. Any of Reprint requests to: J. R. Hillard, M.D., Department of Psychiatry, University of Cincinnati, P.O. Box 670559, the high-potency antipsychotics (e.g., fluphenazine, halo- Cincinnati, OH 45267-0559 peridol, loxapine, thiothixene, trifluoperazine) will give

J Clin Psychiatry 1998;59 (suppl 1) 57 James Randolph Hillard

Table 1. Synonyms for Rapid Medication of Psychotic Patients ratically absorbed from intramuscular administration. Flu- Rapid tranquilization phenazine decanoate or haloperidol decanoate are clearly Rapid neuroleptization inappropriate choices for rapid tranquilization since they Rapid digitalization do not reach therapeutic plasma levels for several days. If a Psychotolysis Chemical restraint patient does respond to acute treatment with a short- acting antipsychotic, however, it may be a good idea to get the patient’s consent to administration of a longer acting agent at the time the patient leaves the emergency service. Table 2. Scorecard Comparing Haloperidol and Lorazepam for Treatment of Acute Psychosis* FIVE YEARS AGO Effect© Copyright Lorazepam 1998 Haloperidol Physicians Postgraduate Press, Inc. Safe, even in the medically ill Yes Yes Minimal postural hypotension Yes Yes By 5 years ago, there was general acceptance that doses No major drug interactions Yesa Yes of antipsychotic medication higher than 10 to 15 mg of ha- Controls agitation Yes Yes loperidol or its equivalent were not substantially better Specific for psychosis No Yes Extrapyramidal reactions No Yes than lower doses and, in fact, might lead to poorer out- Respiratory depression Possibleb No comes.6 It was also generally understood that repeated Paradoxical hostility Maybe No doses of antipsychotics at 30-minute intervals, which had *Adapted from reference 8. been the practice earlier, did not make pharmacodynamic aSome additive effect with other . bRespiratory depression possible with high or repeated doses. sense in that it took about 1.5 to 2 hours after administra- tion for peak tranquilization by orally administered antipsychotics.12 It was also generally understood that in- adequate sedation without excessive Oneside effects. personal Benzodi- copy maytramuscular be printed administration could give an onset of action azepines can achieve the same results. Twenty years ago, within 1.5 hours and that intravenous antipsychotics could when the hope was that psychosis would be “lysed” in the give an onset generally within an hour.13 Intravenous anti- emergency room, were not ordinarily psychotics never came to be widely used because considered. By 10 years ago, however, with the general un- generally patients who might be candidates for them were derstanding that our goal in treatment was tranquilization not patients anyone would start on intravenous treatment. rather than elimination of the psychosis in the short run, Intravenous antipsychotics, at the present time, are used al- benzodiazepines were considered an appropriate alterna- most exclusively in intensive care units where patients tive choice.5,6 Table 2 shows a scorecard comparing loraze- already have indwelling intravenous lines and where the pam with haloperidol. Both of these drugs are safe even in staff has very low tolerance for psychotic behavior. Intra- medically ill patients and have no major drug interactions, venous antipsychotics are generally safe and have been which is desirable since many patients who need to be rap- reportedly used in very medically compromised patients in idly tranquilized are not able to give a reliable history. incredibly high doses (e.g., 10 mg q 15 minutes for 2 Both cause minimal postural hypertension and control agi- weeks),14 but there is evidence for their causing arrhythmi- tation. Benzodiazepines, of course, do not cause extrapyra- as (such as torsade de pointes)15 in some cases. midal reactions and also are not associated with neurolep- Alternative drugs in use 5 years ago included midazo- tic malignant syndrome, a complication which was well lam, which is frequently used in emergency as a known by 10 years ago and which may be associated with pre-endoscopy agent. Unfortunately, it causes substantial high or rapidly escalating doses of antipsychotic medica- anterograde amnesia in many cases,16 which is positive tions.9 The two major potential drawbacks of benzodiaz- when patients forget about their endoscopy procedure, but epines are the possibility of respiratory depression when is negative when they are unable to remember their possi- given in very high doses or in addition to other bly therapeutic reaction with staff. , and the possibility of paradoxical hostility.10 In Concern about respiratory depression from intravenous practice, the paradoxical hostility appears to be relatively midazolam has recently led to a warning in the package in- unusual and confined primarily to patients who are either sert that dosage must be individualized and must never be (1) elderly, (2) damaged or mentally retarded, or (3) given rapidly. Droperidol, a drug similar to haloperidol, is already intoxicated with other sedative drugs.11 marketed as a preanesthetic agent and is still used in many Drugs that clearly do not make any sense for rapid parts of the country in milligram doses equivalent to halo- tranquilization include low-potency antipsychotics, which peridol. It probably has a shorter duration of action and a often have a postural hypertensive effect; chloral hydrate lower incidence of extrapyramidal symptoms than does or sodium amytal, which tend to put patients to sleep at haloperidol, but may have greater hypotensive effects. about the same dose necessary to sedate them; and intra- Droperidol is available only in intravenous formulation so muscular benzodiazepines other than lorazepam or mid- patients who are helped by it in the emergency room can- azolam, since the other benzodiazepines are slowly and er- not be sent out taking the same medication by mouth.17

