by Alina R. Rais, MD; Kristi Williams, MD; Theodor Rais, MD; Tanvir Singh, MD; and Marijo Tamburrino, MD
Dr. Alina Rais is Associate Professor, Director Psychogeriatric Program of the University of Toledo Medical Center (UTMC), Toledo, Ohio; Dr. Williams is Associate Professor, Director Psychiatry Residency Training Program UTMC, Toledo, Ohio; Dr. Theodor Rais is Associate Professor, Program Director, Kobacker Center UTMC, Toledo, Ohio; Dr. Singh is Assistant Professor, Director Inpatient Unit, Kobacker Center UTMC, Toledo, Ohio; and Dr. Tamburrino is Professor, Chair Psychiatry Department UTMC, Toledo, Ohio.

Psychiatry (Edgemont) 2010;7(1):17–24

Funding: The research for this article was funded in part by an unrestricted educational grant from Pfizer, Inc.

Financial disclosure: Dr. A. Rais received an unrestricted educational grant from Pfizer, Inc., to pursue this research. Drs. Williams, T. Rais, Singh, and Tamburrino have no conflicts of interest relevant to the content of this article.

Key Words: geriatric, population, ziprasidone, agitation, inpatient


Objective. This open-label study examined the safety and efficacy of ziprasidone intramuscular with geriatric patients experiencing psychosis or agitation.
Design. During an inpatient stay, consenting subjects who became acutely psychotic or agitated received ziprasidone intramuscular 10mg q 6 to 8 hours, up to a maximum dose of 20mg/24 hours. A within-group repeated measures design was employed to study whether the use of ziprasidone over the 24-hour observation period contributed to decreased agitation or to extrapyramidal side effects. The data were analyzed using an Analysis of Variance with trend analysis.
Setting. The study was conducted on the geriatric psychiatry inpatient unit at the University of Toledo Medical Center, Toledo, Ohio.
Participants. Fourteen patients, six men and eight women with mean age 77±8 years, participated in this study. Each patient had a diagnosis of dementia, co-occurring with one of the following: delirium, major depressive disorder with psychotic features, schizophrenia, bipolar disorder, or schizoaffective disorder.
Measurements. The Brief Psychiatric Rating Scale, Delirium Rating Scale, and the Behavioral Activity Rating Scale were obtained at baseline and at 0.5, 2, and 24 hours after the first dose of ziprasidone intramuscular.
Results. Overall, physiologic measures that would indicate undesirable side effects, including QTc intervals, remained unchanged pre- and post-study. However, there were significant improvements in scores on a variety of measures assessing agitation or psychosis.
Conclusion. This study suggests that ziprasidone intramuscular may be a safe and effective short-term treatment for agitated or psychotic geriatric patients, and, therefore, additional studies should be conducted to confirm these findings.


Agitated geriatric patients sometimes exhibit aggressive/potentially violent behaviors that may require parenteral administration.[1] The use of the newer atypical antipsychotic medications to address these situations has been limited by the unavailability of parenteral formulations.[2,3] Late evidence shows that the intramuscular form of ziprasidone may be considered a possible treatment alternative.[5–8] Besides less risk of extrapyramidal symptom (EPS) development compared to haloperidol,[5,9,12] ziprasidone does not cause the disinhibition, sedation, confusion, or ataxia created by the use of benzodiazepines.[2] An additional advantage of ziprasidone for geriatric patients is its minimal anticholinergic profile.[8,11,13] Ziprasidone also causes less sedation and has fewer postural hypotensive effects than most of the other atypical antipsychotics, which makes it a safer choice in the elderly population.[14–16]

In September 2005, Zimbroff et al[13] published recommendations about the use of ziprasidone intramuscular (IM) in different settings. In their opinion, ziprasidone IM demonstrated clear reduction of patients’ agitation (within 15–30 minutes) as well as improvement in their psychotic symptoms and hostility. These effects were as good or better than when using haloperidol IM and with much less frequency of movement disorders. The most common adverse effects associated with ziprasidone IM when given on a fixed dosing schedule were insomnia, headache, and dizziness. Insomnia and hypotension occurred when ziprasidone was given on a flexible dosing schedule. The changes in QTc associated with ziprasidone were comparable to those seen with haloperidol IM and of no significant clinical concern.

