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Emergency psychopharmacology: A review and update
COLLECTIVE REVIEW psychopharmacologic agents
Emergency Psychopharmacology: A Review and Update [Ellison JM, Jacobs D: Emergency psychopharmacology: A review and update. Ann Emerg Med August 1986;15:962-968.]
James M Ellison, MD Douglas Jacobs, MD Cambridge, Massachusetts
INTRODUCTION Psychopharmacologic agents provide valuable therapeutic control or symptomatic relief in some clinical emergencies and in other settings can precipitate or aggravate behavioral crises. T h e s e m e d i c a t i o n s f r e q u e n t l y are encountered among psychiatric emergency patients. Unpublished data collected by one of the authors from a randomly selected group of 60 patient records in an urban general hospital acute psychiatric service (APS) showed that 30% were currently in medication treatment and 80% claimed to have taken at least one psychiatric medication within the past year. Of those currently or recently medicated, nearly 63% had been on two or more medications. In view of the frequency of psychiatric medication use in emergency psychiatric patients, an awareness of treatment roles and adverse effects must be part of an emergency clinician's special knowledge. We review the field of "emergency psychopharmacology" and the roles of selected psychopharmacologic agents in resolving or precipitating behavioral and toxic psychiatric emergencies. Four major classes of drugs will be considered: antipsychotics, a n t i a n x i e t y agents, antidepressants, and lithium. Additional comments are addressed to the role of psychopharmacologic agents in the treatment of drug abuse emergencies.
From the Department of Biological Therapies in Psychiatry, Cambridge Hospital, Cambridge, Massachusetts; and the Department of Psychiatry, Harvard Medical School, Boston, Massachusetts. Received for publication September 23, 1985. Accepted for publication December 12, 1985. This paper is a revision of a workshop presented at the Tufts University School of Medicine Psychopharmacology Update, Boston, October 1984. Address for reprints: James M Ellison, MD, Department of Psychiatry, Cambridge Hospital, 1493 Cambridge Street, Cambridge, Massachusetts 02139.
ANTIPSYCHOTIC DRUGS Fifty-two percent of patients from the APS sample were acutely or chronically psychotic when seen in the psychiatric emergency service. Psychotic presentations were associated most often with the diagnoses of schizophrenia or major affective disorders, but occurred also with anxiety disorders, substance abuse, organic mental disorders, and personality disorders. Because psychosis is seen commonly in psychiatric emergency services, much attention has been devoted to its rapid control. The use of rapid and frequent doses of antipsychotic drugs, often parenteral, has been called "rapid tranquilization," "neuroleptization," "digitalization," and [most optimistically) "psychotolysis.'l,2 The initial uncontrolled studies of Mountain and Polak 1 indicated that large doses of chlorpromazine were effective in controlling psychotic symptoms. High-potency antipsychotic drugs, such as haloperidol and thiothixene, associated less frequently with unwanted hypotension or oversedation,1 gradually have achieved greater popularity than chlorpromazine. 1 In one 1977 study the enthusiasm for this approach led to the use of half-hourly intramuscular (IM) injections totalling as much as 100 mg over 24 hours. 2 Studies aimed at refining the techniques of rapid tranquilization have explored the importance of dosage, specific pharmacologic agent, and the route of administration.a Several studies cited by Gelenberg have raised questions about each of these elements of the tranquilization protocol. 4 Anderson and associates s showed no difference in efficacy or safety when comparing the use of half-hourly injections of 10 mg haloperidol (up to 55 mg total) to 5 mg haloperidol (up to 30 mg total) after an initial IM injection of 5 15:8 August 1986
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nag in acutely psychotic patients admitted for treatment. Neborsky6 presented data on acutely hospitalized psychotic patients (who were able to give informed consent} one hour following an injection of either 2 mg or 10 mg haloperidol. T h e high-dose group showed only a nonsignificant trend toward greater improvement and both groups improved significantly in hallucinations, suspiciousness, mannerisms, excitement or hyperactivity, hostility, and loud behavior. 6 These studies suggest that use of lower dosage be considered in rapid tranquilization protocols. Patients able to give informed c o n s e n t m i g h t represent a more tractable group than those actually seen in an emergency outpatient setting. The pharmacological specificity of antipsychotic drugs for tranquilization was questioned by Lemer, who compared diazepam (20 mg to 25 mg IV over three hours) to haloperidol (30 mg to 40 mg IV over three hours) in the treatment of acutely psychotic inpatients following two days of drugfree observation on an inpatient unit.7 Four hours after the first injection, patients were assessed using the clinical rating scales BPRS and GCI and the improvement in total scores showed no difference in efficacy or safety between the two treatments. There was a lack of superiority of haloperidol over diazepam in treating thought disorder, a symptom they believe can improve only over a period of days. 7 Another a l t e r n a t i v e is droperidol, a butyrophenone that recently has been advocated for use in rapid tranquilization. s This drug was studied by Resnick and Burton,8 who believe it is less anticholinergic and hypotensive and more sedating than other antipsychotic drugs in use for rapid tranquilization. Given in IM doses of 5 mg every half hour, two or three doses were found to be effective in treating most of a series of acutely agitated involuntary outpatients (who were unable to give informed consent), s This drug deserves further study. Escobar9 and associates have questioned the importance of the parenteral route by comparing hourly injections of prolixin (5 rag) to oral prolixin (2.5 mg) a d m i n i s t e r e d every eight hours in p a t i e n t s h o s p i t a l i z e d for acute exacerbation of schizophrenia or schizoaffective disorder and who were able to give informed consent. The high-dose group developed more extra152/963
pyramidal symptoms but no significantly greater reduction of symptoms as assessed w i t h the BPRS at four, eight, and 24 hours. 9 These results suggest that use of high-dosage parenteral antipsychotics may not be more effective in achieving symptomatic improvement in certain populations of acutely psychotic patients than treatment with lower doses or perhaps even other types of medications and that the parenteral route may not be more effective than the oral route. These suggestions arise g e n e r a l l y f r o m s t u d i e s of inpatients6,7,9 who were able to give informed consent and, even in some studies,6, 7 who remain for untreated observation periods, leaving doubt about the generalizability of results to more severely out-of-control outpatients. Future studies might be directed at determining whether treatment of acutely destructive behavior in outpatients as seen in the emergency d e p a r t m e n t should differ f r o m treatment of other aspects of psychosis in inpatients, One specific area in the behavioral control of outpatients that has not been addressed adequately is the route of administration. Because orally administered antipsychotic drugs take up to four to six hours to reach peak serum levels, as compared with 30 minutes for intramuscularly administered medications;10 the IM route seems preferable when medication is to be used for the control of acutely dangerous behavior, often a matter of rapid sedation and establishment of m o t o r c o n t r o l . n Schaffer and colleagues ~2 advocate an effective combination approach, an initial IM dose for i m m e d i a t e control followed by subsequent oral dosage3 z Talking, offering food, and using physical restraints present p r e l i m i n a r y alternatives or adjunctive approaches in the management of some patients. For others, the use of a benzodiazepine, alone or in combination with a hig hpotency antipsychotic drug, might be an altemative to the use of an antipsychotic drug. ~3 Amytal, ® used in the past for sedation, remains a treatm e n t alternative in certain clinical situations, such as severe violence, when the goal is to render the patient rapidly unconscious for protection of all concerned. 14 Given as an IM injection of 250 mg to 500 mg, this drug is highly effective, but because of the danger of r e s p i r a t o r y arrest, is it Annals of Emergency Medicine
should be given only when resuscitation equipment is available. 14 When a patient requires the rapid establishment of controls to prevent harm to himself or others, the emergency physician has legal precedents to support forcible administration of m e d i c a t i o n . 16 If possible, organic etiologies of acute psychosis [such as hypoxia, hypoglycemia, thiamine deficiency, hypertensive encephalopathy" hemorrhage, anticholinergic delirium, CNS infection) are ruled out first, s Vital signs are measured before each medication dose. lz Deltoid injections, w h e n possible, are better absorbed than gluteal ones.1 In view of the high rate of extrapyramidal reaction to rapid neuroleptization,1 an as-needed or standing order for anticholinergic agents should be given. The complications of hypotension, arrhythmia, seizures, oversedation, dystonia, akathisia, catatonia, and n e u r o l e p t i c malignant syndrome 1 must be anticipated. As soon as possible, a switch to oral dosage is effected, usually by giving one to two times the dose required during the first 24 hours as a divided daily oral dose. t ANTIANXIETY AGENTS Anxiety disorders are second only to substance abuse a m o n g psychiatric disorders in this country.18 Anxiety symptoms occur also with a variety of nonanxiety disorder diagnoses. In the APS sample of patients, 35% complained of or displayed anxiety when visiting the psychiatric emergency service. Situational anxiety symptoms often respond well to treatment with benzodiazepines.19, ~o As with acute psychotic states, organic etiologies must be ruled out to avoid neglect of progressive medical conditions.17, zl Additionally, a differential diagnostic assessment should question the presence of other functional illnesses in which benzodiazepines may be useful initially but serve primarily adjunctively, if at all, during continued treatment.17 In choosing a specific benzodiazepine, kinetics and route of administration are i m p o r t a n t . T h e m o r e rapidly absorbed benzodiazepines (eg, diazepam) provide more noticeable, subjective relief, 22 and therefore seem preferable for acute treatment. Longeracting agents or those with active metabolites may lead to unwanted sedation over an extended course of treat15:8 August 1986
