Treatment of Acute Functional Psychosis

Original Author: Bruce Alexander, Pharm.D., BCPP
Latest Reviser: Bruce Alexander, Pharm.D., BCPP
Creation Date: 1996
Last Revision Date: March 2002
Peer Review Status: Internally Peer Reviewed

This discussion focuses on the acute treatment of functional psychosis. The management of chronic assaultive and/or aggressive behavior secondary to organic causes and the treatment of patients presenting with agitation due to substance abuse is discussed in subsequent chapters.

This patient population includes newly diagnosed patients or patients with relapsing symptoms of schizophrenia, schizophreniform disorder, schizoaffective disorder (manic phase), and bipolar affective disorder (manic phase). These patients may present with delusions and/or hallucinations accompanied by agitation, excitement, assaultiveness, and/or threatening behavior.

The agents and techniques for treating patients with acute functional psychosis depends on whether the patient is in an agitated state. The two classes of drugs most widely studied are antipsychotics and benzodiazepines. Overall, It is unclear if there is an advantage to administering the pharmacologic agents by frequent injections over a period of hours, and whether administering them via different routes (IM, IV, PO) affects the rate and degree of response.

Non-agitated patients
Antipsychotics are the mainstay of treatment for the non-agitated, psychotic patients. A number of different dosage schedules using oral and parenteral procedures are described in the literature as "rapid" treatment techniques. Terminology has included rapid neuroleptization, rapid tranquilization, "crash" tranquilization, and rapid psychotolysis. Antipsychotics studied have included chlorpromazine, haloperidol, droperidol, perphenazine, fluphenazine, trifluoperazine, thiothixene, and loxapine.

Rapid oral techniques
For patients who are able to comply with oral administration, several studies have investigated "oral loading" of antipsychotics.

Donlon et al (1978) in a rater-blind study divided 32 acutely psychotic patients into two groups. One group received fluphenazine 20 mg/d for the 7 days of the study. The other group received 20 mg the first day, and the dosage was increased by 20 mg every 48 hours to a maximum of 80 mg/d. The two groups did not differ in rate or degree of improvement.

Donlon et al (1980) compared the effectiveness of three ten-day dosage schedules of haloperidol in 65 acute schizophrenics: (1) 20 mg on day 1, increasing to 100 mg at a rate of 20 mg per day, (2) 10 mg on day 1, increasing to 100 mg at a rate of 10 mg per day, and (3) 10 mg per day for ten days. The data indicated that all three regimens had similar efficacy and a high initial loading dose did not speed the onset of response. The authors recommended a dose of 5-15 mg per day in treating hospitalized acutely decompensated patients.

Neborsky et al (1981) conducted a similar study. Twenty acutely psychotic male inpatients were randomly assigned to either high or low dose haloperidol treatment. The drug was given in three phases: phase 1 consisted of hourly 2 mg or 10 mg IM injections for up to 4 hours depending upon treatment group; phase 2 consisted of 2 mg or 10 mg oral doses, given as often as hourly until symptoms were reduced satisfactorily; phase 3 consisted of approximately 2 mg or 10 mg oral maintenance doses being given for 6 days. Phases 1 and 2 were completed in 24 hours. Overall, high dose patients received an average of 29 mg of haloperidol during phase 1, 12 mg during phase 2 and 48 mg/d during phase 3. Low dose patients received an average of 7.8, 2 mg and 12.5 mg/d during phase 1, 2, and 3 respectively. BPRS and global rating scales were used to assess the treatment response. Neither response nor the severity of adverse effects differed between the two groups. Thus high dose rapid neuroleptization appears to be no more effective than low dose rapid neuroleptization.