Barak et al17 collected data on 21 patients (age 60–81) who received ziprasidone IM for acute psychotic agitation. Results suggested acceptable safety and efficacy.

Ziprasidone may be an effective treatment option for patients with Parkinson’s disease and psychosis.[18,33,34] Gomez-Esteban et al[18] used ziprasidone in open-label, 12-week trials to treat 12 Parkinsonian patients with psychosis. Two patients withdrew from the trial but the rest of the patients reported a significant improvement in psychiatric symptoms without any significant deterioration of motor symptoms. Similarly, at least two other case reports also support effectiveness of ziprasidone in treatment of Parkinson’s disease and psychosis.[2,3,33,34]

There are very few published studies on the administration of ziprasidone IM to elderly psychiatric patients. Berkowitz[19] described the use of ziprasidone in three frail elderly patients admitted to the hospital for behavioral disturbances due to dementia-related problems. In all three cases, the ziprasidone treatment was beneficial for symptoms of agitation, psychosis, and cognitive impairment. None of the patients had postural hypotension or associated syncope. No significant QTc prolongation was encountered. Drug interactions were not problematic. Somewhat similar results were reported by Cole et al[21] who performed retrospective chart reviews of three patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. (DSM-IV TR) diagnoses of dementia who had been treated with ziprasidone for agitation or psychosis in inpatient psychiatric settings. The authors also reported on a patient with dementia who completed an open trial of oral ziprasidone for six weeks for treatment of agitation, psychosis or dementia. This patient experienced marked behavioral improvements after oral doses of ziprasidone (ranging between 20 and 160mg daily) without any problematic side effects.

Kohen et al[22] performed a naturalistic study of treatment with intramuscular ziprasidone versus conventional agents in agitated elderly patients and concluded that ziprasidone IM was as effective as haloperidol IM with or without concomitant use of lorazepam IM.

When looking at other IM atypical antipsychotics in agitated elderly persons, olanzapine followed ziprasidone to become available in an intramuscular formulation. However, relevant studies on its effectiveness in elderly are lacking. Rappaport et al[23] did a study to evaluate the tolerability of aripiprazole IM for 129 patients with agitation associated with dementia. This study demonstrated 10 to15mg of aripiprazole IM appeared safe and was well tolerated.

In contrast to the above studies demonstrating apparent safety, a public health advisory was issued in 2005 based on 17 short-term, randomized, controlled trials.[24] These trials involved elderly persons with dementia and demonstrated increased incidence of cerebrovascular adverse events, some of which were fatal, following atypical antipsychotic medication or administration. The result was “black box” warnings describing this risk. Atypical antipsychotic labels now advise that these medications are not approved for use in elderly patients with dementia.

Materials and Methods

The purpose of this pilot study was to assess the safety and efficacy of ziprasidone IM for control of acute psychosis and agitation in a geriatric psychiatry inpatient unit. The study was approved by our institutional review board and had an open-label design. Patients age 60 or older admitted to the geriatric psychiatry unit were invited to participate. Informed consent was obtained from either the patient or the patient’s guardian. The first 15 patients who agreed to participate in the study and became agitated or acutely psychotic were included in the trial. Due to the size of the sample, it was not possible to control the distribution of patients over specific diagnostic categories. All of the patients enrolled in this study had a diagnosis of dementia with behavioral problems, resulting in a relatively homogeneous sample. (All other patients who had not agreed to participate in the study received treatment as usual.) Those patients who consented and met criteria to participate received a baseline complete blood count with differential, electrolyte panel including sodium, potassium, magnesium, phosphate, and calcium, liver function tests, urinalysis, renal function tests, and an electrocardiogram.

