Mirtazapine Should Not Be Used for Treating Geriatric Dementia
Mirtazapine is not effective for treating agitation or behavioral symptoms in dementia and may increase mortality risk. The highest quality recent evidence demonstrates no clinical benefit compared to placebo, with concerning safety signals 1, 2.
Evidence Against Mirtazapine for Dementia
Agitation and Behavioral Symptoms
- The 2021 SYMBAD trial found no reduction in agitation scores (Cohen-Mansfield Agitation Inventory) at 12 weeks with mirtazapine 45 mg compared to placebo (adjusted mean difference -1.74,95% CI -7.17 to 3.69; p=0.53) 1.
- Seven deaths occurred in the mirtazapine group versus only one in placebo by week 16, with post-hoc analysis suggesting marginal statistical significance (p=0.065) 1, 2.
- The 2023 HTA-SYMBAD trial confirmed these findings, showing mirtazapine is neither clinically nor cost-effective for agitation in dementia 2.
Depression in Dementia
- The 2011 HTA-SADD trial demonstrated no benefit of mirtazapine over placebo for depression in Alzheimer's disease at 13 weeks (mean difference 0.01,95% CI -1.37 to 1.38; p=0.99) 3.
- Adverse reactions were significantly more common with mirtazapine (41%) than placebo (26%), with p=0.031 3.
- These negative findings persisted through 39-week follow-up 4, 3.
Guideline Recommendations
Weight Loss Context Only
- Current guidelines explicitly state that appetite stimulants, including mirtazapine, should NOT be used in persons with dementia 5.
- The only potential exception: mirtazapine may be considered when a dementia patient has both weight loss AND depression requiring antidepressant treatment 5.
- However, given the lack of efficacy for depression shown in the HTA-SADD trial, even this limited indication is questionable 3.
Evidence Quality
- Only one small retrospective study (n=22) showed weight gain with mirtazapine in dementia, but this was uncontrolled and open-label 5.
- No placebo-controlled trials support mirtazapine use for weight loss in dementia 5.
Clinical Implications
The current practice of prescribing mirtazapine for dementia should be reconsidered based on:
- Absence of benefit for agitation, the most common behavioral indication 1, 2
- Absence of benefit for depression in Alzheimer's disease 4, 3
- Increased adverse event rates compared to placebo 3
- Potential mortality signal requiring further investigation 1, 2
Alternative Approaches
For depression in dementia: The evidence suggests antidepressants as first-line treatment should be reconsidered; non-pharmacological interventions should be prioritized 3.
For agitation: Non-drug patient-centered care remains first-line treatment 1, 2.
For approved dementia medications: Cholinesterase inhibitors and memantine should be initiated or continued regardless of frailty status, as they target core cognitive symptoms rather than behavioral manifestations 5.