- Email: [email protected]
Intramuscular Ziprasidone Treatment of Acute Psychotic Agitation in Elderly Patients With Schizophrenia
Intramuscular Ziprasidone Treatment of Acute Psychotic Agitation in Elderly Patients With Schizophrenia Yoram Barak, M.D., M.H.A. Doron Mazeh, M.D. Igor Plopski, M.D. Yehuda Baruch, M.D., M.H.A.
Objective: Intramuscular (IM) ziprasidone treatment has been shown to be effective and well tolerated in reducing the symptoms of acute psychosis in adults. Few data are available as to safety in the elderly. The growing utilization of health services by elderly psychiatric patients warrants an evaluation in this population. Method: Consecutive elderly patients (60 years of and older) admitted to a psychogeriatric ward in a large, university-affiliated tertiary psychiatric center were treated by IM ziprasidone for acute psychotic agitation. Patients received three days of flexible-dose IM ziprasidone. After an initial dose of 10 –20 mg, a subsequent dose of 10 –20 mg could be given after 12 hours if needed (maximum daily dose: 40 mg). Results: All treatment emergent side effects and adverse events along with the investigators’ assessments of severity were systematically recorded as the primary outcome. The Brief Psychiatric Rating Scale (BPRS) and the Behavioral Activity Rating Scale (BARS) were the secondary outcomes. Twenty-one patients, six male and 15 female, mean age 71.4⫾1.3 years (range: 60 – 81 years) were enrolled. All had completed the three days IM ziprasidone treatment. There was one adverse event in a patient with untreated benign prostatic hypertrophy who developed urinary retention. Two side effects of mild severity that resolved spontaneously were ob-
served: blurred vision and sedation. The BPRS decreased by 26.8 points after three days of treatment (p⫽0.001). The BARS score, reflecting agitation, decreased significantly after each injection, reaching maximal decrease of 2.14 points at completion of study (p⫽ 0.001). Conclusion: Intramuscular ziprasidone in this series of elderly patients suggests acceptable safety and efficacy in the management of acute psychotic agitation among elderly patients with schizophrenia. (Am J Geriatr Psychiatry 2006; 14:629– 633) Key Words: Schizophrenia, elderly, agitation, IM ziprasidone
S
econd-generation antipsychotics (SGA) have gained acceptance as first-line treatment for a variety of psychotic disorders and especially for patients with schizophrenia. In emergency settings, it is suggested that “atypical antipsychotics such as risperidone, ziprasidone, and olanzapine with or without benzodiazepines should be considered first in the treatment of acute agitation.”1 There is also a growing body of data as to the management of acute psychosis accompanied by severe agitation with intramuscular (IM) SGA. The availability of rapid-acting IM preparations of olanzapine and ziprasidone has led to their evaluation in agitated adult patients with schizophrenia.2,3 In many instances, the conclusion reached by researchers was that this approach to the pharmacologic treatment of agitated patients is safe and effective and that IM olanzapine and ziprasidone show promise for treating acute agitation in patients with schizophrenia, especially because of their safer adverse effect profile and faster onset of effectiveness compared with haloperidol.4 Recently, Preval et al.5 reported change in the Behavioral Activity Rating Scale (BARS) agitation scores in a naturalistic study in a psychiatric emergency service using 20 mg IM ziprasidone and various doses of conventional antipsychotics. They report that agitation decreased rapidly from baseline
Received January 9, 2006; revised February 8, 2006; accepted February 16, 2006. From the Abarbanel Mental Health Center, Bat-Yam, Israel, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel. Send correspondence and reprint requests to Prof. Yoram Barak, Director, Psychogeriatrics, Abarbanel MHC., 15 KKL Street., Bat-Yam, 59100, Israel. e-mail: [email protected] © 2006 American Association for Geriatric Psychiatry
Am J Geriatr Psychiatry 14:7, July 2006
629