58 J Clin Psychiatry 1998;59 (suppl 1) Emergency Treatment of Acute Psychosis

Figure 1. Flow Sheet for “Rapid Tranquilization” of Agitated tive, and well tolerated when applied by knowledgeable and Apparently Psychotic Patients personnel. At this point, it is possible to take vital signs and do some physical examination, which, in some cases, will Patient presents agitated, hostile, apparently psychotic lead to the recognition of a medical disorder that needs emergency treatment, such as acute hyperthyroidism. Talk to patient The first branch point on our decision tree is whether the patient has a past history of psychosis or antipsychotic Use physical restraints medication. Initial treatment with a is probably preferable to initial treatment with an antipsy- Take vital signs, physical examination © Copyright 1998 Physicianschotic. Postgraduate If the patient is at least Press, somewhat Inc.cooperative and Past history of psychosis or antipsychotic medication? seems to prefer oral administration, that approach is rea- sonable although frequent readministration of antipsy-

Yes No chotic medications does not make pharmacologic sense. Readministration of a benzodiazepine up to twice for a to- tal of about 6 mg of lorazepam may be reasonable. Appropriate for oral Elderly, brain Yes medication? damaged, If the patient calms down enough to be assessed to be intoxicated with clearly psychotic, it is reasonable to add haloperidol or ris- sedative hypnotics Yes No or history of adverse peridone to the benzodiazepine. Antipsychotic plus benzo- reaction to diazepine even in high doses has been shown to be a safe benzodiazepines Risperidone 2Ð4 mg Haloperidol and effective combination. If the patient has a history of haloperidol 5Ð10 mg im 5Ð10 mg po paradoxical reaction to benzodiazepines, is intoxicated One personalNo copy maywith be sedative printed hypnotics, is elderly (over 70), or is brain damaged, an antipsychotic approach may be more appro- Lorazepam If agitated in 2 hr, consider 2 mg po or im priate. If a patient has a past history of psychosis or anti- adding lorazepam. If haloperidol is used and psychotic medication, the antipsychotic approach is also patient is discharged, If still agitated in indicated. If the patient needs an intramuscular approach, consider adding 30 min, repeat anticholinergics up to twice haloperidol 5Ð10 mg is indicated (10 mg for young healthy people, and 5 mg for older individuals [usually those > 70 If psychotic, years old]). If a patient is appropriate for an oral approach, consider adding risperidone 2Ð4 mg is reasonable, unless the patient prefers risperidone or haloperidol something else. This is higher than the initial dose recom- mended on the package insert, but is generally very well tolerated. The much lower incidence of extrapyramidal side effects often makes oral risperidone more tolerable for NOW patients than oral haloperidol. In either case, antipsychot- ics are generally not readministered within the first 2 Three relatively new drugs are now available for anti- hours. If a patient needs further tranquilization, adding 2 psychotic treatment. The first available was clozapine, mg of lorazepam p.o. or i.m. is acceptable and safe. If pa- which turned out to be inadvisable for rapid tranquiliz- tients are not hospitalized, prophylactic anticholinergics ation. Although very sedating, it also causes severe ortho- should strongly be considered if haloperidol or another static hypertension and other anticholinergic side effects.18 high-potency antipsychotic has been used for rapid Risperidone, on the other hand, has a lower rate of extrapy- tranquilization. ramidal symptoms than does haloperidol, but lacks the se- vere orthostatic hypertension and anticholinergic side ef- SPECIAL CONSIDERATIONS fects of clozapine.19 Olanzapine has similar drawbacks to IN THE TREATMENT OF ACUTE MANIA clozapine.20 In emergency situations for patients ordinarily taking clozapine or olanzapine, it is reasonable to restart Acutely manic patients, whether bipolar I or schizoaf- them on these medications at doses similar to what they fective, are among those most difficult patients to stabilize. were taking previously. These agents, however, are prob- Often they will require both antipsychotics and benzodiaz- ably not the best medications to give patients for the first epines together for any sedation. Recent data have con- time in an emergency room situation. firmed that high doses of haloperidol (over about 10 mg) Figure 1 shows a rapid tranquilization decision tree. The do not lead to increasing effectiveness.21 One case report first approach is, of course, to try to calm the patient by ver- suggested that risperidone might actually lead to worsen- bal means, but if this is unsuccessful, then the next ap- ing of manic symptoms.22 While this does not appear to be proach is to use physical restraints. These are safe, effec- the case frequently, risperidone monotherapy may not be