m e n t . 22 O r a l b e n z o d i a z e p i n e s are absorbed rapidly so that IM or IV administration is needed only when almost instantaneous (seconds to a few minutes) response is sought. 22 Lorazepam is absorbed more rapidly and consistently IM than either chlordiazepoxide or diazepam (which are poorly absorbed) w h e n t h i s a p p r o a c h is used. 22 Pretreatment clinical assessment m u s t take into account a history of substance abuse or chronically poor premorbid functioning. A limited quantity of medication should be dispensed and treatment reviewed periodically. When the acute anxiety is experienced with prominent somatic symptoms, propranolol offers an alternative to benzodiazepines as an acute treatment. 23 Heiser and Defrancisco report successes in lysing panic attacks with low oral doses of propranolol. 24 Single oral doses of l0 mg to 40 mg may be effective in relieving performance anxiety or panic symptoms. 2s Bradycardia, congestive failure, bronchospasm, fatigue, depression, or impaired sexual f u n c t i o n are p o t e n t i a l a d v e r s e effects. 26 Propranolol is contraindicated in patients with asthma or Raynaud's p h e n o m e n o n and is relatively contraindicated when diabetes is present because it m a y mask somatic signs of hypoglycemia. 24 When anxiety is associated with severe "spaciness," distractibility, or illogical thinking, it m a y indicate the presence of a psychotic state. Antipsychotic drugs, contraindicated in other forms of anxiety, m a y provide rapid and valuable relief in this s i t u a t i o n Y A high-potency drug such as thiothixene or haloperidol, administered in low doses (2 mg to 4 mg per day) is o f t e n chosen.27 B r i n k l e y and colleagues 27 have discussed the outpatient treatment of such patients, who should be referred from an emergency setting for more extended outpatient evaluation as soon as feasible. ANTIDEPRESSANT OR LITHIUM TREATMENT Of all diagnoses encountered in the APS sample, depression and m a n i a were the most common, seen in 45% of patients. Because major affective disorders m a y present in an acute condition with symptoms of great severity and potential for harm, emergency services m u s t be prepared to offer rapid treatment, including hospitalization if necessary. Neither lithium nor 15:8 August 1986
antidepressants can be expected to achieve a therapeutic response earlier than one to two weeks, as but antianxiety and antipsychotic drugs may be of use in treating acute agitation and are a mainstay in the acute treatment of psychotic symptoms or agitation associated with severe depression or mania.13,2s When a patient with a moderately severe but nonpsychotic major affective disorder presents, the q u e s t i o n may arise as to whether antidepressant or lithium treatment can be initiated safely in e m e r g e n c y settings. Compliance m a y be reduced if the patient is asked both to await a further appointment and to meet yet another caretaker. For patients capable of compliance with outpatient treatment, a possibly stigmatizing hospitalization may be prevented by initiating pharm a c o t h e r a p y in the e m e r g e n c y service. Prompt initiation of treatment also avoids increasing the interim period between diagnosis and therapeutic response. Such treatment, however, should be undertaken only with several cautions. 29 A patient in crisis m a y appear diagnostically more acute or severe, and f u r t h e r e v a l u a t i o n m a y reveal t h a t t r e a t m e n t w i t h a n t i d e p r e s s a n t s or lithium is not indicated or may sugg e s t t h e p r e s e n c e of a n o r g a n i c etiology. The gathering of this further information often is most easily obtained in an inpatient setting. Hospitalization offers protection to a potentially suicidal patient w h o s e m o t i vation and energy may retum dangerously as the antidepressant takes effect or in w h o m a depression may occur as lithium treatment takes effect on a manic episode. The emergency dispensing of a potentially lethal medi c a t i o n s h o u l d be d o n e in s m a l l amounts (several days' supply or less) and is unsafe unless the emergency service is capable of providing consistent, frequent followup. A careful preliminary medical evaluation is necessary to consider the possibility of renal or cardiac contraindications to treatment or an organic affective disorder presenting in an emergency setting. 30
DRUG A B U S E E M E R G E N C I E S I n a v a r i e t y of d r u g - i n d u c e d behavioral emergencies, psychopharm a c o l o g i c a g e n t s are of value. In some, such as alcohol withdrawal delirium, p s y c h o p h a r m a c o l o g i c agents Annals of Emergency Medicine
are part of a life-saving intervention. 31 In others, such as drug-induced anxiety or psychotic states, the symptomatic relief offered by medications is helpful in reducing a patient's suffering.S2 Alcohol-induced psychiatric emergencies in w h i c h m e d i c a t i o n s m a y play a useful role include intoxication, alcohol idiosyncratic intoxication, alcohol a m n e s t i c s y n d r o m e , a l c o h o l hallucinosis, and alcohol withdrawal delirium.31 Suicidal and homicidal behavior are facilitated by alcohol, alone or in combination with other drugs. 33 Violence to self, others, or property may bring an intoxicated patient voluntarily or involuntarily to emergency t r e a t m e n t . W h e n an e n v i r o n m e n t with reduced stimulation and an attempt at supportive talking fail to relieve the disruptive behavior or intoxication, p h y s i c a l r e s t r a i n t s a n d / o r sedation with a benzodiazepine (eg, 10 mg to 20 m g oral diazepam) m a y be useful,34 although care m u s t be taken to avoid oversedating a patient who might already have abused a variety of CNS depressantsA 4 When assaultiveness or belligerence pose a danger of harm to the patient or caretaking staff, we have found haloperidol (eg, 5 m g to 10 m g IM) a helpfffl pharmacological intervention. A small number of individuals assume an uncharacteristically aggressive style of behavior after consuming a small amount of alcohol. This "idiosyncratic intoxication" may be an alcohol-induced unmasking of a seizure disorder, sometimes preceded by brain injury.aS Physical restraints are often a necessary phase in management, and sedation with IM or oral benzodiazepines or such high-potency antipsychotic drugs as haloperidol m a y be helpful.~s Alcohol a m n e s t i c s y n d r o m e (Korsakoff's syndrome) m a y occur in individuals w h o combine high intake of alcohol with poor nutrition, often over a long period. T h i a m i n e is the key agent in m a n a g e m e n t of this nutritional deficiency. 36 A n oral dose of 50 mg three or four times daily is recommended.a6 Alcohol hallucinosis is a rare withdrawal syndrome associated with decrease or cessation of alcohol intake in an alcohol-dependent individual, d6 Onset typically occurs several days to weeks following decrease of alcohol i n t a k e and the course m a y e x t e n d from weeks to years. Hallucinations 964/153
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are usually auditory and occur in a clear sensorium. Their content often is degrading and accusatory. In addition to physical safety and a balanced diet, t r e a t m e n t with antipsychotic drugs may alleviate the hallucinations. 37 Alcohol withdrawal delirium (delirium tremens) is a true medical emergency, with an untreated mortality rate as high as 15%.33 Onset of this syndrome, w h i c h includes clouded sensorium, anxiety, visual and tactile hallucinations, and symptoms of autonomic hyperactivity, occurs 72 to 96 hours following reduction or cessation of alcohol intake, a8 Medical hospitalization may be necessary for the observation, supportive care, fluid replacement, and sedation with benzodiazepines that are major facets of treatment. 39 Marijuana, the most widely used illicit drug in the United States, 40 is capable of inducing an acute confusional or paranoid state in some individuals.a7, 40 In others, it may provoke a relapse of such psychotic illnesses as schizophrenia or major affective disorder. 40 The psychopharmacologic treatm e n t of marijuana-induced mental states has not been studied systematically. Among illicit stimulants, cocaine, amphetamine, phenylpropanolamine, and caffeine are widely abused. Acute intoxication may lead to delirium or psychotic states. Antipsychotic agents and antianxiety agents have been used to alleviate these symptoms. 37 Jacobs prefers the use of haloperidol in treating amphetamine psychosis, and combines this approach with acidification of the urine (using oral ammonium chloride 500 mg every three to four hours) to hasten drug excretion.14 Stimulant withdrawal can lead to a state of depression that may be of lifethreatening intensity and therefore require protective hospitalization. 37 Narcotics are the only illicit drugs for which a specific antagonist is available, yet this is of use primarily in the restricted situation of overdose because administration of an antagonist may elicit an abrupt and severe state of drug withdrawal. Recent studies 4 of clonidine provide evidence of this drug's usefulness in inpatient and outpatient alleviation of acute narcotic withdrawal symptoms. Because mixed withdrawal states are common, the possibility of a concurrent and potentially more life-threatening seda154/965