IM Ziprasidone for Schizophrenia with ziprasidone and none of the 19 patients given ziprasidone showed electrocardiography changes or lasting side effects. This report is in line with several publications since 2000 all evaluating the use of IM ziprasidone for agitated psychotic patients. Over 400 patients were assessed in the shorter duration trials demonstrating efficacy and acceptable safety.3,5–7 Ziprasidone is a novel antipsychotic agent with a pharmacologic profile distinct from that of other currently available SGA or classic antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative, and affective symptoms of schizophrenia with a favorable tolerability profile, including a low propensity of inducing extrapyramidal adverse effects. In addition, IM ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.8 The evidence for the use of IM ziprasidone has come solely from adult patients. The growing numbers of elderly patients with schizophrenia warrant special consideration. We have previously shown that long-term treatment with SGA confers benefits to elderly patients with schizophrenia.9 However, management of acute agitation in older patients has not yet been addressed specifically. The need to quickly control severe symptoms must not be achieved at the expense of safety. Unfortunately, the poor tolerability of conventional antipsychotics by the elderly compromises their usefulness. The development of IM formulations of olanzapine and ziprasidone offer new treatment options for patients experiencing acute psychotic episodes.1 Thus, the aim of the present study was to evaluate the safety and efficacy of IM ziprasidone in elderly patients with schizophrenia hospitalized during an agitated psychotic exacerbation of their illness.
METHOD This study was supported with an independent research grant from Pfizer Inc. This three-day, openlabel study was conducted at the Abarbanel Mental Health Center, Bat-Yam, Israel, affiliated with the Sackler School of Medicine, Tel-Aviv University. The center serves the greater Tel Aviv area, which is demographically the “oldest” city in the country. At
630
our center, there are 420 inpatients beds and 60 day patients as well as a large outpatient clinic. The psychogeriatric division is composed of two inpatient wards (68 beds), an outpatient clinic, a memory clinic, and a consultation service to nursing homes in the area. All elderly (60 years or older) patients recently hospitalized with acute psychosis related to schizophrenia or schizoaffective disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were allowed to enter the study. Patients were excluded if their acute psychosis was related to substance abuse or of organic origin. Patients were also excluded if they had any relevant physical disorders or an abnormal electrocardiogram as judged by a specialist in internal medicine. After a complete description of the study, written informed consent was obtained from the patient or authorized proxy. The study was conducted in accordance with the Helsinki, Finland, declaration and was approved by the local Institutional Review Board and national committee of the Ministry of Health. The protocol for patients in this IM ziprasidone study stipulated an initial of 10 mg or 20 mg IM. The first intramuscular treatment was started 1– 6 hours after hospitalization and screening. Additional doses could be administered according to clinical need, provided the total daily parenteral dose did not exceed 40 mg IM. A minimum of 12 hours was required between each 10- or 20-mg IM dose. Evaluations Efficacy. Primary efficacy was measured using the BPRS and the BARS.10 Patients completed the BPRS at baseline and on study completion. In addition, the BARS was scored at baseline, before each IM ziprasidone injection, and three times after each injection: after 30 minutes, two hours, and four hours. The BARS is an observer-rated scale scoring patient’s behavioral activity on a continuum from “1”: difficult or unable to rouse through “4”: quiet and awake and to a maximal score of “7”: violent, requires restraint. The scale’s psychometric properties have been well established.10 Safety and Tolerability. Severity, duration, and possible association of adverse events with the study drug were evaluated throughout the study. All observed or volunteered adverse events were recorded
Am J Geriatr Psychiatry 14:7, July 2006