Rapid oral vs parenteral administration
The relative value of oral versus parenteral administration of antipsychotics has been investigated in three studies. Erickson et al studied two groups of patients treated with haloperidol. One group was given a "loading dose" of 60 mg/d IM for the first 5 days of the study, and then their dose was tapered over the next 7 days to 15 mg/d orally (Erickson et al 1978). The other group was given 15 mg/d orally (plus placebo injections) throughout the 3 weeks of the study. Although the plasma haloperidol in the loading dose group rapidly reached significantly higher levels than those attained for the standard dose group, the two groups did not differ significantly in either rate or amount of improvement by the end of the study.

Escobar et al (1983) studied 14 patients with an exacerbation of DSM III diagnosed schizophrenia (N=13) or schizoaffective disorder (N=1). Patients were randomly assigned to a neuroleptization group or a control group. The first 24 hours of the 7-day study was double blind. In the first 24 hours the neuroleptization group received fluphenazine 5 mg IM Q 1o x 6 possible doses, plus PO placebo Q 8o x 3. In addition from 18 to 24 hours this group could receive fluphenazine 5 mg PO Q 1o up to 6 doses. The control group received placebo injections IM Q 1o x 6 possible times, plus fluphenazine PO 2.5 mg Q 8o x 3. In addition the patient could receive PO placebo Q 1o up to 6 doses in the 18 to 24 hour period.

In the first 24 hours the neuroleptization group received an average of 48.5 mg as compared to the control group's 7.5 mg. From day 2 to 7, which was the open part of the study, patients in both groups could receive 10-40 mg/d orally. At the end of 7 days the neuroleptization group averaged 23 mg/d and the control group 18 mg/d. Patients were rated at baseline, 4, 8 to 12, and 18 to 24 hours of the initial phase and on days 4 and 7 of the continuation phase with the BPRS and CGI.

The majority of improvement occurred in the first 4 to 8 hours of the study regardless of the group. It is of interest to note that the control group had only received 2.5 mg of fluphenazine PO by this time! There was no difference between the two groups on either scale at any rating. However, the EPS rating scale indicated a significantly higher score with the neuroleptization group at 24 hours as compared to the control group.

In a study of the same design as Escobar et al described above, Coffman and Nasrallah (1987) evaluated rapid parenteral versus oral fluphenazine administration in 16 patients with acute psychotic illness. Patients in the parenteral group received a mean fluphenazine dose of 16.3 mg in the first 24 hours. The control group received a mean total dose of 7.2 mg orally. the mean doses from day two through seven were 19.4 mg and 18.8 mg for the parenteral and oral groups, respectively. The rate of improvement of psychotic symptoms for the two groups was not different. The results indicate rapid parenteral treatment for acute psychosis produces more risk than benefit.

AGITATED PATIENTS

The immediate goal of treatment of the acutely agitated psychotic individual is to reduce the agitation, irritability, and/or hostility to a level where the patient is not a physical danger to himself or others and, if necessary, to a level where they can be medically managed. The alleviation of hallucinations and/or delusions, which is assumed to be the basis of the agitated behavior, is the ultimate goal.

Current management of acutely agitated patients involves the use of antipsychotics and benzodiazepines either alone or in combination.

ANTIPSYCHOTICS

Antipsychotics alone are the most common chemical intervention in the management of agitated patients. They are usually administered parenterally given the difficulty of administering oral drugs in these patients. There is no information to suggest that there is any difference in efficacy between IM and IV administration. Commonly used IM doses are thiothixene 10 mg, haloperidol 5 mg, fluphenazine 2.5 mg, and loxapine 12.5 mg. If the drug can be administered orally, two times the IM dose is sufficient. There is no difference in efficacy between available antipsychotics in agitated patients.

Rapid intramuscular administration
Frequent intramuscular injections (every 30 to 60 minutes) of antipsychotics have been administered to control psychotic symptoms and behavior. The following studies are reviewed because they are double blind or rater-blind investigations.

