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 RESEARCH ARTICLE

Determining the efficacy and tolerance of quetiapine extended release for the management of psychosis and accompanying acute behavioral disturbance in adult acute psychiatry

Stuart J. Lee, BA, DPsych

Monash Alfred Psychiatry Research Centre, Alfred Health and Monash University, Melbourne, Victoria, Australia

Fiona Foley, BSc, BHSc

Monash Alfred Psychiatry Research Centre, Alfred Health and Monash University, Melbourne, Victoria, Australia

Erica Hannagan, BSc, RN

Monash Alfred Psychiatry Research Centre, Alfred Health and Monash University, Melbourne, Victoria, Australia

Jayashri Kulkarni, MBBS, MPM, FRANZCP, PhD

Monash Alfred Psychiatry Research Centre, Alfred Health and Monash University, Melbourne, Victoria, Australia

Peter Bosanac, MBBS, MMed (Psychiatry), MD, FRANZCP

Department of Psychiatry, St. Vincent’s Health and The University of Melbourne, Fitzroy, South Australia, Australia

David J. Castle, MBBS, MSc, MD, FRCP, FRANZCP

Department of Psychiatry, St. Vincent’s Health and The University of Melbourne, Fitzroy, South Australia, Australia

Yitzchak Hollander, BSc, MD, FRCP(C), FRANZCP

Department of Psychiatry, Alfred Health and Monash University, Melbourne, Victoria, Australia

BACKGROUND: This study was conducted to explore the efficacy and tolerability of quetiapine extended release (XR) to treat psychosis and accompanying acute behavioral disturbance in hospitalized psychiatric patients.

METHODS: Patients with psychosis who displayed aggression were administered quetiapine XR (day 1 mean dose: 293.3 mg). Symptoms and side effects were assessed prospectively over an 8-day period. Symptoms were measured by the Overt Aggression Scale and Brief Psychiatric Rating Scale (BPRS), and side effects were measured using the Simpson-Angus Scale and Barnes Akathisia Rating Scale.

RESULTS: Fifteen of 16 consenting patients completed the study. Aggression was significantly reduced by day 3. Psychopathology also was significantly reduced, with the greatest improvement in BPRS Thinking Disturbance subscale scores. No significant increase in movement side effects was seen by day 8. Seven participants were administered a concomitant sedating antipsychotic on an as-needed basis, particularly in the first 4 days of treatment; these participants displayed much greater aggression—but not psychopathology—at day 1, and it took longer for their aggression and psychopathology to improve compared with patients treated with quetiapine XR as the sole antipsychotic.

CONCLUSIONs: Further research is needed before definitive recommendations can be made. However, current findings provide tentative support for quetiapine XR as a safe and effective medication for treating concurrent psychosis and behavioral disturbance, particularly in less severely aggressive patients.

KEYWORDS: acute inpatient psychiatry, quetiapine extended release, aggression, psychosis, prospective observational study

ANNALS OF CLINICAL PSYCHIATRY 2012;24(4):271-278

  INTRODUCTION

Acute behavioral disturbance (ABD) is a common psychiatric emergency, occurring in 10% to 25% of acute psychiatric admissions.1 Aggression may compound the experience of ABDs in psychotic patients in acute psychiatric settings. Evidence now shows that some people who suffer psychotic illnesses have a propensity for engaging in aggressive behavior toward others, leading to further negative consequences.2 This, in turn, may increase the risk of injury to patients and others, including clinicians.3 The experience of confusion or thought disorder also can increase the likelihood of ABDs or aggression.4 This was demonstrated in a recent study of 152 psychiatric inpatients, which found that scores on the Thinking Disturbance subscale of the Brief Psychiatric Rating Scale (BPRS) were significantly elevated in physically violent patients compared with non-violent patients, with no difference in the Paranoid Disturbance or Withdrawal/Retardation subscales.5

Antipsychotic medications frequently are used in managing acute agitation, particularly when there is an imminent and significant risk to self and/or others and when concurrent nonpharmacological interventions such as ventilation, redirection, and time out6,7 have not been effective. Current practice in managing aggression in acute psychiatry often involves administering atypical antipsychotics, often with benzodiazepines as adjuncts.8 The antipsychotic may then be continued as a primary treatment for the underlying psychotic disorder. Atypical antipsychotics are preferable to typical antipsychotics in managing acute agitation, in particular because of their overall better tolerability.9 There also is an emergent evidence base for oral atypical antipsychotics, including quetiapine, in ABDs of mild-to-moderate severity,10 because of their capacity to decrease irritability, impulsivity, and aggressiveness.

