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For peer review only

Increased Perforated Appendicitis in Patients with

Schizophrenia: A Case Control Analysis (1985-2013)

Journal: BMJ Open

Manuscript ID bmjopen-2017-017150

Article Type: Research

Date Submitted by the Author: 25-Apr-2017

Complete List of Authors: Nishihira, Masafumi McGill, Rita Kinjo, Mitsuyo; Okinawa Chubu Hospital, Rheumatology

<b>Primary Subject Heading</b>:

Emergency medicine

Secondary Subject Heading: Surgery, Mental health

Keywords: appendectomy, Schizophrenia & psychotic disorders < PSYCHIATRY, Adult surgery < SURGERY

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Increased Perforated Appendicitis in Patients with Schizophrenia: A Case Control

Analysis (1985-2013)

Yoshimasa Nishihira1, Rita L. McGIll2, Mitsuyo Kinjo3

1. Department of Psychiatry, Okinawa Chubu Hospital, Japan

2. Division of Nephrology, University of Chicago, USA

3. Department of Medicine, Division of Rheumatology, Okinawa Chubu Hospital,

Japan

Corresponding Author: Yoshimasa Nishihira, MD

Mailing address:

Okinawa Chubu Hospital

281 Azamiyasato Uruma City, Okinawa, 904-2293 Japan

Phone: 81-98-973-4111

Fax: 81-98-973-2703

Email:

Y Nishihira: [email protected]

M Kinjo: [email protected]

Word count 2,225 words

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ABSTRACT

Objective

Altered pain sensitivity may affect the outcome of appendicitis in patients with

schizophrenia. We aim to compare the prevalence of perforation in appendicitis between

patients with and without schizophrenia.

Design

Case Control Analysis

Setting

A single tertiary medical center in Japan

Participants

From 1985-2013, total of 1,821 cases of appendicitis requiring appendectomy were

collected, of whom schizophrenic patients and randomly selected control subjects

without schizophrenia who underwent appendectomy were identified.

Primary and secondary outcome measures

The primary outcome was the rate of perforated appendicitis in patients with and

without schizophrenia. Secondary outcome was the odds of perforated appendicitis by

different clinical factors.

Results

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62 schizophrenia patients and randomly sampled 200 non-schizophrenic patients were

compared.The prevalence of perforation was 55% in patients with schizophrenia vs 18%

in controls (P<0.0001). The adjusted odds ratio (OR) for perforation was 4.73 (95% CI:

2.23-10.0) in schizophrenia; 3.69 (95% CI: 1.62-8.43) for age >55 years; and for

delayed presentation 2.19 (95% CI: 1.11-4.30).

Conclusion

Appendiceal perforation was more frequent in schizophrenic patients than controls,

which may be partly attributable to delayed presentation and altered responses to pain.

Strengths and limitations of this study

� This is one of a few case-controlled studies with real-world clinical data that

evaluated ruptured appendicitis and its complication among schizophrenic patients.

� Detailed clinical parameters with surgical outcome during three decades of clinical

practice allow us to address the magnitude of schizophrenia on excess adverse

outcome independent of other risk factors that may vary over time.

� The retrospective collection of clinical factors is subject to recall bias and other

biases.

� We lack data concerning potential differences in the time course of hospital

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evaluation, and whether the diagnosis of schizophrenia impeded progression of the

diagnostic process.

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Introduction

Early diagnosis of appendicitis is necessary in order to prevent increased

surgical morbidity and mortality due to abscess and perforation1. The mortality of

appendicitis has been estimated at 2.4 per million and the morbidity has been estimated

at 7.7 to 17.8 per million2 3

.

Schizophrenia is a psychiatric disorder consisting of chronic or recurrent

psychosis that affects 15 per 100,000 persons. The median life time morbidity risk for

schizophrenia is 7.2 per 1,000 persons4. Schizophrenic patients have often been noted to

have decreased perception of pain with altered expression of the emotional response to

pain. Pain insensitivity (hypoalgesia) has been described in psychotic disorders since

the early 20th

century 5,6

. Kraepelin noted that patients often become less sensitive to

body discomfort: “They endure uncomfortable positions, pricks of needles, injuries,

without thinking much of it.”6 Bleuler observed unusual self-mutilation such as eye

enucleation and auto-castration and noted the “complete analgesia” in patients with

schizophrenia5. Prior studies indicated diagnostic and surgical delay of somatic

problems may often be encountered among schizophrenia patients7,8

. Schizophrenic

patients who require appendectomy have a high rate of perforation and other adverse

outcomes9. Tsay and his colleagues reported that the rate of appendiceal perforation was

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46.7% among schizophrenic cohort and 25.1% among patients without major

psychiatric disorders, suggesting that schizophrenia was associated with a 2.83 times

higher risk of having a ruptured appendix10

. Cooke et al reported a 66% perforation rate

in a case series of appendicitis in schizophrenic patients9. Smoking and comorbid

conditions such as diabetes and obesity are commonly seen in schizophrenia, and may

partly explain the higher rates of appendiceal rupture. The increased rate of

complications in schizophrenia has been consistent, but the contributions of pain

insensitivity and delayed access to medical care have not been defined.