tive-hypnotic withdrawal state must be considered when opiate withdrawal is diagnosed. At present, street hallucinogens such as mescaline and LSD may actually be disguised PCP (phencyclidme). The emergency presentations sometimes resulting from LSD or mescaline "bad trips" usually can be treated with supportive "talking down" and adjunctive use of benzodiazepines. 14 Jacobs advocates the use of 15 to 30 mg oral diazepam repeated hourly as needed, not exceeding 50 mg during a t h r e e - h o u r period. TM When PCP is involved, however, "talking down" actually may exacerbate a crisis by producing even greater sensory overload in a sensory-dissociated individual who experiences external stimuli as confusing rather than orienting. 14 These patients, therefore, are placed in a quiet environment rather than talked down. PCP can produce severe and persistent states of delirium, psychosis, or relapse of a prior psychotic illness.38, 40 The effect in some cases may persist for days to weeks. 37 The t h o u g h t disorder o f t e n p r o d u c e d makes differential diagnosis complicated, but the physical signs of ataxia, nystagmus, hypertension, and fluctuating alertness should raise a clinician's suspicion. 42 Management of PCP intoxication has been controversial, as some clinicians prefer benzodiazepines and others prefer antipsychotics.14,37 In either case, the medication is an adjunct to measures aimed at decreasing absorption and hastening excretion. The prominence of anxiety in these patients and the tendency for PCP to induce seizures and a n t i c h o l i n e r g i c s y m p t o m s provide a rationale for choosing a benzodiazepine for treatment. Diazepam 5 to 10 mg orally or W, for example, is recommended. 14 In patients with prolonged psychosis the use of high-potency antipsychotic drugs such as haloperidol is recommended.42, 43 A l o w - p o t e n c y agent should not be used, as these tend to induce hypotensive reactions in PCP patients. 37
EMERGENCY ADVERSE REACTIONS
Antipsychotic Drugs In the APS sample of patients, antipsychotic drugs were the most fiequently encountered prescribed psychopharmacological agents. Of the Annals of Emergency Medicine
patients who were or had been on psychiatric medications, 70% reported treatment with these drugs. A variety of acute intoxication and withdrawal syndromes are clinically important. Acute dystonic reactions are seen in office practice probably in less than 5% of patients, 44 but are much more c o m m o n with higher or more frequent doses as often seen in emergency settings, 4s especially during parenteral t r e a t m e n t with high-potency agents. 44 These reactions usually are seen within the first 12 to 36 hours following antipsychotic drug treatment, 44 generally when a high-potency antipsychotic drug has been used, and consist of subjective tightening or actual muscle contraction of neck, jaw, extraocular, or other muscles. 4~ When merely a subjective sense of tightening is present, it is easy to misdiagnose the problem as agitation, which might lead to a counterproductive increase in antipsychotic drug dosage. Therefore, a high index of suspicion is necessary. Treatment begins with IM or IV benztropine 1 mg or diphenhydramine 50 mg. Io Because the half-lives of these drugs are exceeded by those of antipsychotic drugs, oral anticholinergic agents are dispensed to extend therapy at least 48 to 72 hours.lO, 4s To prevent recurrence of this reaction in a patient who requires continuation of antipsychotic drug treatment, continued a n t i c h o l i n e r g i c t r e a t m e n t , change to a lower dose of antipsychotic drugs or use of a less potent drug should be considered.44, 45 With this and all other adverse reactions, the patient's prescribing physician should be contacted and should, when possible, participate in the process of treatment planning. Akathisia, a subjectively uncomfortable desire to be in motion, may occur in as many as 50% of patients on high-potency antipsychotic drugs, and is often mistaken for free-floating anxiety. 44 In some patients the diagnosis is suggested by pacing or other repetitive motions or the presence of cogwheeling. In others, subjective discomfort alone may be great enough to precipitate an emergency visit or a suicide attempt. 46 When the anxiety of akathisia is mistakenly treated by increasing a patient's dosage of antipsychotic drug, the result may be increasing decompensation. 44 Of these reactions, 90% occur within the first three months of treatment. Response 15:8 August 1986
to a n t i c h o l i n e r g i c drugs or benzodiazepines, the customary choices for treatment, may be disappointing.lO,44 Use of a lower dose or lower potency drag may reduce akathisia. 44 Recently some success has been reported using propranolol in small doses (eg, 10 mg three times daily).47 Decompensation of mental status exacerbated or caused by antipsychotic drug treatment has been described by Van Putten. 4s This psychotic state, typically occurring two to nine days after onset of treatment with high-potency drugs, is dose related and always associated with akathisia. Treatment approaches are similar to those used with akathisia, with the exception of propranolol, which has not been investigated in this situation. 48 A catatonic state identical to functional catatonia can develop gradually after the onset of treatment with highpotency antipsychotic drugs. 49 In the emergency setting, this adverse reaction is easily misdiagnosed as functional catatonia, leading to treatment with Increased doses. Catatonia with a history of recent initiation of antipsychotic drug treatment or increasing dose of high-potency drugs should suggest a drug-induced syndrome. 49 A m a n t a d i n e and a n t i c h o l i n e r g i c agents have been useful in the differential diagnosis of this reaction by producing a rapid increase in mobility when the catatonia is drug induced. 49 Neuroleptic malignant syndrome, an uncommon adverse reaction, must be considered when any patient on antipsychotic drugs presents with fever, rigidity, autonomic symptoms, and altered mental status.SO Neuroleptic malignant syndrome is not dose related and occurs with either high- or low-potency antipsychotic drugs, so Though usually seen early in treatment, it may occur even after months of treatment, s0 Elevated CPK and WBC levels may aid the differential diagnosis, so Treatment requires discontinuation of antipsychotic drugs and supportive care in an ICU setting. sl Dantrolene 0.8 to 2.5 mg/kg every six hours or bromocriptine 2.5 mg to 20 mg orally three times per day have been recommended as treatment.So
Antidepressants and Lithium We have seen adverse reactions to antidepressant t r e a t m e n t or withdrawal in emergency settings. In the APS sample, about one third of pa15:8 August 1986
tients were or had recently been treated with these drugs. Antidepressants encountered were tricyclic agents, second-generation antidepressants, and monoamine oxidase inhibitors. These groups share overlapping ranges of adverse effects. Tricyclics, second-generation antidepressants, and monoamine oxidase inhibitors seem able to switch or accelerate the switch process by which a depressed bipolar patient enters a manic state.S2, s3 Tricylics may produce several other m e n t a l status changes of importance. Anxiety, irritability, and racing thoughts occur in some treated patients.S4, ss An acute confusional state resulting from anticholinergic toxicity also has been described, s60verdosage with tricyclics, including amoxapine, constitutes a grave medical emergency. We have seen that anticholinergic delirium and drowsiness often are the presenting symptoms, although some patients reach coma before arriving at the e m e r g e n c y service. Because these drugs are highly protein bound, dialysis is ineffective in reducing their serum level.S7 Gastric lavage, repeated administration of activated charcoal, and alkalinization of blood pH with bicarbonate infusion may be helpful in reducing absorption, speeding excretion and minimizing the serum level of unbound drag.S8,s9 Seizures or potentially fatal cardiac arrhythmias may occur.S7 Abrupt withdrawal from tricyclic agents has been associated with several emergency clinical syndromes.60, 61 Anxiety, hypomania, and even a delusional psychotic state have been reported.S4,ss,60, 61 T h e s e s y n d r o m e s m a y reflect cholinergic overdrive. Case reports describe successful treatment of the anxiety or hypomania syndromes with such anticholinergic agents as atropine or benztropine.S4, ss With respect to the second generation antidepressants, a recently emphasized adverse effect of maprotiline requires mention. At high or rapidly increasing doses, m a p r o t i l i n e has caused seizures even in patients with no prior seizure disorder.6~ The monoamine oxidase inhibitors are known for their ability to produce a hypertensive response when tyramine or other false neurotransmitters are ingested or administered. This response can occur even up to two weeks after discontinuation of the medication and consists of hypertenAnnals of Emergency Medicine
sion associated with severe headache, photophobia, dilated pupils, dyspnea, palpitations, nausea, vomiting, sweating, and chest pain.SZ E m e r g e n c y treatment of the hypertension can be accomplished by a slow IV injection of 5 mg phentolamine, followed by 0.25 to 0.5 mg IM every four to six hours to control blood pressure.SZ Lithium has a low therapeutic index and can be dangerous in overdosage. Overdoses of lithium can lead to neuropsychiatric decompensation progressing through delirium, seizures, and coma to death. 63 The more common side effects rarely lead to emergency visits. In the APS sample patients reporting current or recent use of lithium were rare and all reported concurrent or recent use of antipsychotic drugs, suggesting that they may have represented a more severely ill group of bipolar patients. Abrupt discontinuation of lithium by patients who feel better or who are becoming hypomanic is not uncommon. There is some evidence that an acute confusional state or rebound mania may occur in this situation.64, 6s
Antianxiety Medications Antianxiety drugs are in common use for the appropriate treatment of anxiety, the often inappropriate treatment of depression, 66 and as a drug of abuse. These drugs have the potential for adverse effects, and perhaps of greater importance with this class of medication than others, are various withdrawal reactions. Alone, these medications are relatively non lifethreatening in overdose. 67 Because these medications often are abused in conjunction with alcohol or other drugs, overdose can become a medical emergency as a result of delirium, hallucinosis, stupor, coma, or respiratory arrest. Of particular importance in cases of intoxication is paradoxical disinhibition. Disinhibition of impulses with resultant aggressive behavior has been reported with several benzodiazepines, i n c l u d i n g alprazolam. 68 In one series of 80 patients treated with alprazolam, 10% displayed uncharacteristic verbal or physical hostility, usually very near the start of treatment. 6s Antianxiety drug treatment or abuse should be considered in the differential diagnosis of acute aggressive or destructive behavior. Withdrawal from even therapeutic doses of benzodiazepines has caused 966/155
