Olanzapine Taken with Dinner Keeps Drowsiness at Bay

Richard W. Shulman, MDCM, FRCPC
Geriatric Psychiatrist, Trillium
Health Centre, Mississauga, Ontario
Member, Division of Geriatric Psychiatry,
University of Toronto, Toronto, Ontario

In elderly patients suffering from schizophrenia, psychosis due to Alzheimer's disease, or other illnesses, first line treatment with a second-generation (atypical) antipsychotic--as compared to a first generation (conventional) antipsychotic--should be considered standard therapy. The advantage of treatment with a second-generation antipsychotic is, at least in part, due to improved neurologic side effect profiles. The Canadian Clinical Practice Guidelines for the Treatment of Schizophrenia state that treatment with clozapine, olanzapine, quetiapine, and risperidone (at lower doses) markedly reduces acute extra-pyramidal side effects (EPSE).¹

Elderly patients treated with relatively low doses of first-generation antipsychotics have been shown to have a 29% cumulative annual incidence of tardive dyskinesia (TD). The incidence of TD in patients treated with atypical antipsychotics is likely to be lower given that EPSE has been found to be a risk factor for TD.²

Olanzapine (Zyprexa‚) is a second-generation antipsychotic that has shown promise as a safe and effective drug for the treatment of elderly patients suffering from either schizophrenia or psychosis secondary to dementia.^3,4,5,6

A multicentre study, conducted to determine the efficacy and safety of olanzapine in the treatment of psychotic symptoms and behavioural disturbances associated with Alzheimer's disease, found that it was beneficial in alleviation of these symptoms. Low-dose olanzapine at 5 and 10 mg/day, prescribed for the management of psychosis and agitation/aggression, was well tolerated by patients and its efficacy was significantly superior to that of placebo.⁷

Treatment-emergent side effects that had an incidence = 20% and that were statistically significant when compared to placebo rates, were limited to somnolence, occurring in 25% of the patients on doses of 10 mg/d. No significant cognitive impairment, increase in EPSE, or central anticholinergic effects were found at any olanzapine dose relative to placebo.⁷

In my clinical experience, I have reduced the incidence of somnolence in patients taking olanzapine, by prescribing that the drug should be taken with the patient's evening meal. The reasoning behind this is based on combining a knowledge of the drug's pharmacodynamics--what the drug does to the body--with its pharmacokinetics--what the body does to the drug.

The pharmacokinetic profile of olanzapine is dose-proportional and linear, meaning that changes in the dose lead to predictable changes in its concentration. Olanzapine has a median elimination half-life of approximately 30 hours in adults, and up to approximately 50 hours in the elderly.⁸ This longer elimination half life in the elderly can be secondary to reduced clearance due to slowed oxidative metabolism and/or non-smoking status (smoking induces the metabolism of olanzapine via the CYP1A2 pathway). Elimination may be prolonged in elderly women because of an increased volume of distribution (greater percentage of body weight is adipose tissue). Taken together, this means that it takes longer than one day for 50% of the drug to be metabolized and cleared from the body, allowing for once daily dosing. The prolonged time it takes to eliminate the drug in the elderly does not influence the maximum concentration the drug obtains. Concentration at steady state depends on the dosing rate--the dose multiplied by the dosing interval--divided by the clearance. Clearance is a parameter that helps quantify the hepatic metabolism of the drug, and is not readily open to manipulation by the physician. Therefore, considering that plasma concentration and side effects may correlate according to a concentration-response relationship, oversedation on olanzapine may require dose reduction, although this could lead to a reduction in its effectiveness. Is there a way to maintain the same effective dosing rate, but to alter the dosing schedule so as to reduce the level of sedation?

Since olanzapine has a tendency to cause sedation, one may ask if it should be taken at the patient's bedtime? I have prescribed it to many patients to be taken at bedtime and found that some patients would complain of oversedation the following morning. So, what if the drug is taken earlier in the evening, for instance, with an evening meal? Indeed, in my experience this clinical manoeuvre has resulted in improved tolerability with regards to daytime somnolence. A closer look at the pharmacokinetics of the drug reveals the potential reason for this improvement. Taking olanzapine with food does not affect its absorption into the blood stream. After swallowing the drug, the time it takes to reach its peak plasma concentration is about 5 to 8 hours.⁹ This may result in olanzapine's peak level of sedation being 5 to 8 hours after the patient has taken the drug. By taking it with the evening meal, the plasma concentration and level of sedation is highest during nighttime sleeping hours, and falls during daylight hours. So, in the interests of achieving the maximum benefit from the medication: If an elderly patient on olanzapine is oversedated, rather than concluding that a lower dose is required, why not first try prescribing it with his or her evening meal?

References

1. The Canadian Clinical Practice Guidelines for the Treatment of Schizophrenia. Canadian Journal of Psychiatry 1998; 43 (suppl. 2): 29s-33s.
2. Jeste DV, Rockwell E, Harris MJ, Lohr JB, Lacro J. Conventional vs. newer antipsychotics in elderly patients. American Journal of Geriatric Psychiatry 1999; 7(1): 70-76.
3. Sajatovic M, Perez D, Brescan D, Ramirez LF. Olanzapine therapy in elderly patients with schizophrenia. Psychopharmacology Bulletin 1998; 34(4): 819-823.
4. Madhusoodanan S, Suresh P, Brenner R, Pillai R. Experience with the atypical antipsychotics- risperidone and olanzapine in the elderly. Annals of Clinical Psychiatry 1999; 11(3): 113-118.
5. Solomons K, Geiger O. Olanzapine use in the elderly: a retrospective analysis. Canadian Journal of Psychiatry 2000; 45:151-155.
6. Street JS, Clark WS, Gannon KS, Cummings JL, Bymaster FP, Tamura RN, Mitan SJ, Kadam DL, Sanger TM, Feldman PD, Tollefson GD, Breier A. Olanzapine treatment of psychotic and behavioural symptoms in patients with Alzheimer's disease in nursing care facilities. Archives of General Psychiatry 2000; 57: 968-976.
7. Street JS, Tollefson GD, Tohen M, Sanger TM, Clark WS, Gannon KS, Wei H. Olanzapine for psychotic conditions in the elderly. Psychiatric Annals 2000; 30 (3): 191-196.
8. Zyprexa Product Monograph. CPS 35th edition, 2000.
9. Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine-pharmacokinetic and pharmacodynamic profile. Clinical Pharmacokinetics 1999; 37 (3): 177-193.