Newer antipsychotics may increase the risk of pneumonia in schizophrenia

Pneumonia x-ray

Because of a more favourable side effects profile (not necessarily clinical superiority), second-generation antipsychotics (SGAs) are today the most commonly used drugs to treat psychotic disorders such as schizophrenia (Jones et al., 2006).

While rather frequent adverse reactions, including weight gain, diabetes or sedation, are largely recognised, recent studies point at increased risk of pneumonia in SGA treatment.

To aggregate more statistically sound knowledge on the association between SGAs and pneumonia, Kuo et al. (2013) have published a case-control study of a large cohort of people with schizophrenia.


Built on governmental medical and health insurance records, the authors selected patients with at least one psychiatric hospitalisation between 2000 and 2008, but not earlier (in line with market introduction of SGAs). From these, 33,024 patients between 18 and 65 years with a diagnosis of schizophrenia were extracted as the cohort.

Cases were defined as patients who developed pneumonia that required hospitalisation after first psychiatric admission (1,741) and compared to 6,949 matched controls. Critical period of SGA exposure was set to 30 days before hospitalisation for pneumonia.


Clozapine was associated with a three-fold increased risk of pneumonia

Clozapine was associated with a three-fold increased risk of pneumonia

  • The overall incidence of pneumonia in the study population was 1.12 cases/100 person-years
  • In general, current SGA treatment increases overall risk of developing pneumonia by 69%. Recent or past use (prescription ended 31-180 or more than 180 days before pneumonia-related hospitalisation) did not confer an increased risk
  • This was strongest in case of clozapine, which was associated with an 318% (adjusted risk ratio of 3.18) greater risk of developing pneumonia
  • Olanzapine (RR 1.83), quetiapine (RR 1.63), zotepine (RR 1.48), risperidone (RR 1.32)  but not amisulpride (RR 1.14) were associated with significantly increased risks
  • In the case of clozapine, there was evidence of a dose-dependent association
  • First-generation antipsychotics (e.g. haloperidol) were not associated with pneumonia requiring hospitalisation


The authors conclude that:

Accordingly, we found that clozapine was associated with high risk of pneumonia, that olanzapine, quetiapine, zotepine, and risperidone were associated with moderate risk, and that amisulpride was associated with low risk of developing pneumonia.


Treatment adherence was not assessed, so it is possible that some patients (especially when considering low individual tolerability of some antipsychotics) stopped taking their drugs. While this would, as Kuo et al. (2013) mention, most likely have resulted in an underestimated effect size, discontinuation symptoms might affect the results in a myriad of different ways.

Confounding variables such as smoking were not controlled for in the analysis

Confounding variables such as smoking were not controlled for in the analysis

What is more, some important confounding variables were not controlled for in the analysis. For instance, there is no information on tobacco history, which is itself is associated with pneumonia (Almirall et al., 1999).

Likewise, the fact that only pneumonia cases requiring hospitalisation were assessed, biases the sample towards extreme cases (and most likely more elderly patients).

Unfortunately, only cases with schizophrenia were included in the analysis, even though SGAs are also commonly prescribed in other disorders, including bipolar disorders or sometimes eating disorders. Scientifically speaking, the risk increases described by Kuo and colleagues are therefore limited to schizophrenic cases only.


This case control study underlines the need to fully inform patients about all possible side effects before starting SGA treatment. Especially during the first 30 days of treatment, patients should be more closely monitored for signs of respiratory pathology and pneumonia. While this risk is most pronounced with clozapine (and therefore most severely affects patients with treatment-resistant psychotic disorders), all other SGAs should not be neglected in patient care, irrespective of the diagnosis they are prescribed for.


Kuo, C.-J., Yang, S.-Y., Liao, Y.-T., Chen, W.J., Lee, W.-C., Shau, W.-Y., et al. (2013). Second-generation antipsychotic medications and risk of pneumonia in schizophrenia. Schizophrenia Bulletin39(3), 648-657. [Abstract]

Almirall, J., Gonzalez, C.A., Balanzo, X., & Bolibar, I. (1999). Proportion of community-acquired pneumonia cases attributable to tobacco smoking (PDF). Chest, 116, 375-379.

Jones, P.B., Barnes, T.R., Davies, L., Dunn, G., Lloyd, H., Hayhurst, K.P., et al. (2006). Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1) (PDF). Arch Gen Psychiatry, 63(10), 1079-87.

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