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neuropsychiatric emergencies including anxiety, hallucinosis, confusional states, and seizures.69, 7o The anxiety m u s t be differentiated from a recurrence of functional s y m p t o m s . T h e concurrent prominence of autonomic symptoms, time course, and response to pentobarbitol challenge help establish the presence of a withdrawal syndrome. Propranolol 60 m g to 120 mg per day has been used to attenuate the a n x i e t y and s o m a t i c s y m p t o m s of mild benzodiazepine withdrawal. 71 Halfucinosis during benzodiazepine w i t h d r a w a l is a s y n d r o m e characterized by a clear sensorium, absence of autonomic abnormalities, and the presence of a u d i t o r y hallucinations (often of a perverse sexual or persecutory nature) in the absence of a formal thought disorder, s7 In some patients, a florid delirium tremens-Iike syndrome develops following discont i n u a t i o n of antianxiety agents and can progress to seizures. Seizures also may occur as an isolated symptom on discontinuation of alproazolam, and probably with other benzodiazepines as well.72 SUMMARY The e m e r g e n c y area is a difficult site for the practice of careful psychopharmacology. The detailed h i s t o r y taking and collaborative treatment relationship often found in the consultant's office is rarely present. Instead, rapid decisions are made under a variety of pressures, with patients who may be uncooperative and unwilling to be treated. M a n y e m e r g e n c y patients are concurrently in treatment with a psychotherapist or psychopharmacologist w h o is available for consultation to the e m e r g e n c y service. When this is possible it is of great potential value, both in arriving more quickly at an appropriate treatment and in preventing a harmful opposit i o n of the p a t i e n t ' s t r e a t m e n t resources. For patients who are not curr e n t l y in a n o t h e r t r e a t m e n t , additional helpful information often may be obtained f r o m friends or family members. This is especially useful in treating patients who are acutely psychotic, unable to communicate, or uncooperative with the emergency interview. Although psychopharmacological approaches properly chosen often yield rapid results, m e d i c a t i o n s are only a part of most emergency treatm e n t plans. Medications are ineffec156/967
tire in a variety of crises and cannot replace careful i n t e r v i e w i n g of patients and others aimed at understanding the exogenous stress, change in interpersonal relationships, intrapsychic conflict, or biological disorder that precipitated an emergency visit. Furthermore, the decision to treat with medications m u s t include a consideration of the adverse effects that m a y occur. With these limitations in mind, the area of e m e r g e n c y psychopharm a c o l o g y can provide powerful assistance to emergency clinicians. The authors thank Richard I Shader, MD, and Arthur Barsky, MD, for helpful suggestions during preparation of this manuscript.
REFERENCES 1. Ayd FJ Jr: Guidelines for using shortacting intramuscular neuroleptics for rapid neuroleptization. International Drug Therapy Newsletter February-March 12:1977. 2. C a r t e r RG: P s y c h o t o l y s i s w i t h haloperidol: Rapid control of the acutely disturbed psychotic patient. Diseases of the Nervous System 1977;38:237-239. 3. Donlon PT, Hopkin J, Tupin JP: Overview: Efficacy and safety of the rapid neuroleptization method with injectable haloperidol. A m J Psych 1979;136: 273-278. 4. Gelenberg AJ: Rapid neuroleptization. Biological Therapies in Psychiatry 1983;6:41. 5. Anderson WH, Kuehnle JC, Catanzano DM: Rapid treatment of acute psychosis. Am l Psych 1976;133:1076-1078. 6. Neborsky R, Janowsky D, Munson E, et al: Rapid treatment of acute psychotic s y m p t o m s with high- and low-dose haloperidol. Arch Gen Psych 1981;38: 195-199. 7. Lerner Y, Lwow E, Levitin A, et al: Acute high-dose parenteral haloperidol treatment of psychosis. Am J Psych 1979; 136:1061-1064. 8. Resnick M, Burton BT: Droperidol vs haloperidol in the initial management of acutely agitated patients. J Clin Psychiatry 1984145:298-299. 9. Escobar JI, Barton A, Kiriakos R: A controlled study of neuroleptization with fluphenazine hydrochloride injections. 1 Clin Psychopharmacol 1983;3:359-362. 10. Gelenberg AJ: Psychosis, in The Practitioner's Guide to Psychoactive Drugs. New York, Clemen Medical Book Company, 1983, pp I15-165. 11. Bassuk EL, Panzarino PJ, Schoonover Annals of Emergency Medicine
SC: General principles of pharmacologic management in the emergency setting, in Bassuk EL, Birk AW (eds): Emergency Psychiatry: Concepts, Methods, and Practices, New York, Plenum Press, 1984. 12. Schaffer CB, Shahid A, Javaid JI, et ah Bioavailability of intramuscular versus oral haloperidol in schizophrenic patients. J Clin Psychopharmacol 1982;2:274-277. 13. Salvman C, Green AI, Rodriguez-Villa F, et al: Benzodiazepam combined with neuroleptics for management of severe disruptive behavior. Psychosomatics 1986;27(suppl): 17-21. 14. Jacobs D: Psychopharmacologic management of the psychiatric emergency patient. General Hospital Psychiatry 1984;6:203-210. 15. Tupin JP: Management of violent patients, in Shader RI (ed): Manual of Psychiatric Therapeutics. Boston, Little, Brown & Co 1975;pp 125-136. 16. Arkin HR: Forcible administration of antipsychotic medication. JAMA 1983; 249:2784-2786. 17. Ellison J: DSM-III and the diagnosis of organic mental disorders. Ann Emerg Med 1984; 13:521-528. 18. Robins LN, Helzer JE, Weissman MN, et al: Life-time prevalence of specific psychiatric disorders in three sites. Arch General Psych 1984;41:949-958. 19. Shader RI, Greenblatt D: The psychopharmacologic treatment of anxiety states, in Shader RI (ed): Manual of Psychiatric Therapeutics. Boston, Little, Brown, and Go, 1975. 20. Shader RI, Greenblatt D: Benzodiazepine treatment of specific anxiety states. Psychiatric Annals 1981;11:16-20. 21. Dietch JT: Diagnosis of organic anxiety disorders. Psychosomatics 1981; 22:661-669. 22. Greenblatt DJ, Shader RI, Abemethy DR: Current status of benzodiazepines. N Engl J Med 1983;309:354-358. 23. Ballenger JC: Psychopharmacology of the anxiety disorders. Psychiatric Clin North Am 1984;7:757-771. 24. Heiser JF: The treatment of pathological panic states with propranolol. Am J Psych 1976;133:1389-1393. 25. Noyes R: Beta-adrenergic blocking drugs in anxiety and stress. Psychiatric Clin North Am 1985;8:119-132. 26. The Physicians Desk Reference. Oradell, New Jersey, Medical Economics, Inc, 1986, p 624. 27. Brinkley JR, Beitman BD, Friedel RO: Low-dose neuroleptic regimens in the treatment of borderline patients. Arch Gen Psych 1979;36:319-326. 15:8 August1986
28. Bassuk EL, Schoonover SC, Gelenberg AJ: The Practitioner's Guide to PsychoActive Drugs. New York, Clemen Medical Book Company, 1983, pp XV-421. 29. Brodsky L, Pieczynski B: The use of antidepressants in a psychiatric emergency department. J Clinical Psychopharrnacol 1985;5:35-38. 30. Krauthammer C, Klerman GL: Secondary mania: Manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psych 1978;36:414-419. 31. Holloway HC, Hales RE, Apanabe HK: Recognition a n d m a n a g e m e n t of acute alcohol withdrawal syndromes. Psychiatric Clin North A m 1984;7:729-744. 32. DiSclafani A, Hall RCW, Gardner ER: Drug-induced psychosis: Emergency diagnosis and management. Psychosornatics 1981;22:845-855. 33. Walker JI: Psychiatric emergencies: Intervention and resolution, in Managem e n t of Alcohol Emergencies. Philadelphia, JB Lippincott Company, 1983, pp 68-88. 34. Slaby AE, Lieb J, Pencredi LR: Alcohol intoxication, in Handbook of Psychiatric Emergencies, ed 2. Garden City, New York, Medical Examination Publishing Company, 1981, pp 89-92. 35. Slaby AE, Lieb J, Pencredi LR: Alcohol idiosyncratic intoxication, in Handbook of Psychiatric Emergencies, ed 2. Garden City, New York, Medical Examination Publishing Company, 1981, pp 93-95. 36. Slaby AE, Lieb J, Pencredi LR: Alcohol arnnestic syndrome, in Handbook of Psychiatric Emergencies, ed 2. Garden City, New York, Medical Examination Publishing Company, 1981, pp 92-93. 37. Khantzian EJ, MeKenna GJ: Acute toxic and withdrawal reactions associated with drug use and abuse. Ann Intern Med 1979;90:361-372. 38. M i r i n SM, Weiss RD: Substance abuse, in The Practitioner's Guide to Psychoactive Drugs. New York, Clemen Medical Book Company, 1983, pp XV-421. 39. Clark W: Alcoholism: Blocks to diagnosis and treatment. A m ] Med 1981; 71:275-286. 40. Nicholi AM Jr: The nontherapeutic use of psychoactive drugs. N Engl J Med 1983;308:925-933. 41. Bond WS: Psychiatric indications for clonidine: The neuropharmacologic and clinical basis. J Clin Psychopharmacol
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1986;6:81-87. 42. Slaby AE, Lieb J, Pencredi: LR: Phencyclidine intoxication delusional state and barium, in Handbook of Psychiatric Emergencies, ed 2. Garden City New York, Medical Examination Publishing Company, 1981, pp 187-191. 43. Gelenberg AJ: Treatment of phencyclidine psychosis. Biological Therapies in Psychiatry 1979;2:33. 44. Tarsy D: Movement disorders with neuroleptic drug treatment. Psychiatric Clinics of North America 1984;7:453-471. 45. Corre KA, Niemann JT, Bessen HA: Extended therapy for acute dystonic reactions. Ann Emerg Med 1984;13:194-197. 46. Drake RE, Ehrlich j: Suicide attempts associated with akathisia. A m J Psych 1985; 142:499-500. 47. Lipinski JF, Aubenko GS, Barreira P, et ah Propranolol in the treatment of neuroleptic-induced akathisia (letter). Lancet September 17, 1983;2:685-686. 48. Van Putten T, Mutalipassi LR, Malkin MD: Phenothiazine-induced decompensation. Arch Gen Psych i974;30:102-105. 49. Gelenberg AJ, Mandel MR: Catatonic reactions to high-potency neuroleptic drugs. Arch Gen Psych 1977;34:947-950.
