Dose Optimization in Dementia

Reviewed by Dr. Bernard Groulx
(From: Viewpoints in Psychiatry, Vol. 1, No. 1, 2002, p.10-13.)

Dr. Bernard Groulx, Chief of Psychiatry, Ste. Anne's Hospital (Veterans), Clinical Professor of Psychogeriatrics, McGill University

Abstract

A vital part of improving the quality of life of geriatric patients and their caregivers is determining the efficacy, safety and tolerability of atypical antipsychotic agents in the treatment of depression, psychosis, schizophrenia and behavioural disturbances.¹ The recommended starting dose of olanzapine^† is 5 mg/day in elderly patients or patients with the potential for slower olanzapine metabolism or higher pharmacodynamic sensitivity to olanzapine, with dose escalation performed cautiously. However, olanzapine can be safely given to geriatric patients at 15 mg/day or even higher doses, over short or long periods, and clinical trials described here demonstrate that at least 5 mg is the optimal dose for maximal efficacy in this population.

In dementia, additionally, long-term in vivo data on the muscarinic effects of olanzapine demonstrate that it may have a pro-cholinergic effect, which is thought to be partly responsible for the increased level of cognitive function seen with its use.³ Improvement in cognition can enhance the quality of life for both patients suffering from dementia and their caregivers.

Alzheimer's Disease and Other Dementias

Olanzapine's efficacy has been demonstrated in the treatment of the psychological and behavourial symptoms associated with Alzheimer's disease. A double-blind, placebo-controlled, 6-week trial was carried out in 206 nursing home patients aged 60 or older who had Alzheimer's disease and exhibited psychotic and/or behavioural symptoms. Subjects were randomly assigned to receive placebo or 5, 10 or 15 mg/day olanzapine (titrated up from 5 mg/day every 7 days) for 6 weeks. Results showed that the 5 and 10 mg doses significantly improved the primary outcome measure NPI/NH Core Total score (agitation/aggression, hallucinations and delusions), as well as hostility and anxiety/depression compared to placebo. In addition, occupational disruptiveness, the NPI/NH Total Score and the BPRS Total Score were significantly reduced in the 5 mg group.

At all doses, olanzapine was well tolerated with no significant cognitive impairment, no increase in extrapyramidal symptoms, and no individual central or peripheral anticholinergic effects statistically greater than placebo.⁴ These results make it clear that in dementia - unlike schizophrenia and related psychoses in elderly patients - there is no need to titrate up: 5 mg olanzapine is an appropriate dose in almost all patients.

Olanzapine has also been shown to be safe and effective, demonstrating continued improvement in symptom control, in the long-term therapy of elderly patients with Alzheimer's disease. In an 18-week, open-label extension of the above study, the 105 subjects continued to demonstrate improvement in behavioural disturbances, psychotic symptoms, anxiety, disinhibition and irritability. No patients withdrew due to lack of efficacy, and there was no evidence of significant cognitive decline associated with olanzapine.⁵

A retrospective analysis comparing haloperidol, olanzapine and risperidone monotherapies in 998 hospitalized dementia patients (with a mean age of 81) found that olanzapine was significantly superior to both risperidone and haloperidol on measures of active aggression, verbal aggression, passive aggression and delusions/hallucinations, and was also superior to risperidone on measures of manipulative behaviour and noisiness. On none of the items measured was haloperidol or risperidone significantly superior to olanzapine.⁶

In vivo Pro-cholinergic Effects

A study on the in vivo anticholinergic activity of olanzapine examined the rates of constipation, dry mouth, fecal impaction, tachycardia, urinary retention, vasodilation, fever, intestinal obstruction and amblyopia. No individual event at any dose had an incidence significantly different from that seen with placebo, thereby demonstrating a difference between in vitro and in vivo data.^1-3 In vivo research demonstrated that olanzapine at doses of 5, 10 or 15 mg/day does not impair cognition.^4-5 In fact, it is possible that olanzapine 5 mg/day may improve cognition in patients with Alzheimer's disease.⁷

While earlier research on olanzapine found it to be a potent muscarinic receptor blocker, these studies looked at muscarinic receptors as a whole. In fact, olanzapine is a potent blocker of the auto-receptor M₂, and blockade of M2 receptors can cause the release of acetylcholine. Olanzapine may also produce this effect by blocking serotonin 3 and 6 receptors.¹ In animal studies, olanzapine raised acetylcholine levels in the cortex to a greater extent than did some other antipsychotic agents.⁸

Data from ongoing studies in younger patients with schizophrenia suggest that olanzapine augments or improves cognition by means of this acetylcholinergic activity.¹ Other antipsychotic agents have not demonstrated a similar ability to raise in vivo acetylcholine levels.

Multiple Formulations

In addition to the traditional oral tablet, olanzapine is available in an orally disintegrating tablet form (Zydis*), which offers a non-intrusive option for patients unable or unwilling to swallow traditional tablets. This tablet dissolves on contact with saliva, and then is absorbed through the stomach². No other antipsychotic agent provides this option.

This is of particular benefit to the elderly population and their caregivers, since these patients often have difficulty swallowing tablets. Zydis* enables physicians to optimize doses and achieve desired outcomes in their elderly patients.

In dementia patients with moderate to severe agitation, dissolution of Zydis* by adding it to juice, soft cereal or other appropriate liquid foods or beverages is also effective, and often increases the agent's acceptability to the patients.

Questions & Answers

Question: What dose of olanzapine do you recommend for patients with mood disturbances, milder forms of agitation or some psychosis?