Barak et al. regardless of whether or not an association with the study drug was suspected. In the present study, we used the MedWatch Food and Drug Administration forms for safety information and adverse event-reporting program. Statistical Analysis Data were analyzed using a paired-samples and independent-samples approach. The two-tailed t-test and nonparametric test were undertaken to test for differences between the evaluations for qualitative parameters. The paired t-test and nonparametric sign rank test were applied for testing differences between baseline assessment and end-of-study assessments for quantitative parameters. Examination of differences between the categorical parameters was based on the Pearson chi-square and Fisher exact tests. All tests applied were two-tailed, and p value of 5% or less was considered statistically significant. The data were analyzed using SAS software.11
RESULTS Twenty-one patients, six male and 15 female, mean age 71.4⫾ 1.3 years (range: 60 – 81 years) were enrolled. All patients were community-dwelling and had been hospitalized because of severe psychotic exacerbation. Eleven were married, seven were single, and three were divorced. There were no discontinuations and all had completed the three days IM ziprasidone treatment protocol. No concurrent psychotropic medications were allowed throughout the study. All patients had been previously hospitalized. The mean number of hospitalizations for the group was 14 (range: 2–38). Patients had been exposed to either haloperidol or chlorpromazine during past admissions. However, the treatment administered just before the present study reflects the changing practice and was as follows: 1) typical antipsychotics: haloperidol one of 21, fluphenazine three of 21, and perphenazine three of 21; and 21) second-generation antipsychotics: quetiapine one of 21, clozapine two of 21, risperidone five of 21, and olanzapine six of 21. The majority of patients (16 of 21) had a comorbid physical disorder at the time of enrollment. The most
Am J Geriatr Psychiatry 14:7, July 2006
frequent diagnosis was hypertension (10 of 16) followed by diabetes mellitus (four of 16) and duodenal ulcer (two of 16). In seven patients, more than a single physical disorder was diagnosed. All patients who had a comorbid physical disorder were treated with appropriate drugs, the most frequent being calcium channel blockers and metformin. Safety There was one adverse event in a male patient who had developed acute urinary retention within five hours of the second IM treatment. This patient had a known history of untreated benign prostatic hypertrophy as diagnosed previously by a urologist and a rectal ultrasound scan. The patient continued with IM ziprasidone treatment after insertion of an indwelling urinary catheter and improved on the secondary outcome measures. Two side effects of mild severity were either observed by the nursing staff or reported by a patient. Blurred vision was reported by a female patient. She was examined by a certified neurologist who did not diagnose an organic disorder. The patient reported that her vision cleared spontaneously after 24 hours. Sedation was noted by the nursing staff in a female patient, and this effect also resolved spontaneously by the second day of treatment.
Efficacy The mean BPRS score decreased by 26.8 points after three days of treatment from a baseline mean score of 76.9 (standard deviation [SD]: 2.4) to a mean score at completion of study of 50.1 (SD: 1.9), (p⫽ 0.001). In 15 of 21 patients (71%), there was a reduction greater than 20% in the total BPRS score. The BARS score, reflecting agitation, decreased significantly after each injection reaching maximal decrease of 2.14 points after the sixth injection at completion of the study (p ⫽0.001). Baseline mean scores on the BARS were 5.8 (standard error: 0.16) reflecting a very high level of agitation. In 18 of 21 patients (86%), there was a reduction of at least two points in the BARS score. Figure 1 provides a graphic representation of change in the BARS scores throughout the study. After each IM treatment, there was a decrease in
631
IM Ziprasidone for Schizophrenia
FIGURE 1.
Behavioral Activity Rating Scale
Notes: 1.1: difference between 4 hours after first injection and baseline (BL) score; 1.2: difference between second injection and score after first injection; 2.1: difference between third injection and score after second injection; 2.2: difference between fourth injection and score after third injection; 3.1: difference between fifth injection and score after fourth injection; 3.2: difference between sixth injection and score after fifth injection; end–BL: difference between 4 hours after sixth injection and BL score.
agitation that was somewhat reversed over time until the next treatment.