Man and Chen (1973) compared the effectiveness of intramuscular injections of chlorpromazine with IM haloperidol in controlling agitated, assaultive psychotics. In a double-blind study, 30 patients (mean age = 33) were assigned to receive chlorpromazine 50 mg IM or haloperidol 5 mg IM. The haloperidol dose was about 2 1/2 times as potent as the chlorpromazine dose. The drugs were administered every 30 minutes until the primary symptoms were controlled or until the patient was designated as a nonresponder. Patient evaluations utilizing global impressions, the Brief Psychiatric Rating Scale (BPRS), and target symptom profiles indicated that both drugs were effective in reducing the severity of primary symptoms of hostility, agitation, assaultiveness, and mania in an average of 2 1/2 hours. However, due to chlorpromazine's hypotensive effects, haloperidol appeared to be the safer drug. Two patients given chlorpromazine experienced sudden near fatal hypotensive episodes as the blood pressure fell to zero.

Reschke (1974) reported a study involving 50 patients (43 women, 2 men) who presented a psychiatric emergencies with symptoms such as agitation, excitement, and assaultiveness. Each patient was randomly assigned to receive haloperidol 1, 2 or 5 mg, chlorpromazine 25 mg, or placebo. All were administered under double-blind conditions at 30-minute intervals until symptoms were controlled or the patient had received four IM injections. After control of symptoms, patients were openly treated with haloperidol or chlorpromazine. A 5-point target symptom checklist and the 7-point BPRS were used to evaluate each treatment. At two hours symptoms were adequately controlled (p < 0.05) in patients receiving 2 or 5 mg injections of haloperidol but not haloperidol 1 mg, chlorpromazine 25 mg, or placebo. Eighty-one percent of patients receiving the two higher doses of haloperidol demonstrated at least moderate improvement compared to 28% on haloperidol 1 mg or chlorpromazine 25 mg. Interestingly, the haloperidol 2 and 5 mg groups demonstrated significant improvement over other medications in the factors of thinking disturbance, withdrawal retardation, and paranoid-hostile-suspiciousness scales of the BPRS. In the haloperidol groups, six patients experienced "mild extrapyramidal side effects" and twelve demonstrated sedation. In the chlorpromazine group, six patients were asleep at two hours after the dose and one experienced transient hypotension.

Anderson et al (1976) studied 24 patients with acute psychoses who met RDC criteria for schizophrenia or mania. Patients were randomly assigned after haloperidol 5 mg IM to a high-dose group (haloperidol 10 mg Q 30 min up to 5 times) or to a moderate-dose group (haloperidol 5 mg Q 60 min up to 3 times). Patients were rated blind using the BPRS on an hourly basis. No significant difference was noted in the BPRS scores between the high-dose (x= 33 mg) and the moderate-dose groups (x=13 mg) after 3 hours and 72 hours. Of the 19 people completing the protocol, 11 achieved marked improvement in 3 hours and another 5 within 72 hours. This improvement included not only anxiety but amelioration of "core" psychotic symptoms (i.e., hallucination, unusual thought content, suspiciousness, elevated mood, conceptual disorganization, and grandiosity). Eight patients (4 in each group) experienced dystonic reactions and one patient in the high dose group experienced faintness and pallor upon arising from a recumbent position.

Stotsky et al (1977) in a double-blind study treated 30 acutely agitated and excited patients (24 had a diagnosis of schizophrenia) with IM thiothixene or haloperidol. After random assignment patients could receive haloperidol 4 or 8 mg or thiothixene 4 or 8 mg at 0, 1, 2, 3, or 4 hours. Patients were rated at baseline and hourly up to 6 hours with the BPRS and the Psychiatric Target Symptom Profile. Most patients required 3 or fewer injections (24 patients). The groups received haloperidol 8-32 mg (x = 15 mg) or thiothixene 4-16 mg (x = 10 mg). Global evaluation showed some improvement in each patient and marked improvement in 7 haloperidol and 6 thiothixene patients. The scales showed no significant difference between the 2 drugs. Four patients on haloperidol reported adverse reactions (4 drowsiness) and 2 patients on thiothixene reported drowsiness, which was the only adverse reaction.

