01. Pneumonia in Schizophrenia: Which Antipsychotics Pose the Highest Risk for?

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Pneumonia: An Overlooked Antipsychotic Side Effect

If you’re like me, pneumonia is probably not the first side effect you think of when you’re prescribing antipsychotics. I think much more commonly about a myriad of other side effects including weight gain, metabolic effects, hyperprolactinemia, extrapyramidal symptoms, QT prolongation, NMS and sudden death in older patients.

Nonetheless, it turns out that pneumonia is a significant risk in patients on a variety of antipsychotics, especially those with high anticholinergic burden and the risk appears to be dose dependent.

Study Examines Pneumonia Risk in Schizophrenia

The study used data from the Finnish registry, including patients aged 16 or older with diagnoses of schizophrenia or schizoaffective disorder. During the study period, almost, 9000 patients had more than 15,000 hospital admissions for pneumonia. Strikingly, about 13% of those hospitalized for pneumonia died within 30 days.

Risk Factors: Age, Gender, and Antipsychotics

The risk for pneumonia essentially doubled every five years starting at age 50. Risk for pneumonia was significantly higher for men, especially above age 40. One of the more unexpected results from the study is the finding that antipsychotic polypharmacy was not associated with an increased risk for pneumonia compared to no antipsychotic use. But antipsychotic monotherapy usage was and in a dose-dependent manner.

High-Risk Agents: Quetiapine, Clozapine, and Olanzapine

Looking at specific agents, pneumonia risk was highest with:

• quetiapine at doses greater than 440 mg
• clozapine at doses greater than 180 mg
• olanzapine at doses greater than 11 mg daily

The authors point out that these agents all have a high anticholinergic burden. None of the first-generation antipsychotics were associated with an increased risk.

Anticholinergic Effects Drive Pneumonia Risk

The findings of this study make it pretty clear that it’s the anticholinergic properties of antipsychotics that increase the risk for pneumonia via esophageal dysmotility and dilatation, as well as sedation.

The authors do point out that agents with anticholinergic effects also tend to have antihistaminergic effects so it’s not clear whether there is additional contribution from antihistaminergic properties including, for example, further heightened sedation.

Monotherapy vs. Polytherapy: Surprising Findings

Breaking it down further, the authors found that high-dose monotherapy though not low- or medium-dose monotherapy was associated with an increased risk.

In contrast, polypharmacy was not associated with an increased risk regardless of the total dose burden. These findings certainly seem strange and a little bit counterintuitive to me but the authors of the current study posit that the use of high-dose monotherapy leads to saturation of specific receptors, in this case cholinergic receptors, whereas polytherapy may be more likely to hit multiple different receptors without achieving saturation at any specific receptor group which might actually represent a lower risk in terms of pneumonia.

Implications for Clinical Practice

So where do we go from here?

It seems like it’s definitely worth considering closer monitoring for pneumonia risk in older patients, particularly men who are on higher doses of one of the three most implicated agents – quetiapine, clozapine, or olanzapine.

The authors suggest that at least asking patients about their swallowing and perhaps rudimentarily examining it in the office may be a reasonable starting point.

For patients who are on one of the high-risk regimens and develop pneumonia, it may be worth considering alternative regimens.

I would always caution against reflexively stopping medications that have been helpful in the setting of an adverse event, though.

Instead, careful consideration of the risks, benefits, and alternatives and discussion of such with the patients and the caregivers would seem like a more prudent approach.

Abstract

Pneumonia Risk, Antipsychotic Dosing, and Anticholinergic Burden in Schizophrenia

Jurjen J Luykx, M.D., Christoph U Correll, M.D., Peter Manu, M.D., Antti Tanskanen, M.D., Alkomiet Hasan, M.D., Jari Tiihonen, M.D., & Heidi Taipale, M.D.

Importance: Antipsychotic drugs (particularly clozapine) have been associated with pneumonia in observational studies. Despite studies of the associations between antipsychotic use and incident pneumonia, it remains unclear to what degree antipsychotic use is associated with increased risk of pneumonia, whether dose-response associations exist, and what agents are specifically associated with incident pneumonia.

Objective: To estimate pneumonia risk associated with specific antipsychotics and examine whether polytherapy, dosing, and receptor binding properties are associated with pneumonia in patients with schizophrenia.

Design, setting, and participants: This cohort study identified patients with schizophrenia or schizoaffective disorder (hereafter, schizophrenia) aged 16 years or older from nationwide Finnish registers from 1972 to 2014. Data on diagnoses, inpatient care, and specialized outpatient care were obtained from the Hospital Discharge Register. Information on outpatient medication dispensing was obtained from the Prescription Register. Study follow-up was from 1996 to 2017. Data were analyzed from November 4, 2022, to December 5, 2023.

Exposures: Use of specific antipsychotic monotherapies; antipsychotics modeled by dosage as low (<0.6 of the World Health Organization defined daily dose [DDD] per day), medium (0.6 to <1.1 DDDs per day), or high dose (≥1.1 DDDs per day); antipsychotic polypharmacy; and antipsychotics categorized according to their anticholinergic burden as low, medium, and high.

Main outcomes and measures: The primary outcome was hospitalization for incident pneumonia. Pneumonia risk was analyzed using adjusted, within-individual Cox proportional hazards regression models, with no antipsychotic use as the reference.

Results: The study included 61 889 persons with schizophrenia (mean [SD] age, 46.2 [16.0] years; 31 104 men [50.3%]). During 22 years of follow-up, 8917 patients (14.4%) had 1 or more hospitalizations for pneumonia and 1137 (12.8%) died within 30 days of admission. Compared with no antipsychotic use, any antipsychotic use overall was not associated with pneumonia (adjusted hazard ratio [AHR], 1.12; 95% CI, 0.99-1.26). Monotherapy use was associated with increased pneumonia risk compared with no antipsychotic use (AHR, 1.15 [95% CI, 1.02-1.30]; P = .03) in a dose-dependent manner, but polytherapy use was not. When categorized by anticholinergic burden, only the use of antipsychotics with a high anticholinergic burden was associated with pneumonia (AHR, 1.26 [95% CI, 1.10-1.45]; P < .001). Of specific drugs, high-dose quetiapine (AHR, 1.78 [95% CI, 1.22-2.60]; P = .003), high- and medium-dose clozapine (AHR, 1.44 [95% CI, 1.22-1.71]; P < .001 and AHR, 1.43 [95% CI, 1.18-1.74]; P < .001, respectively), and high-dose olanzapine (AHR, 1.29 [95% CI, 1.05-1.58]; P = .02) were associated with increased pneumonia risk.

Conclusions and relevance: Results of this cohort study suggest that in patients with schizophrenia, antipsychotic agents associated with pneumonia include not only clozapine (at dosages ≥180 mg/d) but also quetiapine (≥440 mg/d) and olanzapine (≥11 mg/d). Moreover, monotherapy antipsychotics and antipsychotics with high anticholinergic burden are associated with increased pneumonia risk in a dose-dependent manner. These findings call for prevention strategies aimed at patients with schizophrenia requiring high-risk antipsychotics.

Reference

Luykx, J. M.D., Correll, C. M.D., Manu, P. M.D., Tanskanen, A. M.D., Hasan, A. M.D., Tiihonen, J. M.D. & Taipale, H. M.D. (2024). 

Pneumonia Risk, Antipsychotic Dosing, and Anticholinergic Burden in Schizophrenia

. 

JAMA Psychiatry ;81

(10):967-975.