DISCUSSION Intramuscular formulations of SGA are the method of choice for managing patients with schizophrenia who require emergency treatment but cannot take oral medication.1,7 In agitated psychotic patients, IM ziprasidone reduces agitation within minutes after administration with improvement sustained for hours, and it is superior to IM haloperidol in improving overall symptom severity. However, data as to the use of IM ziprasidone in acutely agitated elderly psychotic patients is very limited. Greco et al.12 eval-
uated the safety of ziprasidone IM in acute agitation in an elderly population of agitated patients with dementia. These authors focused specifically on cardiac safety, demonstrating no episodes of torsades de pointes and no significant difference in the QTc interval between the baseline and the postziprasidone values. Despite several limitations such as testing effects after a single injection, use on an asneeded basis, and a variety of diagnoses, this is the first analysis of older patients with significant physical comorbidities. Our study enrolled only patients with schizophrenia and schizoaffective disorder, the protocol was rigorous, it was prospective and used a priori defined primary and secondary outcomes. The results of the present study suggest both safety and efficacy of IM ziprasidone in the elderly. There are two limitations that need be acknowledged: this was an open-label study and sample size was modest. However, our findings are in line with reports of similar studies with younger patients.5,7 The successful management of an acute psychotic episode in which patients are highly agitated and distressed is often a critical determinant outcome, especially in elderly patients. To the best of our knowledge, this is the first prospective study specifically designed to evaluate he use of IM ziprasidone among elderly psychotic patients. During this three-day trial, significant improvement in both the BARS and BPRS total scores was observed in elderly patients with schizophrenia treated with IM ziprasidone. It is important to note that ziprasidone was the only psychotropic used during the study period. Ziprasidone demonstrated a favorable safety and tolerability profile. However, because this was an open study with a limited sample size, the findings need to be interpreted cautiously and are suggestive only. We call for larger, double-blind studies to establish our findings. This study was supported with an independent research grant from Pfizer, Inc.
References 1. Yildiz A, Sachs GS, Turgay A: Pharmacological management of agitation in emergency settings. Emerg Med J 2003; 20:339 –346 2. Breier A, Meehan K, Birkett M, et al: A double-blind, placebo-
632
controlled dose–response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry 2002; 59:441–448
Am J Geriatr Psychiatry 14:7, July 2006
Barak et al. 3. Mendelowitz AJ: The utility of intramuscular ziprasidone in the management of acute psychotic agitation. Ann Clin Psychiatry 2004; 16:145–154 4. Miceli JJ, Wilner KD, Swan SK, et al: Pharmacokinetics, safety, and tolerability of intramuscular ziprasidone in healthy volunteers. J Clin Pharmacol 2005; 45:620 –630 5. Preval H, Klotz SG, Southard R, et al: Rapid-acting IM ziprasidone in a psychiatric emergency service: a naturalistic study. Gen Hosp Psychiatry 2005; 27:140 –144 6. Daniel DG, Zimbroff DL, Swift RH, et al: The tolerability of intramuscular ziprasidone and haloperidol treatment and the transition to oral therapy. Int Clin Psychopharmacol 2004; 19:9 –15 7. Brook S: A pilot study of intramuscular ziprasidone in the shortterm treatment of patients with acute exacerbation of schizophrenia. Hum Psychopharmacol 2000; 15:521–524
Am J Geriatr Psychiatry 14:7, July 2006
8. Gunasekara NS, Spencer CM, Keating GM: Spotlight on ziprasidone in schizophrenia and schizoaffective disorder. CNS Drugs 2002; 16:645–652 9. Barak Y, Shamir E, Mirecki I, et al: Switching elderly chronic psychotic patients to olanzapine. Int J Neuropsychopharmacol 2004; 7:165–169 10. Swift RH, Harrigan EP, Cappelleri JC, et al: Validation of the Behavioural Activity Rating Scale (BARS): a novel measure of activity in agitated patients. J Psychiatr Res 2002; 36: 87–95 11. SAS/STAT Users’ Guide, Version 6, 4th Ed, Vols 1, 2.Cary, NC, SAS Institute, 1990 12. Greco KE, Tune LE, Brown FW, et al: A retrospective study of the safety of intramuscular ziprasidone in agitated elderly patients. J Clin Psychiatry 2005; 66:928 –929