Resnick and Burton (1984) in a double-blind study, studied 27 "acutely agitated" inpatients who achieved a baseline BPRS score of <17 (out of a possible 42 points). After random assignment, patients were treated with a IM injection of droperidol 5 mg or haloperidol 5 mg. The injections could be repeated Q 30 minutes x 3 as long as the BPRS --> 17. Of the 16 patients in the haloperidol group, 3 required a single injection and 13 required two or more injections. Two patients required three injections and 1 patient required four injections for adequate control. In the droperidol group, 7 of 11 patients required one injection and 4 required 2 injections. The percentage of patients requiring only one injection for control of symptoms was significantly higher in the droperidol group (64% vs. 19%, p<.05).

Lesem et al (2001) studied the effects of IM ziprasidone 2 or 10 mg in 117 acutely agitated psychotic patients in a randomized, double blind fashion. Patients could receive an injection every 2 hours if needed. The primary outcome measure was the Behavioral Activity Rating Scale (BARS) with possible scores of 1-7 (Swift et al 1998). The mean baseline BARS scores were 4.65 and 4.79 in the 2 (n=54) and 10mg (n=63) groups, respectively. The goal score of 4 places the patient at quiet, but awake at a normal level of activity. A score of 5 means there were signs of overt physical or verbal activity, but that the patient calms with instructions. The 10 mg group had significantly more "responders" as measured by a decrease in BARS score of 2 or more; however, the mean score dropped near 3, which indicated that the patient was somewhat drowsy. The mean BARS in the 2mg group dropped to near 4, the goal. Most of the effect was seen by 2 hours, but maximal effect was usually not until 4 hours post-dose. The 10 mg and 20 mg doses resulted in significantly greater improvements on the CGI-severity and improvement scales than the 2mg dose. It is difficult to interpret the clinical importance of this study because the patients did not have significant agitation at baseline.

Brook et al (2000) evaluated the efficacy of flexible doses of IM ziprasidone (n=90) vs. haloperidol (n=42) in the treatment of 132 inpatients with psychosis and agitation in an open-label trial. Initial doses were 10mg ziprasidone and 2.5-10mg haloperidol, with maximum daily doses of 80mg and 40mg, respectively. The first three days of treatment utilized the IM formulations then patients were switched to PO therapy. Mean baseline BPRS total and agitation item scores were 45.9 and 9.9 in the ziprasidone group and 47.5 and 9.3 in the haloperidol group, respectively. The CGI-severity scores were 5.1 and 4.9 for the groups, respectively. After three days of IM therapy the BPRS total and agitation scores dropped by 6.24 and 1.93 in the ziprasidone group and 3.18 and 0.8 in the haloperidol group, respectively (p=0.015 and 0.002, respectively). The CGI-severity scores decreased by 0.49 and 0.15 (p=0.025) in the ziprasidone and haloperidol group, respectively. The average daily doses ranged from 23.3 to 27.6mg for ziprasidone and 7.6 to 11.0mg for haloperidol over the three days. Two limitations of this study is the nonblind design and as noted in the previous study these patients were not rated as being very agitated at baseline.

Wright et al (2001) evaluated the effects of olanzapine 10mg IM in comparison to haloperidol 7.5mg IM or placebo in 285 patients with schizophrenia with acute agitation. The primary efficacy variable was the change in the PANSS-excitement component score at 2 hours after the first dose (total possible score 35). At baseline the mean PANSS-excitement scores were 18.4, 18.2, and 18.4 for the olanzapine (n=131), haloperidol (n=126), and placebo (n=54) treated patients, respectively. From baseline to 2 hours, mean changes were &endash;7.7 (p<0.001 vs. placebo), -7.6 (p<0.001 vs. placebo), and &endash;3.6 for the olanzapine, haloperidol, and placebo groups, respectively. No difference was noted between the olanzapine and haloperidol groups (p=0.76). Olanzapine demonstrated a difference from placebo at 15 minutes, and haloperidol at 30 minutes. Differences were sustained through the first 2 hours after the dose. Patients appear to have responded faster to olanzapine, as evidenced by significant differences favoring olanzapine at 15 (p<0.001), 30 (p<0.001), and 45 (p=0.01) minutes after injection, respectively. Haloperidol-treated patients experienced significantly more acute dystonic reactions (7.1% vs. 0%, p=0.001), more extrapyramidal syndromes (5.6% vs. 0.8%, p=0.03), and received more anticholinergic agents (20.6% vs. 4.6%, p<0.001) compared to olanzapine-treated patients. The authors concluded that olanzapine injection was as effective as haloperidol in controlling agitated patients with schizophrenia and produced significantly fewer adverse effects.