Drugs. New York, Clemen Medical Book Company, 1983, pp 19-77. 58. Swartz CM, Sherman A: The treatment of tricyclic antidepressant overdose with repeated charcoal. J Clin Psychopharmacol 1985;4:336-340. 59. Pedersen OL, Gram LF, Kristensen CB, et al: Overdosage of antidepressants: Clinical and pharrnacokinetic aspects. Eur J c l m Pharmaeol 1982;23:513-521. 60. Mirin SM, Schatzberg AF, Creasey DE: Hypomania and mania after withdrawal of tricyclic antidepressants. A m J Psych 1981; 138:87-89. 61. Patterson JF: Psychosis after discontinuation of nortriptyline (letter). J Clin Psychopharmacol 1984;4:117. 62. Molnar G: Seizures associated with high maprotiline serum concentrations. Can J Psych 1983;28:555-556. 63. Schoonover SC: Bipolar affective disorder and recurrent quenopolar depression, in The Practitioner's Guide tO Psychoactive Drugs. New York, Clemen Medical Book Company, 1983, pp 79-113. 64. Wilkinson DG: Difficulty in stopping lithium prophylaxis. Brit Med J January 27, 1979;235-236.
50. Levenson JL: Neuroleptic malignant s y n d r o m e . A m J P s y c h i a t r y 1985; 142:1137-1145.
65. Lapierre YD, Gagnon A, Kokkinidis L: Rapid recurrence of mania following l i t h i u m withdrawal. Biol Psych 1980; 15:859-864.
51. Smego RA, Durack DT: The neuroleptic malignant syndrome. Arch Intern Med 1982;t42:1183-1185.
66. Keller MB, Klerman GL, Lavori PW, et ah Treatment received by depressed patients. ]Alga 1982;248:1848-1855.
52. Wehr TA, Goodwin FK: Rapid cycling in manic-depressives induced by trieyclic antidepressants. Arch Gen Psych 1979; 36:555-559.
67. Edwards JG: Adverse effects of antianxiety drugs. Drugs 1981;22:495-514.
53. Pickar D, Murphy DL, Cohen RM, et al: Selective and nonselective monoamine oxidase i n h i b i t o r s . Arch Gen Psych 1982;39:535-540. 54. Dilsaver SC, Feinberg M, Greden JF: Antidepressant withdrawal s y m p t o m s treated with anticholinergic agents: A m J Psych 1983;140:249-251. 55. Dilsaver SC, Kronfol Z, Sackellares JC, et al: Antidepressant withdrawal syndromes: Evidence supporting the cholinergic overdrive hypothesis. J Clin Psychopharmacol 1983;3:157-164. 56. Livingston RL, Zucker DK, Isenberg K, et al: Tricyclic antidepressants and delirium. J Clin Psychiatry 1983;44:173-177. 57. Schoonover SC: Depression, in The Practitioner's Guide to P s y c h o a c t i v e
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68. Rosenbaum JF, Woods SW, Groves JE, et al: Emergence of hostility during alprazolam treatment. A m J Psych 1984; 141:792-793. 69. Winokur A, Rickels K, Greenblatt DJ, et al: Withdrawal reaction from longterm, low-dosage administration of diazepam. Arch Gen Psych 1980;37:101-105. 70. L a d e r M: D e p e n d e n c e on b e n zodiazepines. J Clin Psych 1983;44: 121-127. 71. Tyrer P, Rutherford D, Huggett T: Benzodiazepine withdrawal symptoms and p r o p r a n o l o l . L a n c e t M a r c h 7, 1981;520-522. 72. Breier A, Chamey DS, Nelson JG: Seizures induced by abrupt discontinuation of alprazolam. A m J Psych 1984;141: 1606-1607.
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Emergency Psychopharmacology: A Review and Update [Ellison JM, Jacobs D: Emergency psychopharmacology: A review and update. Ann Emerg Med August 1986;15:962-968.]
James M Ellison, MD Douglas Jacobs, MD Cambridge, Massachusetts
INTRODUCTION Psychopharmacologic agents provide valuable therapeutic control or symptomatic relief in some clinical emergencies and in other settings can precipitate or aggravate behavioral crises. T h e s e m e d i c a t i o n s f r e q u e n t l y are encountered among psychiatric emergency patients. Unpublished data collected by one of the authors from a randomly selected group of 60 patient records in an urban general hospital acute psychiatric service (APS) showed that 30% were currently in medication treatment and 80% claimed to have taken at least one psychiatric medication within the past year. Of those currently or recently medicated, nearly 63% had been on two or more medications. In view of the frequency of psychiatric medication use in emergency psychiatric patients, an awareness of treatment roles and adverse effects must be part of an emergency clinician's special knowledge. We review the field of "emergency psychopharmacology" and the roles of selected psychopharmacologic agents in resolving or precipitating behavioral and toxic psychiatric emergencies. Four major classes of drugs will be considered: antipsychotics, a n t i a n x i e t y agents, antidepressants, and lithium. Additional comments are addressed to the role of psychopharmacologic agents in the treatment of drug abuse emergencies.
From the Department of Biological Therapies in Psychiatry, Cambridge Hospital, Cambridge, Massachusetts; and the Department of Psychiatry, Harvard Medical School, Boston, Massachusetts. Received for publication September 23, 1985. Accepted for publication December 12, 1985. This paper is a revision of a workshop presented at the Tufts University School of Medicine Psychopharmacology Update, Boston, October 1984. Address for reprints: James M Ellison, MD, Department of Psychiatry, Cambridge Hospital, 1493 Cambridge Street, Cambridge, Massachusetts 02139.