Quetiapine immediate release (IR) has been found to be effective in treating and managing aggression in psychosis,11-13 dementia,14,15 and forensic settings.16 The most common adverse effects of quetiapine IR are somnolence, postural hypotension, and dizziness. Quetiapine IR appears to be no more likely than placebo to cause extrapyramidal symptoms, but most studies conducted have been short term.17 Prolongation of the QT interval is no more likely with quetiapine IR than with other dopamine receptor antagonists.18 Studies have shown antipsychotic efficacy in the dose range of 300 mg/d to 800 mg/d.19-21 A recent study in an acute-care psychiatric hospital also found that the most common dose of quetiapine used as needed (PRN) was 50 mg for treating agitation or insomnia.22

Two post-hoc analyses of recent clinical trials of quetiapine for acute psychotic illness found that the effectiveness of quetiapine in reducing agitation is independent of its effects on sedation12 or positive psychotic symptoms.23 This suggests a possible direct effect of quetiapine on calming agitated or hostile behavior. The high affinity of quetiapine for serotonin receptors may offer a potential mechanism for this direct calming effect. It has been proposed that impairments in serotonin functioning may underpin impairments in impulse control and emotional regulation, which can increase the risk of violent behavior.24 Clozapine, which has similar neurotransmitter actions to quetiapine, was shown in a 12-week, randomized, controlled trial to be significantly better than both olanzapine and haloperidol in reducing physical aggression in psychotic inpatients; there was no difference in improvement of positive or negative psychotic symptoms.25 In a similar way, quetiapine may assist in improving patients’ capacity to self-regulate or inhibit agitated behavior, thus reducing the likelihood of aggressive behavior.

The utility of quetiapine’s IR formulation to manage aggression in acute psychiatry has been limited because of the time required to achieve an optimal therapeutic dose (up to 5 days). This delays resolution of aggression or agitation, potentially leaving the patient and others vulnerable to aggressive incidents. This has led to several trials of a rapid initiation dosing regimen26-28 that has proven to result in equivalent tolerance but more rapid efficacy.

Quetiapine extended release (XR) may resolve the clinical challenges associated with delayed time to optimal therapeutic dose. It can be initiated at 300 mg/d and taken once daily instead of twice daily dosing recommended for quetiapine IR. A recent trial comparing quetiapine XR with quetiapine IR and placebo found that both IR and XR formulations produced significantly greater reductions in symptoms of schizophrenia compared with placebo, and an adverse-event profile that was equivalent to the placebo group.29 This provided an initial demonstration of the clinical efficacy and safety of quetiapine XR; efficacy in treating symptoms of schizophrenia,29,30 bipolar depression,31 and major depressive disorder32 also has been demonstrated. The XR formulation allows for achievement of a therapeutic dose more quickly and conveniently (once daily). An effective medication to decrease symptoms of impulsivity, hostility, aggressiveness, and irritability in people with psychotic disorders could be an important asset, particularly if the medication has a favorable side-effect profile.

To our knowledge, however, there are no studies examining the efficacy of quetiapine XR in treating ABD associated with psychosis. This gap prompted the current study, which was designed to investigate the efficacy and tolerability of quetiapine XR for the management of psychotic aggression or agitation in adult acute psychiatry. It was hypothesized that quetiapine XR would produce significant reductions in both aggressive behavior and psychopathology that would be seen within 8 days of commencement of the study medication.

