Professional Documents
Culture Documents
26, 2005
Copyright © 2005 Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
R E V I E W
3 Psychiatric Clinic, Medical Faculty, Masaryk University Brno, Czech Republic
4 Fort England Hospital & Rhodes University Grahamstown, South Africa
5 Eli Lilly, Area Medical Center Vienna, Austria
Neuroendocrinol Lett 2005; 26(4):327–335 PMID: 16136016 NEL260405R03 © Neuroendocrinology Letters www.nel.edu
Abstract
A R T I C L E
Several psychotic disorders, including schizophrenia, may be associated with
symptoms of acute agitation and aggression. While drug treatment of agitation
is often essential, non-pharmacological interventions, both environmental and
behavioral, also play important roles in the complex management of agitated
patients. The most extensively used psychotropic drugs are parenteral formulas
of conventional antipsychotics and benzodiazepines. Recently, injection forms of
two second generation antipsychotics, olanzapine and ziprasidone, have become
available. Both drugs have shown adequate efficacy and tolerability in several
double-blind trials of intramuscular administration in acutely agitated psychotic
patients. Compared to conventional medication, injection forms of the new anti-
psychotics may have a faster onset of action and more favorable profile of adverse
events. Alternative approaches to injection administration include liquid drug
formula, orally disintegrating tablets and wafers, treatment initiation with high
doses, or rapid dose escalation. Evidence suggests that second-generation anti-
psychotics should be among the first-line choices in the treatment of agitation in
acute psychosis.
1. Psychotic agitation
Agitation is a transnosological syndrome; this or physical aggression toward objects or persons;
cluster of pathological behavior occurs in a variety the patients may then pose a danger to others [2,
of psychiatric diseases including schizophrenia, 3]. By definition, violence is a physical aggressive
bipolar disorder, or dementia. Agitation repre- behavior that is intended to inflict harm to other
sents a poorly organized and aimless psychomo- people [4]. While acute aggressive behavior occurs
tor activity stemming from physical or mental as a state phenomenon, the tendency to engage in
unease [1] Motor restlessness, increased respon- aggressive behavior over the lifetime is relatively
siveness to external or internal stimuli, irritabil- stable since childhood [5]. Most frequently, vic-
ity, inappropriate and usually purposeless verbal tims of violent behavior are members of patient’s
and motor activity are the major hallmarks of family; the medical personnel or other patients are
the syndrome. It can readily result into a verbal on the second place [6]. It should be also noted
Pavel Mohr, Ján Pečeňák, Jaromír Švestka, Dave Swingler & Tamás Treuer
that often these are the first symptoms of mental illness escalation that may result in aggressive or violent behav-
that receive medical attention or lead to the psychiatric ior. The primary goal of interventions is to secure safety
hospitalization. of the patient, staff, and other patients. The first step in
Not surprisingly, public opinion on psychiatry is the management of aggressive patients should be talking
significantly influenced by the aggressive or violent to a patient and offering help if needed. The next step is a
behavior of psychiatric patients; community tends to decision to initiate oral drug treatment. In case of need,
over-emphasize frequency of these incidents of violent we may use assistance of other people in order to get
crimes. Currently there are no specific guidelines on sufficient power, outnumber agitated patient and secure
the management of aggressive behavior in psychotic physical control. If necessary, time-limited restraints or
patients. The aim of our paper is to review available placement into seclusion may be used. Restraints should
pharmacological interventions with special focus on the be used only when the patient poses an imminent dan-
new antipsychotics. Data from published controlled tri- ger to himself or others and when other less restrictive
als on the efficacy of the second generation antipsychot- means failed [12]. Their use is temporary (2–4 hours);
ics were critically scrutinized. its application should be used to initiate treatment and
to provide basic physical, instrumental and laboratory
2. Management of agitated patient assessments. Patient in restraints usually calms down
after a while [13]. Use of restraints or seclusion must be
Prediction of risk for violent behavior in psychotic well documented, patient’s mental and physical condi-
patient can be a difficult task. A common accompa- tion carefully monitored and all changes and progress of
nying factor that complicates psychotic agitation is his status recorded. Seclusion or restraints are contrain-
concomitant abuse of alcohol and illicit drugs, which dicated in patients with severe physical conditions; also,
increases the risk of aggression [3]. Other risk factors drugs should be given to patients with head trauma.
