Management of Acute Agitation in Patients With Bipolar Disorder

Abstract

To investigate the efficacy and safety of intramuscular (IM) aripiprazole for the treatment of agitation in patients with bipolar I disorder, manic or mixed episodes. In total, 301 patients experiencing acute agitation were randomized to IM aripiprazole 9.75 mg per injection (n = 78), IM aripiprazole 15 mg per injection (n = 78), IM lorazepam 2 mg per injection (n = 70), or IM placebo (n = 75) in this double-blind multicenter study. Patients could receive up to 3 injections over 24 hours. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component score from baseline at 2 hours after first injection. Mean improvements in Positive and Negative Syndrome Scale Excited Component score at 2 hours were significantly greater with IM aripiprazole (9.75 mg, -8.7; 15 mg, -8.7) and IM lorazepam (-9.6) versus IM placebo (-5.8; P <or= 0.001). For all other efficacy measures, all 3 active treatments showed significantly greater improvements over IM placebo at 2 hours (P < 0.05), with similar improvements across the active treatments. Significant differences over IM placebo were seen by 45 to 60 minutes for several efficacy parameters. Both IM aripiprazole doses were well tolerated; the safety profile was similar to oral aripiprazole. Oversedation (Agitation-Calmness Evaluation Scale score of 8 or 9) during 2 hours after first injection was less frequent with IM aripiprazole 9.75 mg (6.7%) and IM placebo (6.8%) versus IM aripiprazole 15 mg (17.3%) and IM lorazepam (19.1%). IM aripiprazole 9.75 and 15 mg are effective and well tolerated for acute agitation in bipolar disorder, although the low incidence of oversedation suggests a risk-benefit profile for IM aripiprazole 9.75 mg.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…Because of the strength of evidence for efficacy in alleviating agitation in this population, aripiprazole IM (level 2),125, 126 lorazepam IM (level 2),125, 127 loxapine inhaled (Level 1)128, 129 and olanzapine IM (level 2)127, 130, 131, 132, 133 are recommended as the first‐line option. Sublingual asenapine (level 3),134 haloperidol IM (level 3),131, 135, 136 haloperidol IM + midazolam IM (level 3),131, 137 haloperidol IM + promethazine IM (level 3),131, 137, 138 risperidone ODT (level 3),136 and ziprasidone IM (level 3)131, 137, 139 are recommended as a second‐line treatment.…”

Atypical antipsychotics in bipolar disorder: the treatment of mania

“…The first showed improvement within 20 min and greater improvement with the antipsychotic (olanzapine 10 mg) than with the benzodiazepine (lorazepam 2 mg) over 2 h (Meehan et al, 2001). The second showed improvement with both lorazepam (2 mg) and aripiprazole (9.75-15 mg) but a trend towards greater improvement with lorazepam (Zimbroff et al, 2007). By contrast, intravenous valproate (20 mg/kg) was not associated with an improvement in mania within 2 h (Phrolov et al, 2004), suggesting a different mechanism of action.…”

A non‐randomized study to investigate the effects of the atypical antipsychotic aripiprazole on the steady‐state pharmacokinetics of lamotrigine in patients with bipolar I disorder

“…This atypical antipsychotic has a pharmacologically distinct profile of dopamine D 2 /D 3 and serotonin 5HT 1A partial agonism and serotonin 5HT 2A antagonism (Jordan et al, 2002(Jordan et al, , 2004Shapiro et al, 2003) and has been shown to be effective and safe in the treatment of patients with bipolar I disorder (Dillenschneider et al, 2007;Keck et al, 2003Keck et al, , 2006Keck et al, , 2007Sachs et al, 2006;Vieta et al, 2005Vieta et al, , 2007Zimbroff et al, 2007). Aripiprazole is metabolized extensively, primarily through cytochrome P-450 CYP3A4 and CYP2D6 (DeLeon et al, 2004;Swainston Harrison and Perry, 2004).…”