Carefully Weighing the Adverse Outcomes of Antipsychotics in Patients with Dementia

Authors:
Melissa C. Palmer, PharmD, BCPS, BCPP
Jessa Marie Koch, PharmD, APh, BCPP

Reviewers:
Kalin M. Clifford, PharmD, BCGP, BCPS
Stuart T. Haines, PharmD, BCPS, BCACP

Citation: Mok PLH, Carr MJ, Guthrie B, et al. Multiple adverse outcomes associated with antipsychotic use in people with dementia: population based matched cohort study. BMJ. 2024;385:e076268.

The Problem

By 2050, an astounding 150 million people globally are projected to be living with dementia, presenting a profound challenge to healthcare systems worldwide.¹ One of the most debilitating aspects of the disease is the prevalence of behavioral and psychological symptoms of dementia (BPSD), which impacts nearly 90% of patients.² These symptoms significantly diminish the quality of life and functional abilities of those affected. To combat the most severe of these symptoms, antipsychotic medications are often prescribed, but not without possibly harmful consequences. Given the frequency with which these patients and their healthcare advocates seek treatment, there is a need for a deeper understanding of BPSD management to improve patient care and outcomes.  

What’s Known

Behavioral and psychological symptoms of dementia (BPSD) include a wide spectrum from apathy, depression, sleep problems, and anxiety to aggression, paranoia, and delusions. ² Guidelines recommend non-pharmacological strategies first, which include social interaction, relaxation, sensory therapy, structured activities, behavioral therapy, and sleep hygiene based on the predominant BPSD exhibited by the individual.²

Pharmacological interventions are reserved for patients with severe agitation and/or aggression that could lead to harm to oneself or others and severe depression. Based upon multiple studies, the FDA, in 2008, added a boxed warning to all antipsychotics about increased mortality when used in patients for dementia-related psychosis.  A patient-centric evaluation of risk and benefit is necessary, determining if treatment with an antipsychotic is warranted, and should only be prescribed when the patient or their caregiver has consented to its use.  Guidelines recommend that when starting an antipsychotic, the lowest dose should be initiated with slow dose titration to the lowest effective dose.² If there is no significant response to therapy with an antipsychotic after four weeks, the medication should be gradually tapered to discontinuation. Gradual dose reductions should also be attempted after three months of therapy.² 

What’s New

In a recent population-based matched cohort study from the UK, adults at least 50 years of age diagnosed with dementia (1998-2018) were matched based on antipsychotic use (i.e. antipsychotic used versus non-use) and their safety outcomes compared. Electronic health record data was used to obtain general practice, hospital admission, and mortality data. The outcomes of interest were stroke, venous thromboembolism, myocardial infarction, heart failure, ventricular arrhythmia, bone fracture, pneumonia, and acute kidney injury. The follow-up period started with the index date,  which was the date of the first antipsychotic prescription (in the antipsychotic user group). Patients started on antipsychotics were matched with up to 15 patients, using incidence density sampling. The matched patients had the same approximate date of dementia diagnosis but had not been prescribed an antipsychotic. Of note, individuals who had previously experienced one of the outcomes before the index date were excluded from the analysis of that outcome. Additionally, patients prescribed anticholinesterase inhibitors prior to their first dementia diagnosis were also excluded. 

A total of 173,910 adults (63% women) were identified for inclusion. Of these, approximately 20% were prescribed an antipsychotic. Three-quarters of the prescribed antipsychotics were atypicals (i.e., second-generation antipsychotics). Risperidone and haloperidol are licensed for use to treat BPSD in the UK, and in the US, only brexpiprazole is FDA-approved for agitation associated with dementia due to Alzheimer’s Disease. Use of all other antipsychotics for this indication is off-label. 

For all antipsychotics, the adverse outcomes with the highest incidence rates after treatment initiation were pneumonia, fracture, and stroke. The incidence of ventricular arrhythmias was rare, and not associated with increased risk. When the outcomes were evaluated by time, the highest relative hazards were within the first seven days after initiation of antipsychotics. The risk for pneumonia (HR = 9.99, 8.78-11.40) was most significant during the first seven days. (See table 1). 

Table 1: Adjusted Hazard Ratios (HR) and 95% Confidence Interval for Adverse Outcomes Associated with Antipsychotic Use Stratified by Time

Outcome	0-7 days	31-180 days	366 days-2 years
Pneumonia
Current Use	9.99 (8.78-11.40)	2.03 (1.89-2.17)	1.71 (1.58-1.85)
Recent Use		1.93 (1.63-2.29)	1.40 (1.14-1.72)
Past Use			1.48 (1.32-1.67)
Stroke
Current Use	3.75 (3.00-4.69)	1.54 (1.39-1.70)	1.55 (1.38-1.74)
Recent Use		1.72 (1.35-2.20)	1.32 (0.98-1.79)
Past Use			1.04 (0.85-1.28)
Venous Thromboembolism
Current Use	2.05 (1.19-3.56)	1.67 (1.41-1.99)	1.61 (1.33-1.96)
Recent Use		2.14 (1.46-3.15)	1.58 (1.01-2.48)
Past Use			0.95 (0.67-1.35)
Myocardial Infarction
Current Use	2.33 (1.41-3.83)	1.27 (1.06-1.52)	1.02 (0.83-1.27)
Recent Use		0.89 (0.52-1.52)	1.28 (0.80-2.03)
Past Use			0.91 (0.66-1.25)
Heart Failure
Current Use	2.85 (2.15-3.78)	1.32 (1.17-1.49)	0.97 (0.82-1.14)
Recent Use		0.99 (0.72-1.37)	0.80 (0.54-1.20)
Past Use			0.81(0.63-1.04)
Fracture
Current Use	2.22 (1.66-2.98)	1.37 (1.24-1.52)	1.53 (1.38-1.71)
Recent Use		1.07 (0.82-1.41)	1.61 (1.25-2.07)
Past Use			1.07 (0.89-1.28)
Acute Kidney Injury
Current Use	3.79 (2.96-4.87)	2.03 (1.84-2.25)	1.26 (1.10-1.44)
Recent Use		1.36 (1.03-1.81)	1.23 (0.85-1.79)
Past Use			1.08 (0.88-1.32)

