Schizophrenia Research 164 (2015) 275–276

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Letter to the Editor Recurrent urinary tract infections in acute psychosis

Dear Editors, Schizophrenia is associated with increased infections. This association appears to be bidirectional, as infection during childhood/adolescence is associated with increased schizophrenia risk (Nielsen et al., 2014), and schizophrenia is also a risk factor for infections (Benros et al., 2014).

Outside of schizophrenia, infections are also associated with acute psychosis, most notably geriatric patients with psychosis and comorbid urinary tract infection (UTI) in the context of dementia or delirium (Lipowski, 1980). Urologic infections are a risk factor for schizophrenia (Nielsen et al., 2014). We previously found an increased prevalence of UTI in acutely ill inpatients, but not stable outpatients with schizophrenia, versus controls (Miller et al., 2013b; Graham et al., 2014). Whether the association between UTI and acute psychosis in schizophrenia is a recurrent phenomenon has not been investigated.

Table 1 Demographic, clinical, and laboratory characteristics of the study sample. Variable

Level

Sex (n, %)

Male Female Caucasian African descent East/Southeast Asian Hispanic No Yes No Yes No Yes No Yes No Yes Advanced degree Some post-graduate 4 year college degree Some college HS diploma Some HS Through 8th grade Some grade school

Race (n, %)

Ever married (n, %) DM2 (n, %) Smoker (n, %) Alcohol (n, %) UDS positive (n, %) Highest education

Age (mean [SD]) BMI (mean [SD]) Education (mean [SD]) Hospitalizations during study period (mean [SD])

WBC Neutrophils (absolute) Lymphocytes (absolute) Monocytes (absolute) Eosinophils (absolute) Neutrophils (%) Lymphocytes (%) Monocytes (%) Eosinophils (%)

Subject group

p-Value

No UTI (n = 97)

1 UTI (n = 30)

≥2 UTIs (n = 25)

60 37 28 67 1 1 58 31 83 14 64 33 63 34 59 92 1 0 2 11 29 23 5 5 38.9 (11.7) 28.5 (8.1) 5.4 (1.2) 3.0 (1.5)

7 23 12 18 0 1 14 14 25 5 21 8 19 10 23 30 0 0 1 1 10 8 3 0 37.2 (11.0) 31.8 (10.4) 5.5 (0.9) 3.1 (1.4)

5 20 8 14 0 1 8 10 20 5 21 4 17 8 17 23 0 1 0 5 5 8 0 2 39.1 (12.0) 33.8 (13.2) 5.3 (1.4) 4.5 (2.1)

20.0% 80.0% 33.3% 58.3% 0.0% 0.0% 44.4% 55.6% 80.0% 20.0% 84.0% 16.0% 68.0% 32.0% 73.9% 26.1% 0.0% 4.8% 0.0% 23.8% 23.8% 38.1% 0.0% 9.5%

Admissions with UTI

Admissions without UTI

p-Value⁎

8.3 (2.7) 5.1 (1.9) 2.4 (0.9) 0.58 (0.25) 0.18 (0.16) 60 (9) 30 (9) 7.1 (2.6) 2.2 (2.4)

7.8 (3.1) 4.5 (2.3) 2.5 (0.9) 0.49 (0.19) 0.14 (0.13) 56 (11) 34 (11) 7.4 (3.6) 1.9 (17)

0.27 0.13 0.96 0.02 0.04 0.10 0.04 0.68 0.20

7.3 (2.0) 4.3 (1.7) 2.2 (0.7) 0.6 (0.2) 0.2 (0.1) 57.4 (10.9) 31.5 (9.5) 8.1 (2.0) 2.5 (2.0)

61.9% 38.1% 27.8% 69.1% 1.0% 0.0% 63.3% 34.4% 85.6% 14.4% 66.0% 34.0% 64.9% 35.1% 64.1% 35.9% 1.3% 0.0% 2.6% 14.5% 38.2% 30.3% 6.6% 6.6%