  METHODS

Study design and participants

The study (registered with clinicaltrials.gov; identifier NCT00986167) was an open-label trial including male and female patients age 18 to 65 admitted to the adult acute psychiatry inpatient wards of St. Vincent’s Hospital or Alfred Hospital in Melbourne, Victoria, Australia. Additional inclusion criteria were: current psychotic episode (eg, schizophrenia, mania with psychotic features, or drug-induced psychosis); aggressive behavior (as determined by a score of ≥1 on the Overt Aggression Scale [OAS]); appropriateness for treatment with quetiapine XR as determined by the treating psychiatrist; and ability to provide informed consent. Participants were excluded if they were pregnant; were displaying imminent suicidal behavior; had received a depot antipsychotic injection or an antipsychotic other than quetiapine XR within 1 dosing interval prior to recruitment; were refusing oral medication; had used a cytochrome P450 inducer or inhibitor in the 14 days preceding enrollment; were experiencing an unstable medical condition, particularly if it was likely to affect the actions of the study drug; or had an absolute neutrophil count of ≤1,500/μL.

Once enrolled in the study, expectations were for participants to be commenced on a daily dose of 200 to 300 mg of quetiapine XR, increasing to a maximum of 600 mg on day 2, and a minimum dose of 400 mg by day 4. The treating psychiatrist was responsible for determining the treatment regimen. Concomitant use of a benzodiazepine, benztropine, or another sedating antipsychotic on a PRN basis was permitted.

Evaluations

The primary outcomes consisted of measuring change from day 1 to day 8 in OAS scores33 for the measurement of aggression, and BPRS-18 scores34 as a measure of psychopathology. In order to demonstrate potential change in specific symptom clusters, the following BPRS subscales also were calculated: Paranoid Disturbance; Thinking Disturbance; Withdrawal/Retardation; and Anxiety/Depression. Secondary outcomes consisted of measuring the change from day 1 to day 8 in Simpson-Angus Scale (SAS) scores35 for movement side effects and the Barnes Akathisia Scale (BAS)36 to assess akathisia. Participants also were asked at each visit to indicate whether they experienced any additional adverse events.

Procedure

Both the Alfred Hospital’s and St. Vincent’s Hospital’s Human Research and Ethics Committees approved this study. The clinical team discussed potentially eligible patients at the daily clinical business meeting. Following a review of the patient’s psychiatric and medication history, mental state, and blood screen, a decision was made to commence the patient on quetiapine XR. The research nurse would then speak with patients to obtain informed consent. The research nurse was responsible for completing the OAS on a daily basis through both clinical interview and a review of the patient’s medical record. The research nurse again completed the BPRS, BAS, and SAS at days 1, 4, and 8.

Analysis

Analysis was performed with the intent-to-treat population containing all participants with a baseline OAS assessment and ≥1 valid post-baseline OAS assessment. Analysis for each primary and secondary outcome measure involved repeated analysis of variance (ANOVA) measures with time (baseline and follow-up time points) as a repeated measures factor. The frequency of patients reporting adverse events during the trial also was calculated.

  RESULTS

Recruitment took place between January 2010 and December 2010. Sixteen patients were enrolled from the 2 centers. One patient withdrew as a result of moderate-severe sedation that resolved after ceasing the study medication; this patient was excluded from subsequent analyses. A comparison of outcomes for participants of the 2 sites was conducted. As there was no significant effect of site on the primary outcomes, the remaining analyses were conducted with participants from both sites as a single data set. Characterization of the remaining 15 study participants is provided in TABLE 1. This revealed an equal number of males and females, a predominance of a psychotic illness as the primary diagnosis (with symptoms having been present for a number of years in most cases), and that few patients currently were studying or working.


TABLE 1

Demographics and clinical characteristics of participants

Demographic or clinic variable n (%) unless specified
Total participants N = 16
Sex
  Male 8 (50%)
  Female 8 (50%)
Age (years), mean (SD) 35.3 (10.8)
Current employment
  Unemployed or disability support pension 12 (75%)
  Student 2 (12.5%)
  Employed 2 (12.5%)
Living situation
  Independent 9 (56%)
  Supported accommodation or family 6 (38%)
  Homeless 1 (6%)
  Years since illness onset,a mean (SD) 7.9 (6.4)
  Admission length of stay (days), mean (SD) 24.7 (11.7)
Primary diagnosis
  Any psychotic illness 11 (69%)
  Bipolar or manic disorder 5 (31%)
aAge of onset not known for 1 participant.
SD: standard deviation.
Medication use