Intravenous Administration
Although haloperidol and droperidol have successfully been given intravenously, blind comparison studies of efficacy and side effects to IM administration have not been performed for any antipsychotics. Other parenteral techniques

Antipsychotics injected IM less frequently than every 30 to 60 minutes has been described in blind studies. These seven studies included research with chlorpromazine, haloperidol, perphenazine, loxapine, fluphenazine, thiothixene, and trifluoperazine (Ritter et al 1972, Shopsin et al 1969, Fitzgerald 1969, Levenson et al 1976, Brauzer and Goldstein 1968, Fruensgaard et al 1977). The studies usually administered the drugs IM every 6, 8 or 12 hours for 48 to 96 hours. Comparing haloperidol, the response was not as rapid in these studies as compared to every 30 to 60 minute dosing and EPSE were more prevalent (25-80% vs. 21-33%).

As an example of these studies, Paprocki et al (1977) administered haloperidol IM (average daily dose = 12 mg) and loxapine IM (average daily dose = 115 mg) every 6 to 12 hours for 4 days, and reported a mean reduction in total BPRS scores of approximately 20% for both drugs at day 2, and 41% for both drugs at day 4.

Swift et al (1999) in a randomized, open-label study compared the atypical antipsychotic, ziprasidone IM 20 mg/d, 40 mg/d, or 80 mg/d with haloperidol 10 - 40 mg/d administered bid to qid for 3 days. Patients then received oral treatment for the next 4 days. In all 3 ziprasidone groups the reduction in the mean Behavioural Activity Scale (BARS) occurred more rapid than with haloperidol. BPRS scores improved equally with all four treatment groups. Dystonia and akathisia occurred less frequently with all 3 ziprasidone groups compared to haloperidol. The rate of anticholinergic use was >2 times greater with haloperidol compared to the ziprasidone groups.

ANXIOLYTICS

Several studies have examined the effect of benzodiazepine treatment (<2 weeks) on psychotic symptomatology.

The following reports are considered preliminary findings. The lack of adequate controls, heterogeneous patient populations, double blind patient assignment to treatment, and blind patient assessment limit conclusions about this practice. Benzodiazepines should not be considered primary treatment for these patients. However, if these reports are confirmed, benzodiazepines may allow more rapid control of symptoms and decrease the antipsychotic dose requirements in the first days of treatment of these patients.

Lerner et al (1979) randomly assigned 40 inpatients in an open study to receive haloperidol or diazepam IV. Thirty-five of the 40 patients were without medication in the month prior to hospitalization and the majority had a diagnosis of schizophrenia, mania, or schizomania. After 48 hours of observation the haloperidol group received 20-35 mg and the diazepam group received 30-40 mg in the next 24 hours. Based on the 24 hour BPRS and the CGI both groups improved significantly as compared to baseline. However, there was no significant difference between the two groups on either scale. BPRS subscales included anxiety/depression, withdrawal, thought disorder, activation, and hostility/suspiciousness.

Bick and Hannah (1986) reported a retrospective study involving ten patients who had been treated openly on separate admissions to an ER with a single injection of haloperidol 10 mg IM or lorazepam 2 mg IM. The number of hours that the patient subsequently spent in the seclusion room after the injection was recorded. On the average the haloperidol group spent 6.1 hours in seclusion as compared to 1.9 hours for the lorazepam group.