This case control study was designed to examine the clinical characteristics of

appendicitis in schizophrenic subjects, and to compare the rate of complications to

patients without schizophrenia.

Methods

Study Subjects

All patients > 18 years old who had an appendectomy for suspected appendicitis from

1985-2013 were collected retrospectively from the record system at Okinawa Chubu

Hospital, a tertiary medical center in Japan. We stratified patients as to whether

schizophrenia was present, defined as a diagnosis rendered by a psychiatrist or

prescription of antipsychotic medication. The diagnosis of schizophrenia corresponded

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to DSM-4 text revision (DSM4-TR) criteria. Sixty-two schizophrenic patients and 1,759

control subjects without schizophrenia who underwent appendectomy during the

observation period were identified. Two hundred patients were randomly selected as

controls. This study was approved by the Institutional Ethics Committee of Okinawa

Chubu Hospital.

Diagnosis of Appendicitis and Clinical Characteristics

Data collected included the presenting history and physical examination, results of

computed tomography (CT) or ultrasound studies performed prior to surgery.

Appendicitis was confirmed by surgical and pathological findings, and the presence of

rupture or abscess was noted. Patient characteristics were recorded including age,

gender, smoking, body mass index (kg/m2), history of diabetes, and date of

appendectomy. Tobacco use was reported by patients and was dichotomized current vs.

former/never. Diabetes was self-reported. Clinical characteristics of appendicitis that

were collected included abdominal pain, nausea, vomiting. The duration of abdominal

symptoms at the time of emergency department presentation was categorized as either 2

days or longer vs. less than 2 days; vital signs including temperature of 38°C or higher

and tachycardia >100 beats per minute; signs of peritoneal irritation including guarding

and rebound tenderness; leukocytosis (white blood cell count > 10,000/µl). Ultrasound

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or CT findings were recorded, with note of whether appendicitis was reported to be

likely. Medication use was ascertained, including antipsychotic drugs (clozapine,

olanzapine, risperidone, chlorpromazine hydrochloride, levomepromazine, haloperidol,

perospirone, zotepine), benzodiazepine, serotonin selective reuptake inhibitors (SSRI),

tricyclic antidepressants, anticholinergics, corticosteroids and nonsteroidal

anti-inflammatory drugs (NSAIDs).

Statistical analysis

Sample size calculations were based on a 30% frequency of perforation in

appendicitis in general population and a 66% frequency of perforated appendicitis in

schizophrenia 10

. Detecting differences of this magnitude with 80% or 90% power

yielded sample sizes of 29 and 39 patients per group. Controls were selected randomly

from all non-schizophrenic patients, using a table of random numbers. Continuous

variables were compared using Student’s t-test and categorical variable by a two-sided

Fisher’s exact test, as appropriate; all tests were performed at a 5% level of significance.

Logistic regression was performed to assess the odds ratio for perforation

between schizophrenic and non-schizophrenic patients, controlling for age, gender,

body mass index, diabetes, and smoking. All analyses were performed using R (R

Foundation for Statistical Computing, Vienna, Austria https://www.R-project.org/),

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using the EZR statistical interface, version 2.13.0, and STATA version14.2, Texas, USA.

Results

Sixty-two cases of appendicitis in schizophrenic patients were detected, and these cases

were compared with 200 controls. Among schizophrenic patients, the mean age was

43.5 years and 40% were female; in controls, mean age was 40.2 years and 49% were

female (P>0.15 for both comparisons). Baseline characteristics of both groups are

shown in Table 1. Compared to controls, the patients with schizophrenia were more

likely to be current smokers and have diabetes. Most patients with schizophrenia

reported abdominal pain. Consistent with their underlying psychiatric diagnosis, the use

of neuroleptics, anxiolytics, and anti-cholinergic drugs was higher in the schizophrenic

group, but the use of anti-depressants was infrequent in both groups.

Clinical characteristics during the emergency department presentation are

provided in Table 2. Compared to controls, patients with schizophrenia were more likely

to be febrile and tachycardic, and had a higher frequency of guarding upon abdominal

examination. Rebound tenderness was common in both groups (83% vs 73%, P=0.07).

Leukocytosis did not differ between groups. Compared to controls, patients with

schizophrenia were significantly more likely to report that the duration of symptoms

was greater than 48 hours prior to ED presentation (47% vs 25%, P=0.004).