When comparing outcomes between patients taking typical versus atypical antipsychotics, hazard ratios were higher in patients on typical antipsychotics for stroke, heart failure, fracture, pneumonia, and acute kidney injury.  For any antipsychotic use, the number needed to harm was <10 for pneumonia during the first 180 days of antipsychotic use (See Table 2). 

Table 2: Number Needed to Harm (NNH) for Adverse Outcomes Associated with Antipsychotic Use During the First 180 days and After Two Years of Follow-up

Outcome	NNH at 180 days (95% CI)	NNH at Two years (95% CI)
Pneumonia	9 (9-10)	15 (14-16)
Stroke	29 (25-35)	41 (36-47)
Acute kidney injury	35 (30-42)	84 (70-105)
Fracture	40 (32-54)	45 (38-55)
Heart Failure	63 (50-86)	166 (122-260)
Venous thromboembolism	107 (83-149)	167 (134-221)
Myocardial infarction	167 (116-301)	254 (183-413)
Ventricular arrhythmia	No difference	No difference

Our Critical Appraisal

The increased risk of morbidity and mortality associated with antipsychotics has been consistently demonstrated in previous studies, albeit with varying levels of evidence for various conditions. Before this study, the literature was either inconclusive or limited for conditions including myocardial infarction, ventricular arrhythmia, venous thromboembolism, fracture, and acute kidney injury. This study echoes some published findings from numerous studies, including a modest and time-limited increase in myocardial infarction.³ However, a previous study found an association between antipsychotic use in dementia and ventricular arrhythmia / sudden cardiac death in an age-diverse patient population.⁴ Notably, the authors of this analysis did not examine sudden cardiac death or cardiac arrest.  They found stroke risk was highest within the first week of antipsychotic initiation and remained elevated over the two-year follow-up. A meta-analysis found increased stroke risk in the general population but not among patients with dementia.  The association with venous thromboembolism is consistent with a Welsh study in which risk was increased the year following antipsychotic initiation.⁶ Pneumonia results were particularly striking, with the most significant risk within the first week of drug initiation.  This is a concerning finding but may have been due to reverse causality (e.g., delirium from pneumonia leads to antipsychotic use). Overall, the general magnitude of risk for pneumonia was comparable with pre-existing literature.⁷ Acute kidney injury findings were similar to two studies also finding increased risk in the 90 days following initiation.⁸ Studies on fracture risk postulate that increased falls may not be entirely due to the medication itself.⁹ To date, heart failure has been primarily linked to clozapine use.¹⁰ The current study found an increased risk of heart failure only with current antipsychotic use, not recent or past. 

The strengths of this study included the broad assessment of safety outcomes and the use of a very large primary care database that captured hospitalization and mortality data. This enhances generalizability. However, due to the observational nature, confounding cannot be eliminated. The indication for antipsychotic use could not be determined, although exclusion criteria eliminated patients prescribed an antipsychotic in the year prior to their dementia diagnosis. The authors attempted to control for confounding through propensity score methods. However, this can be inadequate in the case of unobserved differences between antipsychotic users and matched comparators. No mention was made of statistical analysis to control for multiple comparisons. 

The study authors weigh the increased risks of harms against the “modest” benefit of using antipsychotics for BPSD. They recommend using the NNH data to help make these risk-benefit decisions.  Similar to current guidelines, we believe regularly reviewing the treatment plan is critical, not just before treatment initiation but during maintenance.  Given the high rates of adverse effects within the first week of antipsychotic use (including mortality), clinicians should be readily available for clinical assessment and have a care plan in place.

The Bottom Line

This study (yet again) documents that antipsychotic use in patients with dementia is associated with higher risks of stroke, venous thromboembolism, myocardial infarction, heart failure, fracture, pneumonia, and acute kidney injury. The risk was highest in the first week following antipsychotic initiation, particularly pneumonia. These data can inform risk-benefit discussions with patients and their caregivers.  Patient/caregiver education regarding warning signs and close follow-up after initiating antipsychotics for the treatment of BPSD is imperative.

The Key Points

• The risk of pneumonia, stroke, venous thromboembolism, fracture, and acute kidney injury may remain elevated up to two years following antipsychotic initiation in patients with dementia.
• Invoke patient-centered care principles; obtain informed consent for the use of antipsychotics in the treatment of BPSD. 
• Educate patients and caregivers on red flag signs and symptoms (i.e. F.A.S.T., constitutional symptoms, fall risk, etc.) and highlight extra awareness during the first week of antipsychotic therapy.

FINAL NOTE:  This program will be available for recertification credit through the American Pharmacists Association (APhA) Board Prep and Recertification Program.  To learn more, visit the APhA Geriatric Board Prep and Recertification website and sign up for the Evidence-Based Practice Series.

References