In an open, uncontrolled report, Modell et al (1986) reported the effects of various doses of PO, IV, and IM lorazepam in a series of 75 agitated patients (40 manic, 15 depressed, 15 schizophrenic, 10 delirious, and 10 with anxiety). Doses ranged from 2 to 120 mg/d with average doses of 30 mg/d po, 16 mg/d IM, and 80 mg/d IV. It was noted that while nonpsychotic patients generally required small doses between 2 to 4 mg/d, psychotic patients required 2 to 3 times this dose. The most common side effects were ataxia (50%), nausea or vomiting (25%), and confusion or disorientation in 13%.

Lenox et al (1992) presented data from a ten-day randomized, double blind study of lorazepam versus haloperidol in 20 hospitalized patients with a DSM-III-R diagnosis of bipolar disorder that were being treated concomitantly with lithium . Patients were rated using the Mania Rating Scale, Brief Psychiatric Rating Scale, Physician Global Impression Scale, and side effects scales. The average mg/day doses for lorazepam and haloperidol were 8.8 and 17.7, respectively. The degree of improvement or the time to response for haloperidol (5.0 +/- .82 days) and lorazepam (6.5 +/- .93) did not differ. Early terminations from the protocol were primary for the reason of nonresponse for lorazepam and side effects for haloperidol.

Antipsychotic/Anxiolytic Combination
Despite the lack of adequate reports studying the use of benzodiazepines alone in the management of acutely agitated psychotic patients, the current trend has been to study the combination of antipsychotics with benzodiazepines. The rationale behind this approach is to take advantage of the anxiolytic/sedative effects of the benzodiazepine to allow for a lower dose of the antipsychotic. A common difficulty in interpreting these studies is that the doses of the benzodiazepines were chosen empirically since there is no established method to determine the equivalence of effects and doses between benzodiazepines and antipsychotics. Mania and schizophrenia are the primary diagnoses of the patients in these reports.

Arana et al (1986), in a retrospective chart review, reported antipsychotic doses in 30 inpatients at the time of discharge. Those patients receiving neuroleptics alone (n=22) were discharged on a mean chlorpromazine equivalent dose of 560 mg/d compared with 265 mg/d in the eight patients also receiving lorazepam at discharge (mean dose = 2.75 mg/d).

From the same report, the authors openly and prospectively treated 14 acutely psychotic patients (DSM-III diagnoses of mania, schizophrenia, and atypical psychosis). Eight received lorazepam alone (mean dose 20.9 mg/d), and six received lorazepam (mean dose 16.5 mg/d) plus haloperidol (mean dose 14.2 mg/d). Patients treated with lorazepam alone showed statistically significant improvement at 48 hours in the symptoms of tension, hostility, suspiciousness, excitement, and conceptual disorganization, unusual thoughts, and emotional withdrawal. These symptoms were more likely to improve at lorazepam doses >30 mg/d. However, these doses were associated with motor retardation and blunted affect. It is important to note although symptoms improved initially with benzodiazepine therapy alone, they typically began to return and worsen over the remainder of the week, necessitating the addition of an antipsychotic drug. In the lorazepam/haloperidol group, significant improvements were seen at 48 hours in the symptoms of grandiosity, unusual thoughts, conceptual disorganization, blunted affect, and emotional withdrawal. The results of this study are difficult to interpret because of mixed diagnoses, small sample size, and differences in BPRS scores between the two groups of patients.

A four-week, randomized double blind, placebo-controlled trial by Altamura et al (1987) compared haloperidol and placebo with haloperidol with clonazepam in 24 schizophrenics. Haloperidol doses ranged from 3 to 19 mg/d (mean = 8.2 mg/d), and the clonazepam dose was 3 mg/d. Extrapyramidal side effects were significantly lower in the group receiving clonazepam despite the fact that haloperidol doses were not different between the two groups. Although BPRS and excitements scores were not different between groups throughout the study, the clonazepam/haloperidol group was significantly different from baseline at one week on the BPRS scale and at 2 weeks on the excitement scale. Differences from baseline appeared at weeks 2 and 3 on the BPRS and excitement scales, respectively, in the haloperidol/placebo group.