include co-morbid personality disorders, unemploy-
ment, hyperactivity on in the clinical presentation and Although oral treatment is preferred, options in the
non-compliance with treatment; nevertheless, the best pharmacotherapy of acute agitation include the paren-
predictor of future violent behavior is a past history of teral (intramuscular [IM], intravenous [IV]) adminis-
violence [2, 7, 8, 9, 10]. Delusional ideas and/or com- tration of the psychotropic drugs in order to facilitate
manding hallucinations may be associated with aggres- onset of drug action and quickly alleviate symptoms.
sive, often unpredictable behavior [2]. Although the first So-called rapid tranquilization is the repeated adminis-
step should be a risk assessment, patients at the psychi- tration of medication over brief time intervals, usually
atric interview are more frequently asked about violent within an hour or half-hour period. It was recommended
thoughts and behavior directed to patient’s themselves previously to use very high doses of haloperidol, but
than about aggression to property or other persons [11]. later studies failed to support the administration of such
Patient evaluation, if possible in an emergency setting, extreme dosing. For example, Neborsky [14] compared
should precede any treatment initiation. mean doses of 48 mg vs. 12.5 mg/day of haloperidol and
Management of agitated/aggressive patient may be Donlon [15] compared three regimens of haloperidol
difficult and perilous as it is usually provided in emer- dose escalation (from 20 mg or 100 mg at the 5th day,
gency setting, often with insufficient data on patient’s 100 mg at the 10th day and stable dose of haloperidol
history and limited possibility for proper evaluation of 10 mg). In both studies, significant differences between
basic psychiatric and physical condition. Timely man- high a lower doses of haloperidol were not found.
agement and targeted treatment intervention prevents Treatment approaches must be comprehensive.
Besides indispensable drug treatment, non-pharmaco-
logical, behavioral and environmental interventions for
acute agitation are employed (Fig. 1). All objects near
Initial evaluation the patient that could be used as weapons (ashtrays,
• vital signs chairs, etc.) have to be removed, a safe passage to the
• brief visual exam secure area secured, and a sufficient number of the staff
• temporary diagnosis must be available. As the situation can be aggravated
(delirium, psychosis, intoxication, etc.) by overstimulation, it is helpful to screen the patient
from others and turn off television and radio. We
Initial intervention should never turn back to the agitated patient. Patients
• talk to patient should be approached with confidence and spoken to
• offer assistance in a soft, calm but authoritative tone. They should be
Oral medication if needed and possible allowed, asked questions designed to encourage them,
to ventilate their needs. While eye contact is important,
it should be broken if it makes the patient uncomfort-
If not possible:
able. The tone of the intervention is set in the first few
Parenteral medication minutes [2].
Restraints or seclusion if dangerous behavior
persists
328 Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Treatment of acute agitation in psychotic disorders
Haloperidol 0,5–10 10–25 Risk of acute dystonia, EPS, akathisia, prolactin elevation, NMS.
Chlorpromazine 25–100 17–30 Risk of acute dystonia, EPS, akathisia, prolactin elevation, NMS.
Levomepromazine 25–50 16–78 Risk of acute dystonia, EPS, akathisia, prolactin elevation, NMS.
Zuclopenthixol 50–150 32 Risk of acute dystonia, EPS, akathisia, prolactin elevation, NMS.
Ziprasidone 10–20 4–38 Prolongation of QTc interval, low risk of EPS, does not induce weight gain.
Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu 329
Pavel Mohr, Ján Pečeňák, Jaromír Švestka, Dave Swingler & Tamás Treuer
The risks of respiratory depression, and dependency, mum plasma concentration which is approximately 5
tolerance and withdrawal in long-term administration, times higher than the maximum plasma concentration
warrant caution. Benzodiazepines can augment seda- produced by a 5 mg oral dose (company data on file).
tive effects of other drugs and substances (alcohol), so The half-life observed after intramuscular administra-
they should not to be used in patients whose medical tion is similar to that observed after oral dosing. The
history is not known, with unknown type of intoxica- pharmacokinetics is linear across the clinical dosing
tion or toxicological analysis. Although rare paradoxi- range. After oral administration to healthy subjects,
cal reactions (hostility, violence) are unlikely to militate the mean terminal elimination half-life was 33 hours
against use in acute clinical situations, a recent French and the mean olanzapine plasma clearance was 26 L/hr.
review indicates that some benzodiazepines are asso- Olanzapine pharmacokinetics varied on the basis of
ciated with an increased risk of aggressive behavior in smoking status, gender, and age.
special patient populations [23]. In a study of 201 patients with bipolar mania or mixed
states [28], olanzapine injection (10 mg) was more effec-
4. Second generation antipsychotics tive than lorazepam (2 mg) and placebo after 2 hours
in calming agitation. At the 24-hour study endpoint,
The second generation antipsychotics are generally olanzapine was still superior over placebo; lorazepam
effective and safe in the management of agitated behav- was not statistically different from both olanzapine and
ior [review in: 17]. It should be noted that clozapine, the placebo. The three treatment arms showed no group
first agent of this group available for IM administration, difference in the frequency of adverse events.
is widely recognized as a very effective antiaggressive In the first of two schizophrenia studies [27], 270
drug in the treatment of aggression and agitation in patients were randomized into six treatment groups
psychiatric patients, independent of psychiatric diag- that were given, over a period of 24 hours, one to three
nosis [24, 25]. However, its use is limited due to the injections of placebo or haloperidol (7.5 mg), or one
safety concerns regarding the risk of agranulocytosis. of four dosages of olanzapine (2.5 mg; 5.0 mg; 7.5 mg;
Recently, parenteral forms of two new antipsychotics 10 mg). Efficacy was assessed two hours after the first
have become available: ziprasidone and olanzapine; par- injection and adverse events after 24 hours. All active
enteral forms of other second generation antipsychotics treatments were significantly better than placebo; 2.5 mg
(e.g., aripiprazole) are under development. of olanzapine was less effective than the higher olan-
zapine doses, and haloperidol. In olanzapine treatment
cells, a trend indicating better efficacy with increas-
ing doses was observed. Moreover, the doses of 5 mg,
Advantages of second-generation AP in acute
7.5 mg, and 10 mg showed faster onset of action: they
treatment:
were statistically superior to placebo already 30 minutes
• i.m. formulation, rapid dissolving tablets, after administration. The most frequent adverse event
wafers, and solutions available for some of the was hypotension in olanzapine treated patients (seven
atypicals patients, none on haloperidol or placebo). Two halo-
• rapid onset of action peridol treated patients developed acute dystonia, one
• rather calming than sedating effects patient on olanzapine and six on haloperidol developed
• better tolerability and safety in comparison with treatment-emergent Parkinsonism and akathisia was
observed in two olanzapine patients and three halo-
typical AP (EPS)
peridol subjects. Concomitant anticholinergic medica-
• more information on pharmacokinetics and tion had to be prescribed for three haloperidol and one
dosage regimen olanzapine treated patients.