ANTIPSYCHOTIC DRUGS Fifty-two percent of patients from the APS sample were acutely or chronically psychotic when seen in the psychiatric emergency service. Psychotic presentations were associated most often with the diagnoses of schizophrenia or major affective disorders, but occurred also with anxiety disorders, substance abuse, organic mental disorders, and personality disorders. Because psychosis is seen commonly in psychiatric emergency services, much attention has been devoted to its rapid control. The use of rapid and frequent doses of antipsychotic drugs, often parenteral, has been called "rapid tranquilization," "neuroleptization," "digitalization," and [most optimistically) "psychotolysis.'l,2 The initial uncontrolled studies of Mountain and Polak 1 indicated that large doses of chlorpromazine were effective in controlling psychotic symptoms. High-potency antipsychotic drugs, such as haloperidol and thiothixene, associated less frequently with unwanted hypotension or oversedation,1 gradually have achieved greater popularity than chlorpromazine. 1 In one 1977 study the enthusiasm for this approach led to the use of half-hourly intramuscular (IM) injections totalling as much as 100 mg over 24 hours. 2 Studies aimed at refining the techniques of rapid tranquilization have explored the importance of dosage, specific pharmacologic agent, and the route of administration.a Several studies cited by Gelenberg have raised questions about each of these elements of the tranquilization protocol. 4 Anderson and associates s showed no difference in efficacy or safety when comparing the use of half-hourly injections of 10 mg haloperidol (up to 55 mg total) to 5 mg haloperidol (up to 30 mg total) after an initial IM injection of 5 15:8 August 1986
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nag in acutely psychotic patients admitted for treatment. Neborsky6 presented data on acutely hospitalized psychotic patients (who were able to give informed consent} one hour following an injection of either 2 mg or 10 mg haloperidol. T h e high-dose group showed only a nonsignificant trend toward greater improvement and both groups improved significantly in hallucinations, suspiciousness, mannerisms, excitement or hyperactivity, hostility, and loud behavior. 6 These studies suggest that use of lower dosage be considered in rapid tranquilization protocols. Patients able to give informed c o n s e n t m i g h t represent a more tractable group than those actually seen in an emergency outpatient setting. The pharmacological specificity of antipsychotic drugs for tranquilization was questioned by Lemer, who compared diazepam (20 mg to 25 mg IV over three hours) to haloperidol (30 mg to 40 mg IV over three hours) in the treatment of acutely psychotic inpatients following two days of drugfree observation on an inpatient unit.7 Four hours after the first injection, patients were assessed using the clinical rating scales BPRS and GCI and the improvement in total scores showed no difference in efficacy or safety between the two treatments. There was a lack of superiority of haloperidol over diazepam in treating thought disorder, a symptom they believe can improve only over a period of days. 7 Another a l t e r n a t i v e is droperidol, a butyrophenone that recently has been advocated for use in rapid tranquilization. s This drug was studied by Resnick and Burton,8 who believe it is less anticholinergic and hypotensive and more sedating than other antipsychotic drugs in use for rapid tranquilization. Given in IM doses of 5 mg every half hour, two or three doses were found to be effective in treating most of a series of acutely agitated involuntary outpatients (who were unable to give informed consent), s This drug deserves further study. Escobar9 and associates have questioned the importance of the parenteral route by comparing hourly injections of prolixin (5 rag) to oral prolixin (2.5 mg) a d m i n i s t e r e d every eight hours in p a t i e n t s h o s p i t a l i z e d for acute exacerbation of schizophrenia or schizoaffective disorder and who were able to give informed consent. The high-dose group developed more extra152/963
pyramidal symptoms but no significantly greater reduction of symptoms as assessed w i t h the BPRS at four, eight, and 24 hours. 9 These results suggest that use of high-dosage parenteral antipsychotics may not be more effective in achieving symptomatic improvement in certain populations of acutely psychotic patients than treatment with lower doses or perhaps even other types of medications and that the parenteral route may not be more effective than the oral route. These suggestions arise g e n e r a l l y f r o m s t u d i e s of inpatients6,7,9 who were able to give informed consent and, even in some studies,6, 7 who remain for untreated observation periods, leaving doubt about the generalizability of results to more severely out-of-control outpatients. Future studies might be directed at determining whether treatment of acutely destructive behavior in outpatients as seen in the emergency d e p a r t m e n t should differ f r o m treatment of other aspects of psychosis in inpatients, One specific area in the behavioral control of outpatients that has not been addressed adequately is the route of administration. Because orally administered antipsychotic drugs take up to four to six hours to reach peak serum levels, as compared with 30 minutes for intramuscularly administered medications;10 the IM route seems preferable when medication is to be used for the control of acutely dangerous behavior, often a matter of rapid sedation and establishment of m o t o r c o n t r o l . n Schaffer and colleagues ~2 advocate an effective combination approach, an initial IM dose for i m m e d i a t e control followed by subsequent oral dosage3 z Talking, offering food, and using physical restraints present p r e l i m i n a r y alternatives or adjunctive approaches in the management of some patients. For others, the use of a benzodiazepine, alone or in combination with a hig hpotency antipsychotic drug, might be an altemative to the use of an antipsychotic drug. ~3 Amytal, ® used in the past for sedation, remains a treatm e n t alternative in certain clinical situations, such as severe violence, when the goal is to render the patient rapidly unconscious for protection of all concerned. 14 Given as an IM injection of 250 mg to 500 mg, this drug is highly effective, but because of the danger of r e s p i r a t o r y arrest, is it Annals of Emergency Medicine
should be given only when resuscitation equipment is available. 14 When a patient requires the rapid establishment of controls to prevent harm to himself or others, the emergency physician has legal precedents to support forcible administration of m e d i c a t i o n . 16 If possible, organic etiologies of acute psychosis [such as hypoxia, hypoglycemia, thiamine deficiency, hypertensive encephalopathy" hemorrhage, anticholinergic delirium, CNS infection) are ruled out first, s Vital signs are measured before each medication dose. lz Deltoid injections, w h e n possible, are better absorbed than gluteal ones.1 In view of the high rate of extrapyramidal reaction to rapid neuroleptization,1 an as-needed or standing order for anticholinergic agents should be given. The complications of hypotension, arrhythmia, seizures, oversedation, dystonia, akathisia, catatonia, and n e u r o l e p t i c malignant syndrome 1 must be anticipated. As soon as possible, a switch to oral dosage is effected, usually by giving one to two times the dose required during the first 24 hours as a divided daily oral dose. t ANTIANXIETY AGENTS Anxiety disorders are second only to substance abuse a m o n g psychiatric disorders in this country.18 Anxiety symptoms occur also with a variety of nonanxiety disorder diagnoses. In the APS sample of patients, 35% complained of or displayed anxiety when visiting the psychiatric emergency service. Situational anxiety symptoms often respond well to treatment with benzodiazepines.19, ~o As with acute psychotic states, organic etiologies must be ruled out to avoid neglect of progressive medical conditions.17, zl Additionally, a differential diagnostic assessment should question the presence of other functional illnesses in which benzodiazepines may be useful initially but serve primarily adjunctively, if at all, during continued treatment.17 In choosing a specific benzodiazepine, kinetics and route of administration are i m p o r t a n t . T h e m o r e rapidly absorbed benzodiazepines (eg, diazepam) provide more noticeable, subjective relief, 22 and therefore seem preferable for acute treatment. Longeracting agents or those with active metabolites may lead to unwanted sedation over an extended course of treat15:8 August 1986
m e n t . 22 O r a l b e n z o d i a z e p i n e s are absorbed rapidly so that IM or IV administration is needed only when almost instantaneous (seconds to a few minutes) response is sought. 22 Lorazepam is absorbed more rapidly and consistently IM than either chlordiazepoxide or diazepam (which are poorly absorbed) w h e n t h i s a p p r o a c h is used. 22 Pretreatment clinical assessment m u s t take into account a history of substance abuse or chronically poor premorbid functioning. A limited quantity of medication should be dispensed and treatment reviewed periodically. When the acute anxiety is experienced with prominent somatic symptoms, propranolol offers an alternative to benzodiazepines as an acute treatment. 23 Heiser and Defrancisco report successes in lysing panic attacks with low oral doses of propranolol. 24 Single oral doses of l0 mg to 40 mg may be effective in relieving performance anxiety or panic symptoms. 2s Bradycardia, congestive failure, bronchospasm, fatigue, depression, or impaired sexual f u n c t i o n are p o t e n t i a l a d v e r s e effects. 26 Propranolol is contraindicated in patients with asthma or Raynaud's p h e n o m e n o n and is relatively contraindicated when diabetes is present because it m a y mask somatic signs of hypoglycemia. 24 When anxiety is associated with severe "spaciness," distractibility, or illogical thinking, it m a y indicate the presence of a psychotic state. Antipsychotic drugs, contraindicated in other forms of anxiety, m a y provide rapid and valuable relief in this s i t u a t i o n Y A high-potency drug such as thiothixene or haloperidol, administered in low doses (2 mg to 4 mg per day) is o f t e n chosen.27 B r i n k l e y and colleagues 27 have discussed the outpatient treatment of such patients, who should be referred from an emergency setting for more extended outpatient evaluation as soon as feasible. ANTIDEPRESSANT OR LITHIUM TREATMENT Of all diagnoses encountered in the APS sample, depression and m a n i a were the most common, seen in 45% of patients. Because major affective disorders m a y present in an acute condition with symptoms of great severity and potential for harm, emergency services m u s t be prepared to offer rapid treatment, including hospitalization if necessary. Neither lithium nor 15:8 August 1986