Inclusion/Exclusion Criteria

DSM-IV TR diagnoses of all subjects in the trial included dementia. Many subjects had additional diagnoses that could include delirium (measured using a delirium scale), major depressive disorder with psychotic features, schizophrenia, bipolar disorder, and schizoaffective disorder, although the diagnosis of dementia with related neuropsychiatric problems was the focus of the study. Study exclusion criteria were history of serious arrhythmias, recent history of myocardial infarction, significant electrolyte imbalance, severe vomiting or diarrhea, or a baseline QTc interval greater than 450 milliseconds.

Primary and Secondary Outcome Measures

The primary outcome measure was an increase in control of agitation and psychosis in the subjects. This was assessed with the Brief Psychiatric Rating Scale (BPRS),[25] Delirium Rating Scale (DRS),[26] and the Behavioral Activity Rating Scale (BARS). BARS is meant to assess the intensity of agitation and has seven levels of activity from 1=difficult to arouse to 7=violent, requires restraint.[15,27] The secondary outcome measure was to assess whether there was a decrease in the extrapyramidal side effects caused by ziprasidone as compared to a classic neuroleptic like haloperidol. This was measured with the Barnes Akathisia Scale (BAS)[28,29] and the Abnormal Involuntary Movement Scale (AIMS).[4]


Once identified as acutely psychotic or agitated, subjects received ziprasidone IM 10mg every 6 to 8 hours, not to exceed a maximum dose of 20mg in 24 hours. The BPRS, DRS, and BARS were done at baseline, and 0.5, 2, and 24 hours after the first dose of ziprasidone. The BAS and AIMS were completed after each injection and at the end of the study to assess for extrapyramidal symptoms. Blood pressure readings were also assessed sitting and lying down after each injection.

Subjects were allowed to receive up to 5mg lorazepam IM per 24 hours for severe agitation. If subjects failed to show any improvement within 24 hours or after the first two doses of ziprasidone, they could receive haloperidol IM or another IM antipsychotic to control agitation or psychosis. They were also allowed oral anticholinergics, and b-blockers for control of akathisia and other extrapyramidal symptoms. Twenty-four hour totals of lorazepam, anticholinergics and b-blockers were compared in patients who received ziprasidone versus those who received haloperidol to control their agitation. EKG was done at baseline and again 24 hours after administration of ziprasidone. QTc intervals were also calculated at 24 hours to compare to those at baseline.

Data analyses. Descriptive analyses–standard sample-based measures of central tendency (mean, median), dispersion (standard deviation, semi-interquartile range), and skewness were calculated for each continuous variable in the study. Categorical variables (e.g., gender, drug type, diagnosis) were placed in tables as appropriate.

Inferential analyses. This study used a within-group repeated measures design. Accordingly, the primary analysis used with the outcome variables (BPRS, DRS, BARS, BAS, and AIMS) was the one way repeated-measures Analyses of Variance (ANOVA) aimed at detecting trends over the time of treatment. The Bonferroni correction for multiple tests was applied. One-way ANOVAs were also performed on QTc intervals and data regarding amount of medication administered.


None of the patients required lorazepam, haloperidol, or other antipsychotic medication to control agitation or psychosis. Data analyses performed included descriptive statistics (mean, minimum, maximum, and SD) for each variable, paired t-tests to compare individual differences between two variables, and one-way repeated measures ANOVA to determine if the means differed across time. Our sample had 14 patients of which 43 percent were men, 77 percent were Caucasian, and the mean age was 77-years-old with a standard deviation of 8.2.

The results of physiological measurements, including heart and respiratory rate, systolic and diastolic blood pressure, measured at baseline, 30 minutes, two hours, and 24 hours, showed no statistically significant differences (Table 1 and Table 2 ).

Repeated measures were done on pulse as well, (Table 1) and no significant statistical difference was found in ANOVA. Therefore, no additional testing was performed.

The BARS scores mean (n=14) measured at baseline was 6.29, and the means of BARS scores measured at 30 minutes, two hours, and 24 hours were 4.43,4.43, and 4.86, respectively. Paired t-tests were done to compare each of the subsequent scores to the baseline mean. All paired t-tests showed statistically significant differences with p<0.001 at 30 minutes, p>0.001 at two hours, and p=0.002 at 24 hours. The repeated measures ANOVA had a p<0.001 and Wilks’ Lambda was 0.103, a statistically significant difference (Figure 1).