J Clin Psychiatry 1998;59 (suppl 1) 59 James Randolph Hillard

Table 3. Relative Receptor Affinities of Newer and Forthcoming Antipsychotics* Histamine Muscaranic α α D1 D2 5-HT1a 5-HT2a 1 2 H1 M1 Approved Haloperidola +++ ++++ … +++…… … Clozapineb ++ ++ + +++ +++ +++ ++++ +++++ Risperidonec ++ ++++ ++ +++++ +++ +++ ++ … Olanzapined +++ +++ … ++++ +++ … ++++ +++++ Quetiapined +++… + ++++ + ++++ +++ Investigational Remoxipridec … + ……………… Sertindoled +++ +++++ ++ ++++ +++ … ++ Ziprasidone©d Copyright+ ++++ 1998 Physicianse ++++ Postgraduate ++ … Press,+ Inc.… *From reference 25. Ratings reflect the author’s judgment of relative potencies (+ to +++++) based on comparison of published IC50 at KI values for these agents.26Ð29 Abbreviations: α = α-adrenergic, D = , 5-HT = serotonin. aPrototype typical neuroleptic. bLow EPS. cDose-dependent EPS. dThorough efficacy and side effect data are not currently available. e Norepinephrine reuptake inhibition, 5-HT1a agonist. very effective in treating acute mania.23 An alternative ap- 10. Gardiner DL, Cowdry RW. Alprazolam-induced dyscontrol in borderline personality. Am J Psychiatry 1985;142:98Ð100 proach for acutely manic patients is oral loading of dival- 11. Dietch JT, Jennings RK. Aggressive dyscontrol in patients treated with ben- proex sodium in a dose of 20 mg/kg, along with lorazepam zodiazepines. J Clin Psychiatry 1988;49:184Ð188 or other benzodiazepine for sedation.24 12. Dubin WR, Waxman HM, Weiss KJ, et al. Rapid tranquilization: the effi- One personal copy may cacybe ofprinted oral concentrate. J Clin Psychiatry 1985;46:475Ð478 13. Menza MA, Murray GB, Holmes VF, et al. Decreased extrapyramidal THE FUTURE symptoms with intravenous haloperidol. J Clin Psychiatry 1987;48: 278Ð280 14. Adams F. Neuropsychiatric evaluation and treatment of delirium in the Table 3 lists the receptor binding profiles associated critically ill cancer patient. Cancer Bulletin 1984;36:156Ð160 with the three currently available “atypical” antipsychot- 15. Hunt N, Stern TA. The association between intravenous haloperidol and ics and with three that are going to be available soon. Torsades de Pointes: three cases and a literature review. Psychosomatics 1995;36:541Ð549 There are too many question marks currently to know 16. Mendoza R, Djenderedjian AH, Adams J, et al. Midazolam in acute psy- whether the newer agents will have advantages for rapid chotic patients with hyperarousal. J Clin Psychiatry 1987;48:291Ð292 tranquilization. Another agent, however, that should be 17. Resnick M, Burton BT. Droperidol vs haloperidol in the initial manage- ment of acutely agitated patients. J Clin Psychiatry 1984;45:298Ð299 available soon is injectable risperidone, which is likely to 18. Safferman A, Lieberman JA, Kane JM, et al. Update on the clinical efficacy find a place in the rapid treatment of acute psychosis. and side effects of clozapine. Schizophr Bull 1991;17:247Ð261 19. Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. 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