633
Objective: Intramuscular (IM) ziprasidone treatment has been shown to be effective and well tolerated in reducing the symptoms of acute psychosis in adults. Few data are available as to safety in the elderly. The growing utilization of health services by elderly psychiatric patients warrants an evaluation in this population. Method: Consecutive elderly patients (60 years of and older) admitted to a psychogeriatric ward in a large, university-affiliated tertiary psychiatric center were treated by IM ziprasidone for acute psychotic agitation. Patients received three days of flexible-dose IM ziprasidone. After an initial dose of 10 –20 mg, a subsequent dose of 10 –20 mg could be given after 12 hours if needed (maximum daily dose: 40 mg). Results: All treatment emergent side effects and adverse events along with the investigators’ assessments of severity were systematically recorded as the primary outcome. The Brief Psychiatric Rating Scale (BPRS) and the Behavioral Activity Rating Scale (BARS) were the secondary outcomes. Twenty-one patients, six male and 15 female, mean age 71.4⫾1.3 years (range: 60 – 81 years) were enrolled. All had completed the three days IM ziprasidone treatment. There was one adverse event in a patient with untreated benign prostatic hypertrophy who developed urinary retention. Two side effects of mild severity that resolved spontaneously were ob-
served: blurred vision and sedation. The BPRS decreased by 26.8 points after three days of treatment (p⫽0.001). The BARS score, reflecting agitation, decreased significantly after each injection, reaching maximal decrease of 2.14 points at completion of study (p⫽ 0.001). Conclusion: Intramuscular ziprasidone in this series of elderly patients suggests acceptable safety and efficacy in the management of acute psychotic agitation among elderly patients with schizophrenia. (Am J Geriatr Psychiatry 2006; 14:629– 633) Key Words: Schizophrenia, elderly, agitation, IM ziprasidone
S
econd-generation antipsychotics (SGA) have gained acceptance as first-line treatment for a variety of psychotic disorders and especially for patients with schizophrenia. In emergency settings, it is suggested that “atypical antipsychotics such as risperidone, ziprasidone, and olanzapine with or without benzodiazepines should be considered first in the treatment of acute agitation.”1 There is also a growing body of data as to the management of acute psychosis accompanied by severe agitation with intramuscular (IM) SGA. The availability of rapid-acting IM preparations of olanzapine and ziprasidone has led to their evaluation in agitated adult patients with schizophrenia.2,3 In many instances, the conclusion reached by researchers was that this approach to the pharmacologic treatment of agitated patients is safe and effective and that IM olanzapine and ziprasidone show promise for treating acute agitation in patients with schizophrenia, especially because of their safer adverse effect profile and faster onset of effectiveness compared with haloperidol.4 Recently, Preval et al.5 reported change in the Behavioral Activity Rating Scale (BARS) agitation scores in a naturalistic study in a psychiatric emergency service using 20 mg IM ziprasidone and various doses of conventional antipsychotics. They report that agitation decreased rapidly from baseline
Received January 9, 2006; revised February 8, 2006; accepted February 16, 2006. From the Abarbanel Mental Health Center, Bat-Yam, Israel, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel. Send correspondence and reprint requests to Prof. Yoram Barak, Director, Psychogeriatrics, Abarbanel MHC., 15 KKL Street., Bat-Yam, 59100, Israel. e-mail: [email protected] © 2006 American Association for Geriatric Psychiatry
Am J Geriatr Psychiatry 14:7, July 2006
629