antidepressants can be expected to achieve a therapeutic response earlier than one to two weeks, as but antianxiety and antipsychotic drugs may be of use in treating acute agitation and are a mainstay in the acute treatment of psychotic symptoms or agitation associated with severe depression or mania.13,2s When a patient with a moderately severe but nonpsychotic major affective disorder presents, the q u e s t i o n may arise as to whether antidepressant or lithium treatment can be initiated safely in e m e r g e n c y settings. Compliance m a y be reduced if the patient is asked both to await a further appointment and to meet yet another caretaker. For patients capable of compliance with outpatient treatment, a possibly stigmatizing hospitalization may be prevented by initiating pharm a c o t h e r a p y in the e m e r g e n c y service. Prompt initiation of treatment also avoids increasing the interim period between diagnosis and therapeutic response. Such treatment, however, should be undertaken only with several cautions. 29 A patient in crisis m a y appear diagnostically more acute or severe, and f u r t h e r e v a l u a t i o n m a y reveal t h a t t r e a t m e n t w i t h a n t i d e p r e s s a n t s or lithium is not indicated or may sugg e s t t h e p r e s e n c e of a n o r g a n i c etiology. The gathering of this further information often is most easily obtained in an inpatient setting. Hospitalization offers protection to a potentially suicidal patient w h o s e m o t i vation and energy may retum dangerously as the antidepressant takes effect or in w h o m a depression may occur as lithium treatment takes effect on a manic episode. The emergency dispensing of a potentially lethal medi c a t i o n s h o u l d be d o n e in s m a l l amounts (several days' supply or less) and is unsafe unless the emergency service is capable of providing consistent, frequent followup. A careful preliminary medical evaluation is necessary to consider the possibility of renal or cardiac contraindications to treatment or an organic affective disorder presenting in an emergency setting. 30
DRUG A B U S E E M E R G E N C I E S I n a v a r i e t y of d r u g - i n d u c e d behavioral emergencies, psychopharm a c o l o g i c a g e n t s are of value. In some, such as alcohol withdrawal delirium, p s y c h o p h a r m a c o l o g i c agents Annals of Emergency Medicine
are part of a life-saving intervention. 31 In others, such as drug-induced anxiety or psychotic states, the symptomatic relief offered by medications is helpful in reducing a patient's suffering.S2 Alcohol-induced psychiatric emergencies in w h i c h m e d i c a t i o n s m a y play a useful role include intoxication, alcohol idiosyncratic intoxication, alcohol a m n e s t i c s y n d r o m e , a l c o h o l hallucinosis, and alcohol withdrawal delirium.31 Suicidal and homicidal behavior are facilitated by alcohol, alone or in combination with other drugs. 33 Violence to self, others, or property may bring an intoxicated patient voluntarily or involuntarily to emergency t r e a t m e n t . W h e n an e n v i r o n m e n t with reduced stimulation and an attempt at supportive talking fail to relieve the disruptive behavior or intoxication, p h y s i c a l r e s t r a i n t s a n d / o r sedation with a benzodiazepine (eg, 10 mg to 20 m g oral diazepam) m a y be useful,34 although care m u s t be taken to avoid oversedating a patient who might already have abused a variety of CNS depressantsA 4 When assaultiveness or belligerence pose a danger of harm to the patient or caretaking staff, we have found haloperidol (eg, 5 m g to 10 m g IM) a helpfffl pharmacological intervention. A small number of individuals assume an uncharacteristically aggressive style of behavior after consuming a small amount of alcohol. This "idiosyncratic intoxication" may be an alcohol-induced unmasking of a seizure disorder, sometimes preceded by brain injury.aS Physical restraints are often a necessary phase in management, and sedation with IM or oral benzodiazepines or such high-potency antipsychotic drugs as haloperidol m a y be helpful.~s Alcohol a m n e s t i c s y n d r o m e (Korsakoff's syndrome) m a y occur in individuals w h o combine high intake of alcohol with poor nutrition, often over a long period. T h i a m i n e is the key agent in m a n a g e m e n t of this nutritional deficiency. 36 A n oral dose of 50 mg three or four times daily is recommended.a6 Alcohol hallucinosis is a rare withdrawal syndrome associated with decrease or cessation of alcohol intake in an alcohol-dependent individual, d6 Onset typically occurs several days to weeks following decrease of alcohol i n t a k e and the course m a y e x t e n d from weeks to years. Hallucinations 964/153
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are usually auditory and occur in a clear sensorium. Their content often is degrading and accusatory. In addition to physical safety and a balanced diet, t r e a t m e n t with antipsychotic drugs may alleviate the hallucinations. 37 Alcohol withdrawal delirium (delirium tremens) is a true medical emergency, with an untreated mortality rate as high as 15%.33 Onset of this syndrome, w h i c h includes clouded sensorium, anxiety, visual and tactile hallucinations, and symptoms of autonomic hyperactivity, occurs 72 to 96 hours following reduction or cessation of alcohol intake, a8 Medical hospitalization may be necessary for the observation, supportive care, fluid replacement, and sedation with benzodiazepines that are major facets of treatment. 39 Marijuana, the most widely used illicit drug in the United States, 40 is capable of inducing an acute confusional or paranoid state in some individuals.a7, 40 In others, it may provoke a relapse of such psychotic illnesses as schizophrenia or major affective disorder. 40 The psychopharmacologic treatm e n t of marijuana-induced mental states has not been studied systematically. Among illicit stimulants, cocaine, amphetamine, phenylpropanolamine, and caffeine are widely abused. Acute intoxication may lead to delirium or psychotic states. Antipsychotic agents and antianxiety agents have been used to alleviate these symptoms. 37 Jacobs prefers the use of haloperidol in treating amphetamine psychosis, and combines this approach with acidification of the urine (using oral ammonium chloride 500 mg every three to four hours) to hasten drug excretion.14 Stimulant withdrawal can lead to a state of depression that may be of lifethreatening intensity and therefore require protective hospitalization. 37 Narcotics are the only illicit drugs for which a specific antagonist is available, yet this is of use primarily in the restricted situation of overdose because administration of an antagonist may elicit an abrupt and severe state of drug withdrawal. Recent studies 4 of clonidine provide evidence of this drug's usefulness in inpatient and outpatient alleviation of acute narcotic withdrawal symptoms. Because mixed withdrawal states are common, the possibility of a concurrent and potentially more life-threatening seda154/965
tive-hypnotic withdrawal state must be considered when opiate withdrawal is diagnosed. At present, street hallucinogens such as mescaline and LSD may actually be disguised PCP (phencyclidme). The emergency presentations sometimes resulting from LSD or mescaline "bad trips" usually can be treated with supportive "talking down" and adjunctive use of benzodiazepines. 14 Jacobs advocates the use of 15 to 30 mg oral diazepam repeated hourly as needed, not exceeding 50 mg during a t h r e e - h o u r period. TM When PCP is involved, however, "talking down" actually may exacerbate a crisis by producing even greater sensory overload in a sensory-dissociated individual who experiences external stimuli as confusing rather than orienting. 14 These patients, therefore, are placed in a quiet environment rather than talked down. PCP can produce severe and persistent states of delirium, psychosis, or relapse of a prior psychotic illness.38, 40 The effect in some cases may persist for days to weeks. 37 The t h o u g h t disorder o f t e n p r o d u c e d makes differential diagnosis complicated, but the physical signs of ataxia, nystagmus, hypertension, and fluctuating alertness should raise a clinician's suspicion. 42 Management of PCP intoxication has been controversial, as some clinicians prefer benzodiazepines and others prefer antipsychotics.14,37 In either case, the medication is an adjunct to measures aimed at decreasing absorption and hastening excretion. The prominence of anxiety in these patients and the tendency for PCP to induce seizures and a n t i c h o l i n e r g i c s y m p t o m s provide a rationale for choosing a benzodiazepine for treatment. Diazepam 5 to 10 mg orally or W, for example, is recommended. 14 In patients with prolonged psychosis the use of high-potency antipsychotic drugs such as haloperidol is recommended.42, 43 A l o w - p o t e n c y agent should not be used, as these tend to induce hypotensive reactions in PCP patients. 37
EMERGENCY ADVERSE REACTIONS
Antipsychotic Drugs In the APS sample of patients, antipsychotic drugs were the most fiequently encountered prescribed psychopharmacological agents. Of the Annals of Emergency Medicine
patients who were or had been on psychiatric medications, 70% reported treatment with these drugs. A variety of acute intoxication and withdrawal syndromes are clinically important. Acute dystonic reactions are seen in office practice probably in less than 5% of patients, 44 but are much more c o m m o n with higher or more frequent doses as often seen in emergency settings, 4s especially during parenteral t r e a t m e n t with high-potency agents. 44 These reactions usually are seen within the first 12 to 36 hours following antipsychotic drug treatment, 44 generally when a high-potency antipsychotic drug has been used, and consist of subjective tightening or actual muscle contraction of neck, jaw, extraocular, or other muscles. 4~ When merely a subjective sense of tightening is present, it is easy to misdiagnose the problem as agitation, which might lead to a counterproductive increase in antipsychotic drug dosage. Therefore, a high index of suspicion is necessary. Treatment begins with IM or IV benztropine 1 mg or diphenhydramine 50 mg. Io Because the half-lives of these drugs are exceeded by those of antipsychotic drugs, oral anticholinergic agents are dispensed to extend therapy at least 48 to 72 hours.lO, 4s To prevent recurrence of this reaction in a patient who requires continuation of antipsychotic drug treatment, continued a n t i c h o l i n e r g i c t r e a t m e n t , change to a lower dose of antipsychotic drugs or use of a less potent drug should be considered.44, 45 With this and all other adverse reactions, the patient's prescribing physician should be contacted and should, when possible, participate in the process of treatment planning. Akathisia, a subjectively uncomfortable desire to be in motion, may occur in as many as 50% of patients on high-potency antipsychotic drugs, and is often mistaken for free-floating anxiety. 44 In some patients the diagnosis is suggested by pacing or other repetitive motions or the presence of cogwheeling. In others, subjective discomfort alone may be great enough to precipitate an emergency visit or a suicide attempt. 46 When the anxiety of akathisia is mistakenly treated by increasing a patient's dosage of antipsychotic drug, the result may be increasing decompensation. 44 Of these reactions, 90% occur within the first three months of treatment. Response 15:8 August 1986