On average, the 15 participants who completed the study were commenced on quetiapine XR 1.1 days (standard deviation [SD] = 1.2) after admission. The mean (SD) quetiapine XR dose at day 1 was 293.3 mg (110.0) and 673.3 mg (240.4) at day 8. FIGURE 1 displays the frequency of PRN concomitant benzodiazepine or sedating antipsychotic use. PRN use of another sedating antipsychotic, in particular quetiapine IR, was most evident in the first 4 days of participation.

FIGURE 1: Frequency of participants (n = 15) with a concomitant benzodiazepine or use of another sedating antipsychotic PRN
IR: immediate release; PRN: as needed.

Aggression

For the 15 participants who completed the study, the mean OAS total score across each of the study days is displayed in FIGURE 2. Repeated measures t tests comparing the change from day 1 with each follow-up day, applying the Bonferroni correction (adjusted a = .007) found that by day 3 there was a significant reduction in aggressive behavior, which was sustained across the remaining study days. By day 8, the 13 participants (87%) exhibited no aggressive behavior.

Psychopathology

Mean BPRS scores at days 1, 4, and 8 are shown in TABLE 2. Analysis of change over time was conducted using a 1-way repeated ANOVA measure with a = .01 as the significance threshold to adjust for multiple comparisons. The assumption of sphericity was violated for the BPRS Paranoid Disturbance subscale, so the Huynh-Feldt correction was applied to the degrees of freedom. Analysis revealed that significant reductions in BPRS total score were seen for the sample, with 11 participants (73%) having achieved ≥20% reduction in total BPRS by day 8. However, after controlling for multiple comparisons, the only BPRS subscale that revealed a significant change over time was the Thinking Disturbance subscale.

Outcomes for participants with or without another antipsychotic PRN

From the group results displayed in TABLE 2 and FIGURE 2, it is unclear whether quetiapine XR or the concomitant sedating antipsychotics given PRN were responsible for the improvements observed in psychopathology or aggressive behavior. As a result, a comparison of the rate of change in the OAS (FIGURE 3) and BPRS total scores (FIGURE 4) is provided for participants administered (n = 7) or not administered (n = 8) another sedating antipsychotic PRN.

Owing to the limited sample size, a formal statistical analysis was not conducted. Instead, group means at key study timepoints are displayed, revealing that participants given another antipsychotic PRN were, on average, 6.7 points higher on the OAS on day 1, with reductions in aggression seen for both groups. In contrast, participants given another sedating antipsychotic as PRN were only 2.8 points higher on the BPRS on day 1, and beyond day 4 showed a reduced rate of improvement in psychopathology compared with participants who were not given another antipsychotic as PRN.


TABLE 2

BPRS total and subscale scores for participants who completed all study visits (n = 15)a

  Day 1 Day 4 Day 8 P value
BPRS total score 50.5 (10.2) 41.5 (10.8) 33.9 (12.3) <.001
BPRS PD 8.9 (4.7) 7.1 (3.6) 5.2 (3.5) .017
BPRS TD 11.2 (3.6) 8.1 (3.4) 6.0 (3.7) <.001
BPRS WR 5.5 (2.4) 5.6 (3.2) 3.9 (2.6) .093
BPRS AD 7.4 (2.5) 6.0 (3.1) 6.1 (3.0) .053
aAll values are expressed as mean (SD).
AD: Anxiety Depression subscale; BPRS: Brief Psychiatric Rating Scale; PD: Paranoid Disturbance subscale; SD: standard deviation; TD: Thinking Disturbance subscale; WR: Withdrawal/Retardation subscale.

FIGURE 2: Mean OAS total scores at each day of the 8-day studya
aError bars indicate 1 standard error.
bBonferroni corrected (P < .007) significant change from day 1 to each study day.
OAS: Overt Aggression Scale.

FIGURE 3: Mean OAS score for participants given or not given another antipsychotic PRNa
aError bars indicate 1 standard error.
OAS: Overt Aggression Scale; PRN: as needed.