Garza-Trevino et al (1989) recently examined the effect of the combination of IM antipsychotics and sedative/hypnotics in a three part report. The population studied in this report included the diagnoses of mania, schizophrenia, OBS, atypical psychosis, and others. The main criterion for inclusion in these studies was an agitation score of > 50 mm on a 100 mm analog scale. An agitation score of < 20 mm within 210 minutes was the measure of response.

In the first study, a pilot study, 33 patients with a median agitation score of 80 mm were administered lorazepam 4 mg and haloperidol 5 mg IM every 30 minutes for up to seven doses to investigate the tolerance, safety, and efficacy of the combination of IM antipsychotics and benzodiazepines in agitated patients. Thirty-one of thirty-three responded in a median of 60 minutes (range 30-210 minutes). Doses ranged from 4 to 24 mg for lorazepam and 5 to 65 mg for haloperidol.

The second study was an unblinded randomized comparison of haloperidol 5 mg and lorazepam 4 mg alone and in combination in 68 agitated patients. The median agitation score was 60 mm. The patients in the combination group responded more rapidly, typically within 60 minutes, than those patients receiving either drug alone. It was noted that the more agitated patients were less likely to respond regardless of the treatment administered.

The third study was designed to examine other antipsychotics in combination with other sedative/hypnotics. This study compared thiothixene 5 mg/dose plus lorazepam 4 mg/dose with haloperidol 5 mg/dose plus phenobarbital 130 mg/dose in 53 agitated patients. No difference in rate of response or likelihood of response was noted between the two groups.

Barbee et al (1992) studied 28 acutely ill patients with schizophrenia in a 72-hour study. Fourteen patients each received haloperidol 5 mg plus alprazolam 1 mg po versus haloperidol 5 mg plus placebo. The first 24 hours each group could receive up to 4 doses administered q2h. On days 2 and 3, total doses administered in the first 24-hours were administered on a bid or tid. basis depending if the number of doses were odd or even. Patients were rated at 0, 2, 4, 6, 8, 24, 48, and 72 hours with the BPRS, a BPRS subscale, SAPS, SANS, and Simpson-Angus Side Effect scales. The average total dose in the combination group was 2.1 (haloperidol 10.5/alprazolam 2.1) versus 3.2 (haloperidol 16 mg) in the haloperidol-only group (p<0.05). There was no significant difference between the groups in either time to respond or quality of response. The haloperidol-only group experienced 16 dystonic reactions compared to only 7 in the combination group.

In 61 acute schizophrenic patients the effects of haloperidol and lorazepam combined vs. haloperidol alone were evaluated in a 28-day study (Stevens et al 1992). Patients were assigned to groups randomly in this open design study. Psychopathology was evaluated on the basis of BPRS scores, while extrapyramidal side effects were rated according to the Simpson and Angus Scale. Serum levels of lorazepam, haloperidol, and reduced haloperidol were measured. Mean daily dosages (mg/kg) were lorazepam 0.05 and haloperidol 0.5. None of the patients treated with lorazepam and haloperidol achieved better BPRS total or sub scores, nor did their condition improve faster than in patients treated with haloperidol alone. A significant linear relationship between lorazepam serum levels and oral dosage was found; however, no relationship between lorazepam serum levels and BPRS total score, sub score reduction, or extrapyramidal side-effects existed.

