A Double-blind, Placebo-Controlled Dose-Response Comparison of Intramuscular Olanzapine and Haloperidol in the Treatment of Acute Agitation in Schizophrenia

Breier, Alan; Meehan, Karena; Birkett, Martin; David, S.R.; Ferchland, Iris; Sutton, Virginia K.; Taylor, Cindy C.; Palmer, R.; Dossenbach, M.; Kiesler, Geri; Brook, S.; Wright, Pádraig

doi:10.1001/archpsyc.59.5.441

Cited by 254 publications

(201 citation statements)

References 32 publications

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“…Slowed movement (bradykinesia) is a prominent symptom of hypodopaminergic states, whether induced acutely with supratherapeutic doses of dopamine-blocking neuroleptic drugs (Fleminger, 1992;Breier et al, 2002) or by chronic lesions of dopamine pathways (Denny-Brown, 1968;Marsden, 1989;Breier et al, 2002;Obeso et al, 2002). Although bradykinesia is ultimately caused by abnormal development of muscle force (Berardelli et al, 2001), the link from dopamine dysfunction to peripheral dynamics remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Bradykinesia Induced by Dopamine D2 Receptor Blockade Is Associated with Reduced Motor Cortex Activity in the Rat

Parr‐Brownlie

Hyland²

2005

Journal of Neuroscience

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Disruption of motor cortex activity is hypothesized to play a major role in the slowed movement (bradykinesia) associated with reduced dopaminergic function. We recorded single neurons in the motor cortex of free-moving rats performing a forelimb-reaching task. The same neurons were examined before and after induction of bradykinesia with the D 2 dopamine receptor antagonist haloperidol. Withincell changes in the firing rate and firing pattern of individual cells and the correlation between simultaneously recorded cells after injection of haloperidol were statistically compared with vehicle-only control experiments. During haloperidol-induced bradykinesia (mean movement time increase, ϩ231%), there was an average 11% decrease in baseline firing rate. Movement-related peaks in firing rate were more dramatically affected, with an overall reduction in peak amplitudes of 40%. Bradykinesia was also associated with decreased intensity of bursting and amplitude of cross-correlation peaks at rest. The results show for the first time that significant reductions can be detected in motor cortex activity at rest in animals with impaired ability to generate movements induced by reduced dopamine action and confirm that impaired movements are associated with reduced cortical activation. Together, these changes in neural activity may reduce recruitment and rate modulation of motor units in the spinal cord.

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Section: Introductionmentioning

confidence: 99%

Bradykinesia Induced by Dopamine D2 Receptor Blockade Is Associated with Reduced Motor Cortex Activity in the Rat

Parr‐Brownlie

Hyland²

2005

Journal of Neuroscience

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“…The intramuscular form of loxapine is no longer marketed in the United States, but is frequently used in France for the acute treatment of agitation. 13 Intramuscular antipsychotics have a T max of 90 minutes and can take up to 60 minutes to reduce agitation, [14][15][16][17] and symptoms can escalate during this period. Moreover, intramuscular administration is often resisted by patients.…”

mentioning

confidence: 99%

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

Spyker

Riesenberg²,

Cassella

2015

The Journal of Clinical Pharma

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This randomized, double-blind, placebo-controlled, parallel-group study was to determine the pharmacokinetic characteristics, safety, and tolerability of multiple doses of inhaled loxapine aerosol in subjects on a stable, oral, chronic antipsychotic regimen. Loxapine was delivered by means of a unique thermally generated aerosol comprising drug particles of a size designed for deep lung delivery and absorption. Thirty-two subjects were randomized 1:1:1:1 to receive inhaled loxapine (total doses of 15, 20, or 30 mg) or inhaled placebo administered in 3 divided doses, given 4 hours apart. Following inhalation, the median T max was 2 minutes, and concentrations declined to about half C max approximately 5 minutes later across the 3 dose levels. The dose proportionality across data from this study combined with data from the single-dose study showed a slope (90%CI) of log AUC inf versus log dose of 0.818 (0.762-0.875) across the 8 doses (n ¼ 60 subjects) studied, indicating reasonable dose proportionality. The most common adverse events were cough (3 of 32, 9%), sedation (3 of 32, 9%), and dysgeusia (2 of 32, 6%). The inhalation of multiple doses of inhaled loxapine were well tolerated in study subjects and provided a safe, well-tolerated means for rapidly and reliably achieving therapeutic plasma concentrations of loxapine. ClinicalTrials. gov identifier: NCT00555412

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“…Olanzapine Two trials (Brier et al, 2002;Wright et al, 2001 À sponsored by Eli Lilly) evaluated i/m olanzapine against i/m haloperidol and against i/m placebo. Both studies were large multisite, multi-country studies (571 participants in total).…”

Section: Atypical Antipsychoticsmentioning

confidence: 99%

“…Olanzapine was significantly more effective than haloperidol in reducing agitation at 15, 30 and 45 minutes. The group sizes in Brier et al (2002) did not allow comparison with placebo. Acute dystonia was not associated with olanzapine, but was found in 7% of the haloperidol group (Wright et al, 2001).…”

Section: Atypical Antipsychoticsmentioning

confidence: 99%

Establishing gold standard approaches to rapid tranquillisation: A review and discussion of the evidence on the safety and efficacy of medications currently used

Pratt

Chandler-Oatts

Nelstrop

et al. 2008

JPI

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Background: Rapid tranquillisation is used when control of agitation, aggression or excitement is required. Throughout the UK there is no consensus over the choice of drugs to be used as first line treatment. The NICE guideline on the management of violent behaviour involving psychiatric inpatients conducted a systematic examination of the literature relating to the effectiveness and safety of rapid tranquillisation (NICE, 2005). This paper presents the key findings from that review and key guideline recommendations generated, and discusses the implications for practice of more recent research and information. Aims: To examine the evidence on the efficacy and safety of medications used for rapid tranquillisation in inpatient psychiatric settings. Method: Systematic review of current guidelines and phase III randomised, controlled trials of medication used for rapid tranquillisation. Formal consensus methods were used to generate clinically relevant recommendations to support safe and effective prescribing of rapid tranquillisation in the development of a NICE guideline. Findings: There is a lack of high quality clinical trial evidence in the UK and therefore a 'gold standard' medication regime for rapid tranquillisation has not been established. Rapid tranquillisation and clinical practice: The NICE guideline produced 35 recommendations on rapid tranquillisation practice for the UK, with the primary aim of calming the service user to enable the use of psychosocial techniques. Conclusions and implications for clinical practice: Further UK specific research is urgently needed that provides the clinician with a hierarchy of options for the clinical practice of rapid tranquillisation.

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A Double-blind, Placebo-Controlled Dose-Response Comparison of Intramuscular Olanzapine and Haloperidol in the Treatment of Acute Agitation in Schizophrenia

Abstract: Intramuscular olanzapine at a dose of 2.5 to 10.0 mg per injection exhibits a dose-response relationship in the rapid treatment of acute agitation in patients with schizophrenia and demonstrates a favorable safety profile.

Cited by 254 publications

References 32 publications

Bradykinesia Induced by Dopamine D2 Receptor Blockade Is Associated with Reduced Motor Cortex Activity in the Rat

Bradykinesia Induced by Dopamine D2 Receptor Blockade Is Associated with Reduced Motor Cortex Activity in the Rat

Multiple dose pharmacokinetics of inhaled loxapine in subjects on chronic, stable antipsychotic regimens

Establishing gold standard approaches to rapid tranquillisation: A review and discussion of the evidence on the safety and efficacy of medications currently used

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