• continuing treatment with the same drug In the second study [26], 321 patients were randomly
during acute and maintenance treatment assign to olanzapine (N=131), haloperidol (N=126), or
placebo (N=54); 285 patients (91.6%) completed the
study. IM olanzapine patients were administered one
to three IM injections of olanzapine (10 mg) over a
a. Olanzapine period of 24 hours. Evaluation at the a-priori set time
points showed that olanzapine and haloperidol reduced
The efficacy of olanzapine injection form has been agitation significantly better than placebo. Moreover,
tested in two double-blind trials of schizophrenia at assessments after 15, 30, and 45 minutes, patients
[26, 27], in the treatment of acutely agitated patients receiving olanzapine displayed significantly greater
with mania in bipolar disorder [28], and dementia of improvement on the PANSS EC compared to haloperi-
Alzheimer or vascular types [29] (Table 2). Most study dol-treated patients, again suggesting faster onset of
subjects required a single injection to produce therapeu- action. Olanzapine was also better tolerated: EPS were
tic effects. The time interval needed to reach maximum observed in 0.8% olanzapine treated patients compared
plasma concentrations (15–45 min after the IM applica- to 5.6% patients on haloperidol. In the haloperidol
tion) indicates fast onset of action. In a pharmacokinetic group, there was a 7% incidence of acute dystonia (none
study in healthy subjects, a 5 mg intramuscular dose of in the olanzapine group). Anticholinergic medication
olanzapine for injection produced on average a maxi-
330 Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu
Treatment of acute agitation in psychotic disorders
had to be prescribed to 20.6% patients on haloperidol, nificantly more reduced with olanzapine than placebo
4.6% olanzapine patients, and 3.7% placebo subjects. (p < .05). In the incidence of adverse events indicative
Lastly, in a double-blind trial in patients with mixed of sedation there was no significant difference between
dementia [29], 272 patients were randomized to three olanzapine and the comparator drugs. For the treatment
groups: olanzapine injections (dosage 2.5 mg and of acute agitation associated with schizophrenia, bipolar
5.0 mg, respectively), were compared with injection mania, or dementia, intramuscular olanzapine-treated
lorazepam (1.0 mg) and placebo. Two hours after the patients did not experience more sedation than halo-
administration both doses of olanzapine and loraz- peridol- or lorazepam-treated patients and experienced
epam were more effective than placebo. This outcome distinct calming rather than nonspecific sedation; i.e.,
was endorsed at the final 24-hour assessment: olanzap- they became calm without sleepiness.
ine 2.5 and 5.0 mg and lorazepam were superior over In a double-blind follow-up of the study of Wright
placebo according to the PANSS Excited Component and collaborators, 311 patients were switched to con-
Score (PANSS-EC); moreover, olanzapine 5.0 mg and tinuation oral treatment with olanzapine or haloperidol
lorazepam were statistically better than placebo also (both 5–20 mg/day) [31]. The results of the 4-day trial
on the Agitation-Calmness Evaluation Scale (ACES). confirmed sustained efficacy during the transition from
Important finding is a good tolerability of olanzapine injection to tablet forms of the two drugs. Moreover, in
injection and absence of serious adverse events in a contrast to haloperidol, olanzapine administration was
population of elderly patients with frequent comorbid- not associated with severe adverse events, such as dys-
ity of other medical conditions. tonia, akathisia, or other treatment-emergent adverse
The rapid reduction in agitation achieved by IM events.
olanzapine is a direct advantage to the patients. More- The manufacturer of olanzapine recommends 10 mg
over, they also benefit indirectly from the absence of the of olanzapine injection administered as a single intra-
potential adverse events associated with repeated IM muscular injection for agitated patients with schizo-
injections, concomitant parenteral benzodiazepines, phrenia and bipolar mania. On the basis of individual
or intravenous administration. A review of the above clinical status, a second injection, 5–10 mg, may be
described double-blind studies investigated sedative administered as early as 2 hours after the first injection.
and calming effects of olanzapine [30]. The ACES scale Repeated injections should not be administered unless
and treatment-emergent adverse events were used to patients remain substantially agitated; the maximum
assess sedation. Across all studies, 1 patient (lorazepam- daily dose of olanzapine of 20 mg (including all for-
treated, bipolar) became unarousable. There were no mulations) should not be exceeded. Duration of injec-
significant between-group differences in ACES scores of tion treatment should not be longer than 3 consecutive
deep sleep or unarousability at any time across. Exclud- days.
ing patients who fell asleep, agitation remained sig-
Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu 331
Pavel Mohr, Ján Pečeňák, Jaromír Švestka, Dave Swingler & Tamás Treuer
Neuroendocrinology Letters No.4 August Vol.26, 2005 Copyright © Neuroendocrinology Letters ISSN 0172–780X www.nel.edu 333
Pavel Mohr, Ján Pečeňák, Jaromír Švestka, Dave Swingler & Tamás Treuer
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