The DRS baseline mean was 19.1429 while the means for the measurements at 30 minutes, two hours, and 24 hours were 14.7857, 12.2143, and 15.5714, respectively. Paired t-tests were done to compare the baseline measurements to those at 30 minutes, two hours, and 24 hours. All showed statistically significant differences (Table 3). Paired t-tests were also done to compare the 30-minute mean scores with the score at two hours and to compare between the mean scores at two hours and 24 hours. Both comparisons showed statistically significant differences with t=2.838, p=0.014 for the former test, and t=-3.589, p=0.003 for the latter. Altogether, after a 24-hour time interval, the DRS mean scores remained significantly different and lower, compared with the baseline score. The Wilks’ Lambda=0.137 and ANOVA showed p<0.001 (Figure 2). BPRS mean baseline scores were compared with those at 30 minutes, two hours, and 24 hours (Figure 3). Also, the mean BPRS score at 30 minutes was compared with the score at two hours, and the mean score at two hours was compared with the score at 24 hours. The comparisons were performed using the same statistical tools mentioned previously. All scores showed statistically significant differences (Table 3). The extrapyramidal effects of ziprasidone IM were assessed by measuring the BAS scores in 14 patients at 30 minutes and 24 hours after the medication was administered (Figure 4). The paired t-test showed no statistically significant difference (t=-1.198, p=0.254). To check the reliability of the BARS results, AIMS scores were measured for five patients chosen at random from the group studied. The AIMS scores taken at 30 minutes and 24 hours were compared through the paired t-test and showed no statistically significant difference (Table 4).


This open-label study of ziprasidone IM for the treatment of acute psychosis or agitation found the medication to be effective and well-tolerated in this population. There was a significant improvement in BARS score means from baseline (6.29 indicating extreme activity) to measurements at 30 minutes (4.43, indicating an activity stage between normal level and increased activity that is easily redirectable).[15,27] The activity levels remained at the same stage of improvement at the two hours and 24 hours measurements. These results indicate that ziprasidone IM had a beneficial effect on the patients’ behavioral disturbances. Similarly, there was significant improvement in the level of the delirium over this same time period as measured by the DRS. The authors speculate that the initial BPRS scales may have been elevated due to patients experiencing agitated delirium, and as the delirium responded to ziprasidone, the BPRS scales were reduced.

The psychiatric literature on the use of ziprasidone IM in general is still limited, especially regarding its use in elderly populations.[19,21,22,30] We are not aware of any other published work duplicating our present study. Kohen et al[22] searched the records of patients older than 65 years who received a single 20mg dose of ziprasidone IM for the treatment of acute agitation. The efficacy of this treatment was compared with a matched sample of patients receiving treatment with conventional medications (haloperidol with or without lorazepam). In some of the patients, BARS scores were obtained by having psychiatrists blinded to specific treatment complete the rating scale. Their sample included 15 patients who received ziprasidone IM (9 men and 6 women ranging from 65–87 years old). The decrease in BARS scores compared to the baseline BARS scores was statistically significant, as in our study. No significant effects on blood pressure or heart rate were observed, and there were no cardiac events or pathological EKG changes, although the EKG was performed at 24 hours and could have missed changes due to the peak in ziprasidone blood levels, which can be seen as a limitation.

The small sample size, lack of a control group, and open-label design in the current study clearly limit the generalizability of the results. However, as demonstrated with the BARS, DRS and BPRS, the efficacy of ziprasidone IM for elderly agitated delirious or psychotic patients was statistically significant. This efficacy was enhanced by the lack of significant EPS, cardiovascular events, and serious interactions with other medications. More research with larger, randomly chosen samples and double-blind, placebo-controlled design is necessary in the future to corroborate our findings that ziprasidone IM may be considered a treatment alternative for some agitated or delirious geriatric patients.

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