23.3% 76.7% 40.0% 60.0% 0.0% 0.0% 46.4% 50.0% 83.3% 16.7% 72.4% 27.6% 65.5% 34.5% 76.7% 23.3% 0.0% 0.0% 4.3% 4.3% 43.5% 34.8% 13.3% 0.0%

7.1 (2.1) 4.0 (1.7) 2.4 (0.7) 0.6 (0.2) 0.1 (0.1) 55.2 (10.0) 34.1 (10.1) 8.3 (2.4) 2.0 (1.3)

DM2 = diabetes mellitus, type 2. UDS = urine drug screen. ⁎ p-Values are for the difference between admissions with versus without UTI among subjects with recurrent UTI.

http://dx.doi.org/10.1016/j.schres.2015.02.018 0920-9964/© 2015 Elsevier B.V. All rights reserved.

b0.01 0.37

0.45 0.79 0.21 0.96 0.36 0.35

0.70 0.03 0.87 b0.01

276

Letter to the Editor

All subjects age 18–64 with ≥ 2 hospitalizations at our institution between 2008–2013 for schizophrenia or schizoaffective disorder were identified by chart review. Exclusion criteria have been reported elsewhere (Graham et al., 2014). The Georgia Regents University IRB approved the study, and a waiver of informed consent was granted. 345 patient records were screened, and 152 met study inclusion/exclusion criteria. UTI was defined as positive leukocyte esterase and/or nitrites and ≥ 5–10 leukocytes/high-powered field on urinalysis (Miller et al., 2013b; Graham et al., 2014). Subjects were trichotomized into 0, 1, and ≥2 UTI groups. Data on blood white blood cell (WBC) counts were also recorded for each admission. Associations between subject group and demographic, clinical, and laboratory variables were determined using chi-square or one-way ANOVA. For subjects with ≥2 UTIs, mean WBC counts were compared for admissions with and without UTI using a paired t-test, 2-sided. p-Values b0.05 were considered statistically significant, and were not corrected for multiple comparisons. Statistical analyses were performed using SPSS, version 22 (IBM SPSS, Chicago, Illinois). As shown in Table 1, 16% of subjects (n = 25) had ≥2 UTIs. Recurrent UTIs were associated with female sex, higher BMI, and more hospitalizations. These 25 subjects had a UTI on 59% (n = 64 of 109) of their admissions, and had significantly higher absolute monocyte (p = 0.02) and eosinophil (p = 0.04) counts, and lower differential lymphocytes (p = 0.04) during admissions with versus without UTI. A substantial proportion of patients with schizophrenia have recurrent UTIs at the time of hospitalization for acute psychosis. We also replicated our previous finding that blood differential WBC counts distinguish patients with versus without UTI, raising the possibility that the inflammatory response to infection may contribute to acute psychosis (Miller et al., 2013a). Limitations of this study are the small sample size, definition of UTI (based on urinalysis versus urine cultures), potential residual confounding (e.g., self-care and sexual activity), and non-standardized blood draws. The potential mechanism(s) underlying the association between UTI and acute psychosis remain largely unknown. Psychiatric disorders or psychotropic medications may result in physiologic changes that increase UTI risk. Acute psychosis may also result in behavioral changes that impact UTI risk (e.g., impaired hygiene or impulsivity). However, UTI may also precede and precipitate acute psychosis. UTI has been proposed as a sufficient cause for delirium (Lipowski, 1980), and may worsen neurologic deficits in patients with pre-existing neurologic disorders, (Hufschmidt et al., 2010). There are case reports of acute exacerbations of chronic schizophrenia that resolved with treatment of UTI (Rajagopalan and Varma, 1997; Reeves, 2007; Yeh et al., 2012). Our findings provide stronger support for the hypothesis that UTIs may be clinically relevant to acute psychosis, and highlight the potential importance of monitoring for UTI as a routine part of health screening in patients with schizophrenia. Longitudinal studies are needed to investigate issues of causality and temporality regarding this association. Role of funding source Direct funding for this study was provided in part by the Georgia Regents University Dean's Medical Scholars Program (Mr. Laney). This program had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Contributors Dr. Miller designed the study. Mr. Laney and Dr. Miller managed the literature searches. Mr. Laney and Mr. Philip reviewed and extracted data, which was verified by Dr. Miller. Dr. Miller managed the analyses. Mr. Laney and Dr. Miller wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript. Conflict of interest Mr. Laney received grant support from the Georgia Regents University Dean's Medical Scholars Program. Mr. Philip has nothing to disclose. Dr. Miller has nothing to disclose for the work under consideration. In the past 12 months, Dr. Miller has received grant support from the National Institute of Mental Health (K23MH098014); Research support from the National Institutes of Health Clinical Loan Repayment Program; and Speaker fees for grand round lectures from Emory University. Acknowledgments The authors wish to acknowledge Dr. Peter Buckley and Dr. Richard Cameron for their leadership of the GRU Dean's Medical Scholars Program.