FIGURE 4: Mean BPRS total score for participants given or not given another antipsychotic PRNa
aError bars indicate 1 standard error.
BPRS: Brief Psychiatric Rating Scale; PRN: as needed.

Adverse events

During the 8-day study period, 2 participants (12.5%) reported sedation, 1 reported slurred speech, and 2 (12.5%) reported constipation. For participants completing all study visits (n = 15), the mean (SD) score on the SAS at day 1 was 0.20 (0.56), with no significant change over time revealed by repeated-measures ANOVA (F[2,28] = 0.98; P = .39). For the BAS, the day 1 mean (SD) score was 0.20 (0.78), and repeated-measures ANOVA found no significant change over time (F[2,28] = 1.68; P = .20).

  DISCUSSION

We conducted the current study to address the lack of previous research on the use of quetiapine XR for treating aggression in psychiatric inpatients with psychotic symptoms. In support of the primary hypotheses, the findings revealed that a significant reduction in aggression was achieved by day 3 and sustained for the remainder of the study period. By day 8, 13 participants displayed no aggressive behavior, with the remaining 2 participants exhibiting only minor aggressive behavior. This reduction in aggression also was accompanied by a significant reduction in psychopathology. However, analysis of the BPRS subscales revealed that while improvement in all BPRS subscales was seen over time, after controlling for multiple comparisons, only the improvement in BPRS Thinking Disturbance subscale remained significant.

The timecourse for changes in psychotic symptoms and aggression also were of interest. Aggression was reduced more quickly than psychotic symptoms, suggesting that it was not simply the antipsychotic effects of quetiapine that assisted in resolving the aggressive behavior. Instead, this provided some evidence for the direct antiaggressive effects of quetiapine which, as has been suggested by previous research linking serotonin and aggression,24,25 may stem from quetiapine’s serotonergic actions. Further exploring the potential for medications such as quetiapine to promote impulse inhibition and emotional regulation may enhance the capacity for managing aggression in patients with psychosis.

Consideration also should be given to the dose needed to achieve antiaggressive effects. A recent study exploring the use of quetiapine IR on a PRN basis for agitation or insomnia at an acute care psychiatric hospital, found that the mean dose used was 50 mg/d.22 Adjunctive use of a low dose of the atypical antipsychotic aripiprazole in depressed patients who were inadequate responders to antidepressant treatment demonstrated marginal efficacy in improving psychopathology. Further investigation into whether lower doses of quetiapine can achieve antiaggressive effects therefore is warranted.

Of clinical interest, our findings also revealed that a group of participants displaying more severe aggression at day 1 were more likely to be administered another sedating antipsychotic PRN, particularly within the first 4 days of quetiapine XR commencement. This practice was consistent with acute sedation guidelines governing clinical practice at both sites.37 In general, aggression took longer to resolve in these patients, and there was a reduction in the rate of improvement in psychopathology between days 4 and 8. In contrast, participants exhibiting less severe aggression were able to manage effectively on quetiapine XR alone or with a concomitant benzodiazepine, with reductions in psychopathology continuing at a similar rate throughout the 8-day study.

Quetiapine XR generally was well tolerated. Two cases of self-reported sedation—1 was sufficient to prompt withdrawal from the study—were observed, along with 2 cases of self-reported constipation during the 8-day study. Somnolence, in particular, has been identified in previous studies involving quetiapine IR11,38 and XR.29 Hence, monitoring for these side effects is warranted. There also were low levels of observed akathisia or movement side effects that did not increase significantly following enrollment in the study.

The study findings offer some support for the efficacy and tolerability of quetiapine XR in treating aggressive behavior, particularly in patients exhibiting mild or moderate aggression, adding credence to previous research that has demonstrated the effectiveness of quetiapine IR in treating psychotic aggression.11,12,39 Regarding the amelioration of psychopathology, the strongest treatment effect was for thought disorder; this is the symptom subtype that most strongly distinguishes patients who are physically aggressive from those who are not, according to several studies.4,5 Quetiapine XR therefore may assist in the treatment of both ABD and underlying psychotic symptoms, in particular thought disorder, which may reduce the risk for aggressive behavior. However, it should be noted that in patients displaying more severe aggressive behavior, a second sedating antipsychotic typically was administered PRN, particularly in the first 4 days, to enhance efficacy; this was most commonly done by adding quetiapine IR, highlighting the potential for clinical combination of the XR and IR formulations of quetiapine.