to a n t i c h o l i n e r g i c drugs or benzodiazepines, the customary choices for treatment, may be disappointing.lO,44 Use of a lower dose or lower potency drag may reduce akathisia. 44 Recently some success has been reported using propranolol in small doses (eg, 10 mg three times daily).47 Decompensation of mental status exacerbated or caused by antipsychotic drug treatment has been described by Van Putten. 4s This psychotic state, typically occurring two to nine days after onset of treatment with high-potency drugs, is dose related and always associated with akathisia. Treatment approaches are similar to those used with akathisia, with the exception of propranolol, which has not been investigated in this situation. 48 A catatonic state identical to functional catatonia can develop gradually after the onset of treatment with highpotency antipsychotic drugs. 49 In the emergency setting, this adverse reaction is easily misdiagnosed as functional catatonia, leading to treatment with Increased doses. Catatonia with a history of recent initiation of antipsychotic drug treatment or increasing dose of high-potency drugs should suggest a drug-induced syndrome. 49 A m a n t a d i n e and a n t i c h o l i n e r g i c agents have been useful in the differential diagnosis of this reaction by producing a rapid increase in mobility when the catatonia is drug induced. 49 Neuroleptic malignant syndrome, an uncommon adverse reaction, must be considered when any patient on antipsychotic drugs presents with fever, rigidity, autonomic symptoms, and altered mental status.SO Neuroleptic malignant syndrome is not dose related and occurs with either high- or low-potency antipsychotic drugs, so Though usually seen early in treatment, it may occur even after months of treatment, s0 Elevated CPK and WBC levels may aid the differential diagnosis, so Treatment requires discontinuation of antipsychotic drugs and supportive care in an ICU setting. sl Dantrolene 0.8 to 2.5 mg/kg every six hours or bromocriptine 2.5 mg to 20 mg orally three times per day have been recommended as treatment.So
Antidepressants and Lithium We have seen adverse reactions to antidepressant t r e a t m e n t or withdrawal in emergency settings. In the APS sample, about one third of pa15:8 August 1986
tients were or had recently been treated with these drugs. Antidepressants encountered were tricyclic agents, second-generation antidepressants, and monoamine oxidase inhibitors. These groups share overlapping ranges of adverse effects. Tricyclics, second-generation antidepressants, and monoamine oxidase inhibitors seem able to switch or accelerate the switch process by which a depressed bipolar patient enters a manic state.S2, s3 Tricylics may produce several other m e n t a l status changes of importance. Anxiety, irritability, and racing thoughts occur in some treated patients.S4, ss An acute confusional state resulting from anticholinergic toxicity also has been described, s60verdosage with tricyclics, including amoxapine, constitutes a grave medical emergency. We have seen that anticholinergic delirium and drowsiness often are the presenting symptoms, although some patients reach coma before arriving at the e m e r g e n c y service. Because these drugs are highly protein bound, dialysis is ineffective in reducing their serum level.S7 Gastric lavage, repeated administration of activated charcoal, and alkalinization of blood pH with bicarbonate infusion may be helpful in reducing absorption, speeding excretion and minimizing the serum level of unbound drag.S8,s9 Seizures or potentially fatal cardiac arrhythmias may occur.S7 Abrupt withdrawal from tricyclic agents has been associated with several emergency clinical syndromes.60, 61 Anxiety, hypomania, and even a delusional psychotic state have been reported.S4,ss,60, 61 T h e s e s y n d r o m e s m a y reflect cholinergic overdrive. Case reports describe successful treatment of the anxiety or hypomania syndromes with such anticholinergic agents as atropine or benztropine.S4, ss With respect to the second generation antidepressants, a recently emphasized adverse effect of maprotiline requires mention. At high or rapidly increasing doses, m a p r o t i l i n e has caused seizures even in patients with no prior seizure disorder.6~ The monoamine oxidase inhibitors are known for their ability to produce a hypertensive response when tyramine or other false neurotransmitters are ingested or administered. This response can occur even up to two weeks after discontinuation of the medication and consists of hypertenAnnals of Emergency Medicine
sion associated with severe headache, photophobia, dilated pupils, dyspnea, palpitations, nausea, vomiting, sweating, and chest pain.SZ E m e r g e n c y treatment of the hypertension can be accomplished by a slow IV injection of 5 mg phentolamine, followed by 0.25 to 0.5 mg IM every four to six hours to control blood pressure.SZ Lithium has a low therapeutic index and can be dangerous in overdosage. Overdoses of lithium can lead to neuropsychiatric decompensation progressing through delirium, seizures, and coma to death. 63 The more common side effects rarely lead to emergency visits. In the APS sample patients reporting current or recent use of lithium were rare and all reported concurrent or recent use of antipsychotic drugs, suggesting that they may have represented a more severely ill group of bipolar patients. Abrupt discontinuation of lithium by patients who feel better or who are becoming hypomanic is not uncommon. There is some evidence that an acute confusional state or rebound mania may occur in this situation.64, 6s
Antianxiety Medications Antianxiety drugs are in common use for the appropriate treatment of anxiety, the often inappropriate treatment of depression, 66 and as a drug of abuse. These drugs have the potential for adverse effects, and perhaps of greater importance with this class of medication than others, are various withdrawal reactions. Alone, these medications are relatively non lifethreatening in overdose. 67 Because these medications often are abused in conjunction with alcohol or other drugs, overdose can become a medical emergency as a result of delirium, hallucinosis, stupor, coma, or respiratory arrest. Of particular importance in cases of intoxication is paradoxical disinhibition. Disinhibition of impulses with resultant aggressive behavior has been reported with several benzodiazepines, i n c l u d i n g alprazolam. 68 In one series of 80 patients treated with alprazolam, 10% displayed uncharacteristic verbal or physical hostility, usually very near the start of treatment. 6s Antianxiety drug treatment or abuse should be considered in the differential diagnosis of acute aggressive or destructive behavior. Withdrawal from even therapeutic doses of benzodiazepines has caused 966/155
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neuropsychiatric emergencies including anxiety, hallucinosis, confusional states, and seizures.69, 7o The anxiety m u s t be differentiated from a recurrence of functional s y m p t o m s . T h e concurrent prominence of autonomic symptoms, time course, and response to pentobarbitol challenge help establish the presence of a withdrawal syndrome. Propranolol 60 m g to 120 mg per day has been used to attenuate the a n x i e t y and s o m a t i c s y m p t o m s of mild benzodiazepine withdrawal. 71 Halfucinosis during benzodiazepine w i t h d r a w a l is a s y n d r o m e characterized by a clear sensorium, absence of autonomic abnormalities, and the presence of a u d i t o r y hallucinations (often of a perverse sexual or persecutory nature) in the absence of a formal thought disorder, s7 In some patients, a florid delirium tremens-Iike syndrome develops following discont i n u a t i o n of antianxiety agents and can progress to seizures. Seizures also may occur as an isolated symptom on discontinuation of alproazolam, and probably with other benzodiazepines as well.72 SUMMARY The e m e r g e n c y area is a difficult site for the practice of careful psychopharmacology. The detailed h i s t o r y taking and collaborative treatment relationship often found in the consultant's office is rarely present. Instead, rapid decisions are made under a variety of pressures, with patients who may be uncooperative and unwilling to be treated. M a n y e m e r g e n c y patients are concurrently in treatment with a psychotherapist or psychopharmacologist w h o is available for consultation to the e m e r g e n c y service. When this is possible it is of great potential value, both in arriving more quickly at an appropriate treatment and in preventing a harmful opposit i o n of the p a t i e n t ' s t r e a t m e n t resources. For patients who are not curr e n t l y in a n o t h e r t r e a t m e n t , additional helpful information often may be obtained f r o m friends or family members. This is especially useful in treating patients who are acutely psychotic, unable to communicate, or uncooperative with the emergency interview. Although psychopharmacological approaches properly chosen often yield rapid results, m e d i c a t i o n s are only a part of most emergency treatm e n t plans. Medications are ineffec156/967
tire in a variety of crises and cannot replace careful i n t e r v i e w i n g of patients and others aimed at understanding the exogenous stress, change in interpersonal relationships, intrapsychic conflict, or biological disorder that precipitated an emergency visit. Furthermore, the decision to treat with medications m u s t include a consideration of the adverse effects that m a y occur. With these limitations in mind, the area of e m e r g e n c y psychopharm a c o l o g y can provide powerful assistance to emergency clinicians. The authors thank Richard I Shader, MD, and Arthur Barsky, MD, for helpful suggestions during preparation of this manuscript.
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