Answer: The olanzapine dosage depends on whether or not the patient has dementia. In a patient with dementia, 5 mg/day is an ideal dosage and if it doesn't appear effective at first, I wait for it to work. I occasionally use other medications to calm the patient until the olanzapine has begun to work.

In a patient with a psychiatric illness but no dementia, the dosage depends on the nature of the problem. In geriatric patients, I will sometimes begin dosing at 1.25 mg/day for two to three days, then 2.5 mg/day for two to three days, then 5 mg/day and continue to titrate up by 5 mg every two weeks (or every week, if the patient is aggressive), as high as is necessary. This can occasionally mean as high as 20 or 25 mg/day in some patients.

Question: What dose of olanzapine do you recommend for patients who are primarily agitated –for example, verbally aggressive or very combative patients?

Answer: This again depends on the type of patient involved. In patients with late-stage dementia and these symptoms, 5 mg/day is the recommended dose. In a schizophrenic patient with no dementia, the recommended dose could easily be much higher.

Question: The literature reports that the mean untreated Alzheimer's disease group MMSE decline is about 1.35 points over 6 months. Data from the Street study open extension showed that the olanzapine-treated group declined less than expected in the literature. What has been your clinical experience? Would you consider olanzapine a "cognitive enhancer"?

Answer: This effect has been entirely corroborated in my practice. Olanzapine was once thought to be anticholinergic in effect, but it's clear now that it's exactly the opposite and has at least a mild cholinergic effect. In dementia patients, I definitely consider it a mild to moderate cognitive enhancer and this, of course, improves quality of life for both the patients and the caregivers.

Question: What has been your clinical experience with low maintenance doses of 1.25 to 2.5 mg/day?

Answer: Although I sometimes start at these doses, I then titrate up as necessary. Ideal maintenance doses are 5 mg/day or higher, depending on the patient.

Case Study

• BW was an 82-year-old male who was diagnosed with Alzheimer's disease 3 years previously. At that time, his MMSE was measured at 14. His wife wished to care for him at home, so he remained at home for the next 3 years. He did not take any medication for his dementia.
• BW's wife then reported that he had significantly regressed over the previous few months. He lost speech and comprehension capacity, was incontinent, could not handle activities of daily living, and wandered. This was stressful for his wife, but she continued to care for him at home. However, he then became agitated and gave the impression that he was afraid of her harming him. In one instance, he pushed her and she fell, fortunately sustaining no serious injury.
• BW was rapidly admitted to a geriatric hospital. Initial tests found that his MMSE had fallen to 9. Apparently due to the change in environment, he became very distressed and increasingly agitated, sometimes posing a danger to other patients.
• BW was initiated on olanzapine 5 mg/day, given at night, and oxazepam 15 mg/day. During the first 2 days of therapy, he began sleeping normally; over the following week, he exhibited significant behavioural improvement with decreasing belligerence.
• Oxazepam was discontinued after 10 days, and behavioural improvement was maintained. After a few weeks, BW exhibited mood improvement and began to smile and interact positively with others.
• Over 10 months of follow-up, BW's cognition did not decline and he experienced no side effects. His improved mood and behaviour continued.

Commentary

Question: How important is tolerability in geriatric patients?

Answer: Frankly, tolerability is as important as efficacy. Geriatric patients, particularly those suffering from dementia, are extremely sensitive to side effects. The two worst, which I call the two enemies of the elderly, are extrapyramidal symptoms (EPS) and anticholinergic side effects. Olanzapine has an excellent profile for EPS –better than other agents –and not only is not anticholinergic, but actually has cholinergic properties.

Question: What do you consider the long-term benefits of prescribing olanzapine for the elderly population?

Answer: Olanzapine is a true psychotropic medication, not just an antipsychotic agent like others in its class. It therefore has multiple effects and we've seen clear improvements in depression, anxiety, agitation and cognition as well as in psychosis. It is also well tolerated in geriatric patients.

* Trademark of Scherer DDS Ltd.

+lanzapine is indicated for the acute and maintenance treatment of schizophrenia and related psychotic disorders. In clinical trials a dose range of 5 to 20 mg/day was studied. The safety and efficacy of doses above 20 mg/day have not been evaluated.

References

1. Atypical antipsychotic therapy in elderly patients with dementia, American Association for Geriatric Psychiatry, 14th Annual Meeting, San Francisco (CA); February 23-26, 2001. Priority Press, Kirkland (PQ): Medical Education Network Canada Inc.., 2001.
2. ZYPREXA®and ZYPREXA®Zydis Product Monograph. Eli Lilly Canada Inc., November 2000.
3. Kinon BJ et al. "Favorable anticholinergic profile of olanzapine in elderly patients with dementia", Eur Neuropsychopharmacol, 2001;11(Suppl. 3):5323-324.
4. Street JS et al. for the HGEU Study Group. "Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities", Arch Gen Psychiatry, 2000;57:968-976.
5. Street JS et al. "Long-term efficacy of olanzapine in the control of psychotic and behavioral symptoms in nursing home patients with Alzheimer's dementia", Int J Geriatr Psychiatry, 2001;16(Suppl. 1):S62-70.
6. Edell WS, Tunis SL. "Antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric inpatients", Am J Geriatr Psychiatry, 2001;9(3):289-297.
7. Kennedy JS et al. "The central cholinergic system profile of olanzapine compared with placebo in Alzheimer's disease", Int J Geriatr Psychiatry, 2001;16(Suppl. 1)S24-32.
8. Ichikawa J et al. "Atypical, but not typical, antipsychotic drugs increase cortical acetylcholine release without an effect in the nucleus accumbens or striatum", Neuropsychopharmacology, 2002;26(3):325-339.