IM Ziprasidone for Schizophrenia with ziprasidone and none of the 19 patients given ziprasidone showed electrocardiography changes or lasting side effects. This report is in line with several publications since 2000 all evaluating the use of IM ziprasidone for agitated psychotic patients. Over 400 patients were assessed in the shorter duration trials demonstrating efficacy and acceptable safety.3,5–7 Ziprasidone is a novel antipsychotic agent with a pharmacologic profile distinct from that of other currently available SGA or classic antipsychotics. In preclinical studies, ziprasidone was predicted to have efficacy against positive, negative, and affective symptoms of schizophrenia with a favorable tolerability profile, including a low propensity of inducing extrapyramidal adverse effects. In addition, IM ziprasidone shows efficacy and good tolerability in the treatment of acute agitation associated with psychotic disorders.8 The evidence for the use of IM ziprasidone has come solely from adult patients. The growing numbers of elderly patients with schizophrenia warrant special consideration. We have previously shown that long-term treatment with SGA confers benefits to elderly patients with schizophrenia.9 However, management of acute agitation in older patients has not yet been addressed specifically. The need to quickly control severe symptoms must not be achieved at the expense of safety. Unfortunately, the poor tolerability of conventional antipsychotics by the elderly compromises their usefulness. The development of IM formulations of olanzapine and ziprasidone offer new treatment options for patients experiencing acute psychotic episodes.1 Thus, the aim of the present study was to evaluate the safety and efficacy of IM ziprasidone in elderly patients with schizophrenia hospitalized during an agitated psychotic exacerbation of their illness.
METHOD This study was supported with an independent research grant from Pfizer Inc. This three-day, openlabel study was conducted at the Abarbanel Mental Health Center, Bat-Yam, Israel, affiliated with the Sackler School of Medicine, Tel-Aviv University. The center serves the greater Tel Aviv area, which is demographically the “oldest” city in the country. At
630
our center, there are 420 inpatients beds and 60 day patients as well as a large outpatient clinic. The psychogeriatric division is composed of two inpatient wards (68 beds), an outpatient clinic, a memory clinic, and a consultation service to nursing homes in the area. All elderly (60 years or older) patients recently hospitalized with acute psychosis related to schizophrenia or schizoaffective disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition were allowed to enter the study. Patients were excluded if their acute psychosis was related to substance abuse or of organic origin. Patients were also excluded if they had any relevant physical disorders or an abnormal electrocardiogram as judged by a specialist in internal medicine. After a complete description of the study, written informed consent was obtained from the patient or authorized proxy. The study was conducted in accordance with the Helsinki, Finland, declaration and was approved by the local Institutional Review Board and national committee of the Ministry of Health. The protocol for patients in this IM ziprasidone study stipulated an initial of 10 mg or 20 mg IM. The first intramuscular treatment was started 1– 6 hours after hospitalization and screening. Additional doses could be administered according to clinical need, provided the total daily parenteral dose did not exceed 40 mg IM. A minimum of 12 hours was required between each 10- or 20-mg IM dose. Evaluations Efficacy. Primary efficacy was measured using the BPRS and the BARS.10 Patients completed the BPRS at baseline and on study completion. In addition, the BARS was scored at baseline, before each IM ziprasidone injection, and three times after each injection: after 30 minutes, two hours, and four hours. The BARS is an observer-rated scale scoring patient’s behavioral activity on a continuum from “1”: difficult or unable to rouse through “4”: quiet and awake and to a maximal score of “7”: violent, requires restraint. The scale’s psychometric properties have been well established.10 Safety and Tolerability. Severity, duration, and possible association of adverse events with the study drug were evaluated throughout the study. All observed or volunteered adverse events were recorded
Am J Geriatr Psychiatry 14:7, July 2006