References Benros, M.E., Pedersen, M.G., Rasmussen, H., Eaton, W.W., Nordentoft, M., Mortensen, P.B., 2014. A nationwide study on the risk of autoimmune diseases in individuals with a personal or a family history of schizophrenia and related psychosis. Am. J. Psychiatry 171 (2), 218–226. Graham, K.L., Carson, C.M., Ezeoke, A., Buckley, P.F., Miller, B.J., 2014. Urinary tract infections in acute psychosis. J. Clin. Psychiatry 75 (4), 379–385. Hufschmidt, A., Shabarin, V., Rauer, S., Zimmer, T., 2010. Neurological symptoms accompanying urinary tract infections. Eur. Neurol. 63 (3), 180–183. Lipowski, Z.J., 1980. Delirium due to infection. In: Lipowski, Z.J. (Ed.), Delirium: Acute Brain Failure in Man. Charles C Thomas, Springfield, pp. 409–425. Miller, B.J., Bodenheimer, C.M., Culpepper, N.H., Graham, K.L., Buckley, P.F., 2013a. Differential white blood cell counts may predict urinary tract infection in acute non-affective psychosis. Schizophr. Res. 147 (2–3), 400–401. Miller, B.J., Graham, K.L., Bodenheimer, C.M., Culpepper, N.H., Waller, J.L., Buckley, P.F., 2013b. A prevalence study of urinary tract infections in acute relapse of schizophrenia. J. Clin. Psychiatry 74 (3), 271–277. Nielsen, P.R., Benros, M.E., Mortensen, P.B., 2014. Hospital contacts with infection and risk of schizophrenia: a population-based cohort study with linkage of Danish national registers. Schizophr. Bull. 40 (6), 1526–1532. Rajagopalan, M., Varma, S.L., 1997. Urinary tract infection and delusion of pregnancy. Aust. N. Z. J. Psychiatry 31 (5), 775–776. Reeves, R.R., 2007. Exacerbation of psychotic symptoms associated with gatifloxacin. Psychosomatics 48 (1), 87. Yeh, Y.W., Kuo, S.C., Chen, C.Y., 2012. Urinary tract infection complicated by urine retention presenting as pseudocyesis in a schizophrenic patient. Gen. Hosp. Psychiatry 34 (1), 101.

Dan Laney Medical College of Georgia, Georgia Regents University, Augusta, GA, United States Niju Philip Brian J. Miller⁎ Department of Psychiatry and Health Behavior, Georgia Regents University, Augusta, GA, United States ⁎Corresponding author at: Department of Psychiatry and Health Behavior, Georgia Regents University, 997 Saint Sebastian Way, Augusta, Georgia 30912, United States. Tel.: +1 706 721 4445; fax: +1 706 721 6602. E-mail address: [email protected] (B.J. Miller) 24 October 2014

Recurrent urinary tract infections in acute psychosis.

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