The major limitation for the current study was that the final sample size was lower than initially anticipated, limiting the robustness of study findings. We initially planned to recruit 72 participants, which was expected to overcome the limitation experienced by Ganesan et al,11 who found only a trend for a reduction in aggression with quetiapine IR at day 5. This was explained in part by limited power, with only 17 participants having completed the trial. Difficulties with recruitment for the current study were in part a reflection of the stringent inclusion and exclusion criteria; for example, review of baseline blood results may have precluded enrollment of some participants who may have otherwise consented to participation. The recruitment also was slower than expected, which is likely a reflection of the challenges associated with conducting a clinical study in a population of patients experiencing psychotic symptoms and aggressive behavior.

Balancing this limitation, however, the sample size still was sufficient to demonstrate a statistically significant reduction in both aggression and psychopathology by day 8, highlighting a potentially clinically meaningful effect. A second limitation was the lack of a comparison group that would have provided a context for determining the efficacy of quetiapine XR. As a result, it is unclear the extent to which the aggressive behaviors and psychotic symptoms would have resolved independently of active treatment.

Future research should consist of a comparator trial in which the efficacy of quetiapine XR is compared against existing evidence-based treatments for psychotic aggression (eg, olanzapine). A final limitation related to the relative paucity of side effects reported by participants. This may have been caused by collecting spontaneous reports of side effects rather than utilizing a systematic side-effect screen. Future research would benefit from the use of a standardized screen assessing for a broader array of potential medication-induced side effects alongside psychopathology and aggression measures.

  CONCLUSIONS

Although the sample size was smaller than initially planned, we were able to demonstrate significant reductions in aggression within 3 days of commencing treatment with quetiapine XR. Accompanied by improvements in thought disorder in particular, the concurrent treatment of aggressive behavior and acute psychotic symptoms may provide some support for the role of quetiapine XR in the treatment of aggression in patients experiencing acute psychotic symptoms. However, the use of concomitant sedating antipsychotics, particularly in the first 4 days for participants displaying more severe aggression, may suggest that monotherapy treatment with quetiapine XR is most appropriate for patients exhibiting mild or moderate aggression. Further research in a larger patient sample that also compares treatment outcomes for quetiapine XR with other best-practice treatment approaches is needed before any concrete recommendations can be made about the role of quetiapine XR as a treatment for ABD in psychotic patients.

DISCLOSURES: Dr. Kulkarni receives grant or research support from AstraZeneca, the Australian Research Council, Brain Resource Centre, Department of Health (Victoria, Australia), Department of Justice (Victoria, Australia), Eli Lilly and Company, Hospira, Janssen-Cilag, National Health and Medical Research Council (Australia), and the Stanley Medical Research Institute; is a consultant to Janssen-Cilag and Lundbeck; and is a speaker for Eli Lilly and Company, Janssen-Cilag, and Lundbeck. Dr. Bosanac receives grant or research support from AstraZeneca. Dr. Castle receives grant or research support from Allergen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Hospira, Janssen-Cilag, Lundbeck, Pfizer, and Roche. Dr. Hollander receives grant or research support from AstraZeneca. Dr. Lee, Ms. Foley, and Ms. Hannagan report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

ACKNOWLEDGEMENTS: Funding for the conduct of this investigator-initiated study was provided by AstraZeneca Australia (Study Code: D1443C00043). The authors would like to thank research assistants Matt Donato and Sara Greenbaum who conducted recruitment for this project.

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CORRESPONDENCE: Stuart J. Lee, BA, DPsych, Monash Alfred Psychiatry Research Centre, The Alfred Hospital, PO Box 315, Prahran, Victoria 3181 Australia E-MAIL: s.lee@alfred.org.au