A double blind, parallel, randomized study was performed at 5 emergency room sites (Battaglia et al 1997). Ninety-eight patients with a score of at least 5 (moderate severity) on a scale of 1 to 7 for >3 of 11 psychosis/anxiety items from the BPRS were enrolled. The seven psychosis items were hostility, suspiciousness, uncooperativeness, unusual thought content, disorganized conceptualization, hallucinatory behavior, and grandiosity. The four anxiety items were anxiety, excitement, tension, and mannerism/posturing. The patient received either lorazepam 2 mg IM, haloperidol 5 mg IM, or the two therapies combined. The patient could receive up to 6 injections in 12 hours, but the frequency could not be <1 hour for the first 3 injections with the remainder at least 2 hours apart. Patients were rated hourly for 12 hours after the last injection with the BPRS, the Agitated Behavior Scale (ABS), CGI, and Alertness Scale. The majority of patients received at least 3 injections. Within the first 3 hours the combination of lorazepam and haloperidol produced the most rapid onset of action (p < 0.03). After that period of time there was no difference between the 3 treatments. Also, the total sleep time was significantly longer for the combination treatment and lorazepam compared to haloperidol (p < 0.05). Side effects did not differ among the three groups except the haloperidol group experienced more extrapyramidal reactions.

Currier and Simpson (2001) reported the effects of risperidone oral concentrate 2mg plus lorazepam 2mg po versus haloperidol 5mg IM combined with lorazepam 2mg IM in 60 patients presenting with psychotic agitation. Patients were not randomized to one of the two treatments, but were presented with the option of PO or IM medication. Groups were similar at baseline except that men were significantly more likely to choose PO medication. Mean PANSS-agitation score (total possible score = 35) at baseline was 28.5 for the PO group and 26.7 for the IM group. At 30 minutes after treatment the mean scores had decreased to 15.9 and 14.0, and after 1 hour to 10.1 and 8.2, in the PO and IM medication groups, respectively. No significant differences were seen between the groups on efficacy rating scales at any time point. One patient in the IM group developed acute dystonia, while there were no adverse events reported in the PO group. One patient in the PO group required IM haloperidol due to lack of treatment efficacy.

Rapid neuroleptization techniques aim to titrate drug against psychotic symptomatology by providing a series of doses over a period of hours. These characteristics differentiate rapid neuroleptization from other high dose treatments for acute psychosis. The use of rapid tranquilization has been reviewed (Dubin 1988). Most studies reviewed indicate that parenteral techniques produce not merely effective sedation of the majority of excited patients, but also some improvement in core psychotic symptoms.

Overall, one antipsychotic has not been demonstrated to be more effective than another in rapid treatment of the agitated psychotic patient. As expected, low-potency antipsychotics, i.e. chlorpromazine, are associated with a higher incidence of hypotension while high-potency antipsychotics, i.e., haloperidol, are associated with a higher incidence of acute extrapyramidal side effects.

No investigation has established the superiority of rapid parenteral techniques over conventional intramuscular pharmacotherapy by direct comparison, e.g., fluphenazine given in hourly injections and in injections every 6 to 8 hours. One study comparing high dose rapid parenteral treatment and low dose oral treatment demonstrated no difference between these two strategies.

The studies comparing oral high dose versus an oral minimal antipsychotic dose demonstrated that higher doses do not effect a greater rate of improvement or amount of improvement than lower doses. In addition, side effects tend to be higher with the higher doses.

Finally, several authors note the important contributions of research procedures to improvement of the patients, e.g., the frequent administration of medications (primarily injections) and the increased attention provided by medical and nursing personnel (Kirkpartrick and Burnet 1982).

The role of anxiolytics in the early acute management of the psychotic patient warrants further investigation (Salzman 1988). Since antipsychotics are still the preferred treatment for controlling psychotic symptoms in the violent patient, BZD may play an adjunctive role in early acute control of agitation where recommended doses of antipsychotics are ineffective for this symptom. Recent studies have also indicated that the combination of benzodiazepines and antipsychotics may allow for a lower antipsychotic dose and minimize antipsychotic side effects. Further evaluation of this therapy is also warranted.

REFERENCES

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Barbee JG, Mancuso, DM, Freed CR, Todorov AA (1992). Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia. Am J Psychiatry 149:506-10.

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ADDITIONAL READINGS

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