Barak et al. regardless of whether or not an association with the study drug was suspected. In the present study, we used the MedWatch Food and Drug Administration forms for safety information and adverse event-reporting program. Statistical Analysis Data were analyzed using a paired-samples and independent-samples approach. The two-tailed t-test and nonparametric test were undertaken to test for differences between the evaluations for qualitative parameters. The paired t-test and nonparametric sign rank test were applied for testing differences between baseline assessment and end-of-study assessments for quantitative parameters. Examination of differences between the categorical parameters was based on the Pearson chi-square and Fisher exact tests. All tests applied were two-tailed, and p value of 5% or less was considered statistically significant. The data were analyzed using SAS software.11
RESULTS Twenty-one patients, six male and 15 female, mean age 71.4⫾ 1.3 years (range: 60 – 81 years) were enrolled. All patients were community-dwelling and had been hospitalized because of severe psychotic exacerbation. Eleven were married, seven were single, and three were divorced. There were no discontinuations and all had completed the three days IM ziprasidone treatment protocol. No concurrent psychotropic medications were allowed throughout the study. All patients had been previously hospitalized. The mean number of hospitalizations for the group was 14 (range: 2–38). Patients had been exposed to either haloperidol or chlorpromazine during past admissions. However, the treatment administered just before the present study reflects the changing practice and was as follows: 1) typical antipsychotics: haloperidol one of 21, fluphenazine three of 21, and perphenazine three of 21; and 21) second-generation antipsychotics: quetiapine one of 21, clozapine two of 21, risperidone five of 21, and olanzapine six of 21. The majority of patients (16 of 21) had a comorbid physical disorder at the time of enrollment. The most
Am J Geriatr Psychiatry 14:7, July 2006
frequent diagnosis was hypertension (10 of 16) followed by diabetes mellitus (four of 16) and duodenal ulcer (two of 16). In seven patients, more than a single physical disorder was diagnosed. All patients who had a comorbid physical disorder were treated with appropriate drugs, the most frequent being calcium channel blockers and metformin. Safety There was one adverse event in a male patient who had developed acute urinary retention within five hours of the second IM treatment. This patient had a known history of untreated benign prostatic hypertrophy as diagnosed previously by a urologist and a rectal ultrasound scan. The patient continued with IM ziprasidone treatment after insertion of an indwelling urinary catheter and improved on the secondary outcome measures. Two side effects of mild severity were either observed by the nursing staff or reported by a patient. Blurred vision was reported by a female patient. She was examined by a certified neurologist who did not diagnose an organic disorder. The patient reported that her vision cleared spontaneously after 24 hours. Sedation was noted by the nursing staff in a female patient, and this effect also resolved spontaneously by the second day of treatment.
Efficacy The mean BPRS score decreased by 26.8 points after three days of treatment from a baseline mean score of 76.9 (standard deviation [SD]: 2.4) to a mean score at completion of study of 50.1 (SD: 1.9), (p⫽ 0.001). In 15 of 21 patients (71%), there was a reduction greater than 20% in the total BPRS score. The BARS score, reflecting agitation, decreased significantly after each injection reaching maximal decrease of 2.14 points after the sixth injection at completion of the study (p ⫽0.001). Baseline mean scores on the BARS were 5.8 (standard error: 0.16) reflecting a very high level of agitation. In 18 of 21 patients (86%), there was a reduction of at least two points in the BARS score. Figure 1 provides a graphic representation of change in the BARS scores throughout the study. After each IM treatment, there was a decrease in
631
IM Ziprasidone for Schizophrenia
FIGURE 1.
Behavioral Activity Rating Scale
Notes: 1.1: difference between 4 hours after first injection and baseline (BL) score; 1.2: difference between second injection and score after first injection; 2.1: difference between third injection and score after second injection; 2.2: difference between fourth injection and score after third injection; 3.1: difference between fifth injection and score after fourth injection; 3.2: difference between sixth injection and score after fifth injection; end–BL: difference between 4 hours after sixth injection and BL score.
agitation that was somewhat reversed over time until the next treatment.
