Background The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated. Methods A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18–75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam ( n = 56), olanzapine ( n = 54), or haloperidol ( n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118). Findings Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine ( p = 0·03) and haloperidol ( p = 0·002). Adverse event rates were similar across the three arms. Dystonia ( n = 1) and cardiac arrest ( n = 1) were reported in the haloperidol group. Interpretation Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects. Funding Research Grants Council, Hong Kong.

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Di-n-propylacetate (DPA), aminooxyacetic acid (AOAA), and gabaculine were administered alone or in combination to Swiss mice. Six hours after administration of the drugs the anticonvulsant action (against isonicotinic acid hydrazide-induced seizures) of AOAA and DPA combined was less than that of AOAA alone. The cause of this phenomenon appeared to be an interaction between DPA and AOAA with respect to inhibition of GABA-T activity, resulting in a long-term diminished inhibition by AOAA, which in turn led to a lessening of the AOAA-induced elevation in the GABA content of nerve endings (synaptosomes). An excellent correlation was observed between the delay in onset of seizures and the elevation of synaptosomal GABA content.

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The intramuscular administration of a gamma-aminobutyrate-alpha-oxoglutarate aminotransferase (GABA-T) inhibitor, gabaculine, to mice resulted in significant increases in GABA content and decreases in the content of aspartate, glutamate, and glutamine in the nerve endings (synaptosomes). These effects were ameliorated by the concurrent administration of the GABA uptake inhibitor ketamine. A major cause of these effects was the gabaculine-induced inhibition of GABA-T activity and the lessening of this inhibition by ketamine. The latter phenomenon was not due to a direct action of ketamine on the enzyme, nor to an interaction between gabaculine and ketamine. Rather, it appeared that ketamine might be interfering with the transport of gabaculine into the cellular structures. The anticonvulsant action of the GABA-T inhibitor and the GABA uptake inhibitor together was little different from that of the GABA-T inhibitor alone.