June 2010

Olanzapine Long-Acting Injection
Extended-release injectable olanzapine (Zyprexa Relprevv) appears to be similar in efficacy to oral olanzapine for relapse prevention in patients with schizophrenia.

Preventing Relapse in Bipolar I Disorder: Lithium, Valproate, or the Combination?
In an open-label trial, the combination of lithium and valproate (Depakote and others) was more effective at preventing breakthrough mood episodes than valproate monotherapy in patients with bipolar I disorder.

Choosing among SSRIs: How Does Fluvoxamine Rate?
Fluvoxamine (Luvox and others) is similar to other selective serotonin reuptake inhibitors (SSRIs) in efficacy and overall tolerability for the acute treatment of major depression. Specific side effects vary among antidepressants.

In Brief
"Traditional" Diet Lowers Risk of Depression and Anxiety; ECT Benefits Patients with Chronic PTSD

Green Tea and the Risk of Depression
In a cross-sectional study, increased consumption of green tea was associated with a decreased risk of depression.

Olanzapine Long-Acting Injection

June 2010

An extended-release injectable preparation of olanzapine (Zyprexa Relprevv) recently became available by prescription (BTP 2010:33:9). Olanzapine long-acting injection (LAI), a salt of olanzapine and pamoic acid suspended in an aqueous vehicle, is administered intramuscularly. Therapeutic levels are achieved after a first injection, but repeated injections over approximately 3 months are required to achieve steady state. Kane and associates conducted a relapse prevention study of olanzapine LAI in outpatients with schizophrenia.1

Over 1000 subjects were stabilized on oral olanzapine, 10 to 20 mg/day, for 4 to 8 weeks, then assigned randomly in double-blind fashion to one of five treatment regimens: 150 mg IM every 2 weeks ("low" dose); 405 mg IM every 4 weeks ("medium" dose); 300 mg IM every 2 weeks ("high" dose); 45 mg IM every 4 weeks ("ultra-low" dose—chosen to be a subtherapeutic reference in lieu of placebo); or their previously stabilized dose of oral olanzapine.

Patients who continued to take oral olanzapine fared surprisingly well in the 24 weeks of assessment: 93% remained free of psychotic exacerbation. The three therapeutic doses of olanzapine LAI were statistically indistinguishable from oral olanzapine—high, 95%; medium, 90%; low, 84%—and were statistically superior (P < .05) to the ultra-low dose (69% exacerbation-free). The most frequent treatment-emergent adverse events with olanzapine were increased weight, somnolence, insomnia, anxiety, increased appetite, and headache. Overall, mean weight gain was 1.1 kg (2.4 lb). The percentage of patients who gained 7% or more of their baseline body weight was 21% for oral olanzapine and 21%, 15%, 16%, and 8% for the descending doses of olanzapine LAI, respectively. Two patients receiving olanzapine LAI experienced sedation and delirium consistent with olanzapine overdose, following possible accidental intravascular (IV) injection—a known serious complication of olanzapine LAI.

The high rate of clinical stability in patients taking oral olanzapine stands in contrast to the results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study (BTP 2005;28:47-48).2 In an accompanying editorial, Davis suggests this may reflect the fact that patients were preselected for response and presumed adherence to oral olanzapine before randomization.3 The editorialist further observes that, although differences did not achieve statistical significance, higher doses of olanzapine LAI appeared to afford slightly greater benefit than lower doses.

Davis notes that at steady state, a 300-mg dose of olanzapine LAI every 2 weeks produces blood levels similar to those achieved with a 20-mg daily oral dose. Because steady state is not usually reached until after a third injection, however, he suggests that oral olanzapine be continued at full dose for 2 to 4 weeks following the first injection, then gradually decreased over a month or two.

Accidental IV administration of olanzapine LAI occurs roughly once in 200 injections and, as we have noted previously (BTP 2009;32:9-10), can produce delirium or deep sedation. Half of subjects will show effects within 20 minutes and the remainder, within 3 hours. Recovery can take up to several days, but all patients recover. Patients should be observed for 3 hours after every injection to avoid the risk of falls or motor vehicle accidents.

If a depot antipsychotic formulation is being considered, Davis suggests, the patient should first show efficacy and tolerance with the oral formulation of the same agent, which is usually seen in the first month of treatment. With olanzapine, about 50% of weight gain tends to occur in the first few months of therapy, so the patient's susceptibility to this adverse effect should be apparent. Several months of oral olanzapine should allow a fair assessment of its risks and benefits before switching to the LAI form.

1Kane JM, Detke HC, Naber D, Sethuraman G, Lin DY, Bergstrom RF, McDonnell D: Olanzapine long-acting injection: A 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia. Am J Psychiatry 2010;167:181-189.

2Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK, for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-1223.

3Davis JM: The use of depot medications in the treatment of schizophrenia. Am J Psychiatry 2010;167:125-126.