DISCUSSION Intramuscular formulations of SGA are the method of choice for managing patients with schizophrenia who require emergency treatment but cannot take oral medication.1,7 In agitated psychotic patients, IM ziprasidone reduces agitation within minutes after administration with improvement sustained for hours, and it is superior to IM haloperidol in improving overall symptom severity. However, data as to the use of IM ziprasidone in acutely agitated elderly psychotic patients is very limited. Greco et al.12 eval-
uated the safety of ziprasidone IM in acute agitation in an elderly population of agitated patients with dementia. These authors focused specifically on cardiac safety, demonstrating no episodes of torsades de pointes and no significant difference in the QTc interval between the baseline and the postziprasidone values. Despite several limitations such as testing effects after a single injection, use on an asneeded basis, and a variety of diagnoses, this is the first analysis of older patients with significant physical comorbidities. Our study enrolled only patients with schizophrenia and schizoaffective disorder, the protocol was rigorous, it was prospective and used a priori defined primary and secondary outcomes. The results of the present study suggest both safety and efficacy of IM ziprasidone in the elderly. There are two limitations that need be acknowledged: this was an open-label study and sample size was modest. However, our findings are in line with reports of similar studies with younger patients.5,7 The successful management of an acute psychotic episode in which patients are highly agitated and distressed is often a critical determinant outcome, especially in elderly patients. To the best of our knowledge, this is the first prospective study specifically designed to evaluate he use of IM ziprasidone among elderly psychotic patients. During this three-day trial, significant improvement in both the BARS and BPRS total scores was observed in elderly patients with schizophrenia treated with IM ziprasidone. It is important to note that ziprasidone was the only psychotropic used during the study period. Ziprasidone demonstrated a favorable safety and tolerability profile. However, because this was an open study with a limited sample size, the findings need to be interpreted cautiously and are suggestive only. We call for larger, double-blind studies to establish our findings. This study was supported with an independent research grant from Pfizer, Inc.
References 1. Yildiz A, Sachs GS, Turgay A: Pharmacological management of agitation in emergency settings. Emerg Med J 2003; 20:339 –346 2. Breier A, Meehan K, Birkett M, et al: A double-blind, placebo-
632
controlled dose–response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry 2002; 59:441–448
Am J Geriatr Psychiatry 14:7, July 2006
Barak et al. 3. Mendelowitz AJ: The utility of intramuscular ziprasidone in the management of acute psychotic agitation. Ann Clin Psychiatry 2004; 16:145–154 4. Miceli JJ, Wilner KD, Swan SK, et al: Pharmacokinetics, safety, and tolerability of intramuscular ziprasidone in healthy volunteers. J Clin Pharmacol 2005; 45:620 –630 5. Preval H, Klotz SG, Southard R, et al: Rapid-acting IM ziprasidone in a psychiatric emergency service: a naturalistic study. Gen Hosp Psychiatry 2005; 27:140 –144 6. Daniel DG, Zimbroff DL, Swift RH, et al: The tolerability of intramuscular ziprasidone and haloperidol treatment and the transition to oral therapy. Int Clin Psychopharmacol 2004; 19:9 –15 7. Brook S: A pilot study of intramuscular ziprasidone in the shortterm treatment of patients with acute exacerbation of schizophrenia. Hum Psychopharmacol 2000; 15:521–524
Am J Geriatr Psychiatry 14:7, July 2006
8. Gunasekara NS, Spencer CM, Keating GM: Spotlight on ziprasidone in schizophrenia and schizoaffective disorder. CNS Drugs 2002; 16:645–652 9. Barak Y, Shamir E, Mirecki I, et al: Switching elderly chronic psychotic patients to olanzapine. Int J Neuropsychopharmacol 2004; 7:165–169 10. Swift RH, Harrigan EP, Cappelleri JC, et al: Validation of the Behavioural Activity Rating Scale (BARS): a novel measure of activity in agitated patients. J Psychiatr Res 2002; 36: 87–95 11. SAS/STAT Users’ Guide, Version 6, 4th Ed, Vols 1, 2.Cary, NC, SAS Institute, 1990 12. Greco KE, Tune LE, Brown FW, et al: A retrospective study of the safety of intramuscular ziprasidone in agitated elderly patients. J Clin Psychiatry 2005; 66:928 –929
633