03. Alzheimer’s Disease: Olanzapine vs. Risperidone for BPSD

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Antipsychotics for Dementia Agitation

A few months ago, we discussed the limited landscape for managing agitation in Alzheimer’s and other forms of dementia. Antipsychotics remain widely used agents despite carrying FDA warnings about sudden death risk in dementia patients and despite guidelines recommending them only for severe agitation that places the patient or caregiver at risk.

Only brexpiprazole has an official US indication, with limited use by a variety of factors. In Europe, risperidone has an indication for short-term use in Alzheimer’s behavioral disturbance. Many other medications are used off-label, with varying evidence and side effects.

Olanzapine vs. Risperidone Meta-Analysis

A new systematic review and meta-analysis compares olanzapine and risperidone for safety and efficacy in dementia-related behavioral disturbances, hoping to provide some additional evidence to help guide clinicians in choosing between limited options. The study, published in the journal Medicine Open, analyzed 23 prospective controlled clinical trials with 2,427 participants. This is a relatively small n for a meta-analysis, limiting the conclusions we can draw. Most studies weren’t blinded, and the majority had potential for bias, leading to lower quality ratings. Studies generally examined short-term medication use of eight weeks or less.

BPSD: A Broad Term

The authors use the term BPSD (behavioral and psychological symptoms of dementia) throughout the article. This broad category includes five distinct subcategories:

1. Cognitive perceptual disturbances (hallucinations, delusions)
2. Motor symptoms (pacing, wandering)
3. Verbal symptoms (yelling, verbal aggression)
4. Emotional symptoms (mood fluctuations)
5. Vegetative symptoms (insomnia, decreased appetite)

This heterogeneity of target symptoms across studies makes comparison challenging in a meta-analysis and further limits conclusions.

Main Findings: Olanzapine’s Potential Advantages

The study suggests that olanzapine may be more effective than risperidone in reducing BPSD, particularly for delusions and nighttime behavioral disturbances. Olanzapine also showed slightly better side effect profiles for EPS, agitation, and sleep disturbance, though it caused more weight gain.

Some findings align with expectations:

• Risperidone’s higher risk for EPS (high-potency agent)
• Olanzapine’s greater weight gain potential
• Olanzapine’s sedating effects, improving sleep disturbances

Delusions in Dementia: A Unique Phenomenon?

The finding that olanzapine outperforms risperidone for delusions is less intuitive. An emerging theory suggests that delusions in dementia differ from those in primary psychiatric illnesses like schizophrenia.

While schizophrenia delusions are thought to be dopaminergic, dementia delusions may represent disruptions in the default mode network and cholinergic system. They might be more akin to confabulations filling cognitive gaps than true delusions. For example, delusions of theft (the most common and earliest in Alzheimer’s) may arise because patients forget where they placed objects, and their brain fills gaps by constructing a story about theft. Similar theories exist for other common delusions in dementia (e.g., delusions of infidelity, delusions of home intruders moving furniture or objects).

If these are not classic delusions influenced by dopamine, olanzapine’s advantage might stem from its “dirty” pharmacological profile with multiple mechanisms.

Study Limitations

The study’s small sample size and heterogeneous outcomes limit its conclusions. The results contradict at least three prior systematic reviews that found no efficacy difference between risperidone and olanzapine.

The authors attribute this discrepancy to outcome measures—this study compared objective response rates (dichotomous better/worse outcomes), whereas prior reviews compared individual scores (continuous scaled outcomes). Although the authors contend their method has advantages, comparing scaled scores is generally considered scientifically superior.

Clinical Implications and Future Directions

Given the study’s limitations, I hesitate to prioritize olanzapine over risperidone based on these findings alone. Instead, I’ll continue to tailor antipsychotic choices to specific patient needs, target symptoms, and side effect profiles.

The potential difference in pathophysiology between perceptual disturbances in dementia and other conditions is worth considering. Future research might explore agents targeting glutamate, acetylcholine, and serotonin for managing these symptoms in dementia patients.

Abstract

Comparative efficacy and safety of olanzapine and risperidone in the treatment of psychiatric and behavioral symptoms of Alzheimer’s disease: Systematic review and meta-analysis

Zhang, Zhihua MD; Zhang, Xijuana; M.D. & Xu, Lingyana, M.D.

Objectives: 

Olanzapine and risperidone have emerged as the most widely used drugs as short-term prescription in the treatment of behavioral disturbances in dementia. The present systematic review and meta-analysis was hence performed to investigate the effectiveness and safety profile of olanzapine and risperidone in the treatment of behavioral and psychological symptoms of dementia (BPSD), aiming to provide updated suggestion for clinical physicians and caregivers.

Design: 

Prospective controlled clinical studies were included, of which available data was extracted. Outcomes of BEHAVE-AD scores with the variation of grades, specific behaviors variables, as well as safety signals were pooled for the analysis by odds rates and weighted mean differences, respectively.

Data sources: 

Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and WanFang.

Eligibility criteria: 

Prospective, controlled clinical studies, conducted to compare the effectiveness and safety profile of olanzapine and risperidone in the treatment of BPSD.

Data extraction and synthesis: 

Interested data including baseline characteristics and necessary outcomes from the included studies were extracted independently by 2 investigators. BEHAVE-AD scale was adopted to assess the efficacy in the present study. All behaviors were evaluated at the time of the initiation of the treatment, as well as the completion of drugs courses. Adverse events were assessed with the criteria of Treatment Emergent Symptom Scale, or Coding Symbols for a Thesaurus of Adverse Reaction Terms dictionary. Weighted mean difference was used for the pooled analysis.

Results: 

A total of 2427 participants were included in the present meta-analysis. Comparative OR on response rate, and remarkable response rate between olanzapine and risperidone was 0.65 (95% CI: 0.51–0.84; P = .0008), and 0.62 (95% CI: 0.50–0.78; P < .0001), respectively. There were statistical differences observed by olanzapine on the improvement of variables including delusions (WMD, −1.83, 95% CI, −3.20, −0.47), and nighttime behavior disturbances (WMD, −1.99, 95% CI, −3.60, −0.38) when compared to risperidone.

Conclusion: 

Our results suggested that olanzapine might be statistically superior to risperidone on the reduction of BPSD of Alzheimer’s disease, especially in the relief of delusions and nighttime behavior disturbances. In addition, olanzapine was shown statistically lower risks of agitation, sleep disturbance, and extrapyramidal signs.

Reference

Zhihua, Z. MD; Xijuana, Z. M.D. & Lingyana, X. M.D. Comparative efficacy and safety of olanzapine and risperidone in the treatment of psychiatric and behavioral symptoms of Alzheimer’s disease: Systematic review and meta-analysis. (2024). Medicine 103(27):p e35663.