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The unadjusted odds of having perforated appendicitis were 2.9 times higher in

patients aged 55 or older, 3.1 times higher for delayed presentation, and 5.6 times higher

in patients with schizophrenia (Table 3). Schizophrenia remained the strongest risk

factor for perforation, even after adjustment for age, gender, body mass index, diabetes,

and tobacco use (adjusted OR=4.73, 95% CI 2.23, 10.0), however, adjusting for delayed

presentation in our model attenuated the association between schizophrenia and

perforation (OR=2.19, 95% CI 1.11, 4.30). Among schizophrenic patients, the odds of

perforation did not differ between early vs delayed presentation (53% vs 57%, p=0.8).

Once diagnosed, schizophrenic patients were more likely to have longer hospital length

of stay, more post-operative complications, and unfavorable histopathology (Table 4).

The rate of ruptured appendicitis did not differ before and after the year 2000

(58% vs 52%, p=0.79 in schizophrenia, 19% vs 12%, p=0.7 in controls), when CT scan

began to be used more frequently for the diagnosis of appendicitis.

Discussion

This case control study described the features of appendicitis in patients with

schizophrenia. We demonstrated patients with schizophrenia had substantially greater

odds of having perforation at the time of operation independent of known risk factors

such as age, smoking or diabetes, compared to non-schizophrenics. Most patients with

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schizophrenia reported classic abdominal symptoms. This study provided insights into

the poor outcomes experienced by this vulnerable patient group.

Contrary to the notion that schizophrenic patients are insensitive to pain and

somatic sensation11 12

, the present study demonstrated that most patients with

schizophrenia presented with classic symptoms of appendicitis including abdominal

pain as reported previously9. In our study, some clinical signs such as fever, tachycardia,

and abdominal guarding were more pronounced in schizophrenics. About half (47%) of

schizophrenic patients took more than 2 days to access hospital care after the onset of

abdominal symptoms, so delay in seeking medical attention may partly explain the

discrepant clinical presentation and higher incidence of perforated appendicitis in

schizophrenia.

Diabetes and tobacco use have been associated with increased risk of

perforation in appendicitis13-15

. Our findings are concordant with other studies in which

schizophrenic patients are more likely to be overweight, diabetic, and less likely to

adhere to a healthy lifestyle16

. Bushe reported the prevalence of diabetes was

approximately 15% in a sample of schizophrenic patients17

. In another study, 65-79% of

schizophrenic patients were reported to be smokers18

. Despite this, our data showed that

adjustment for traditional risk factors did not attenuate the association of schizophrenia

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with increased appendiceal rupture. Schizophrenia was more strongly associated with

ruptured appendicitis than any of the other variables we evaluated.

The increased risk of perforation in schizophrenia was attenuated when the

model was adjusted for delayed presentation, suggesting that schizophrenic patients

may be systematically less likely to seek medical care in response to abdominal pain.

Delayed presentation has been associated with the risk of perforation in other

populations19

. Nearly all of our schizophrenic patients reported abdominal pain,

contradicting the notion that they don’t experience pain. However, patients with

schizophrenia may have abnormal perception and reporting of pain, which may be

related to medications or the underlying psychiatric disorder20

. Delay in seeking medical

attention may be partially attributable to altered pain sensitivity in schizophrenia. Lack

of insurance and financial restrictions are minimized under the national health care

system in Japan, but our data do not permit us to speculate upon non-financial factors

such as perceptions of stigma in the health care setting. Our data contrast with those of

Marchand, who reported that 37% of schizophrenia patients with appendicitis reported

no pain21

.

Once hospitalized, schizophrenic patients with appendicitis had more

unfavorable surgical findings, and had poorer outcomes with increased complications.

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Our data are consistent with those of Daumit et al, who noted that schizophrenic

patients have a greater than 2-fold risk of major avoidable in-hospital complications22

.

Patients with schizophrenia suffered from more medical complications and longer

lengths of stay, partially reflecting later presentation with more advanced inflammatory

deterioration of the appendix and surrounding tissues. Regardless of the timing of

presentation, however, our data indicate that there is still substantial excess risk of

perforation associated with schizophrenia. We cannot rule out the possibility that the

pathophysiology of appendicitis may be different in schizophrenic patients, due to

alterations in the microbiome or altered inflammatory responses11,12

.

Our data do not permit us to draw conclusions about the associations between

antipsychotic medication use or severity of schizophrenia and appendicitis perforation.

Schizophrenic patients tend to have more severe psychiatric symptoms in the inpatient

setting, and often require increased medications. However, our results show that the rate

of perforation did not differ between hospitalized and non-hospitalized schizophrenic

patients (50% vs 71% p=0.11), suggesting that schizophrenia itself, rather than the

medications for schizophrenia, is a risk factor for perforated appendicitis.

There are several strengths in this study. First, this is one of a few controlled

studies that evaluated ruptured appendicitis and its complication among schizophrenic

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patients. Second, detailed clinical parameters with surgical outcome during three

decades of clinical practice allow us to address the magnitude of schizophrenia on

excess adverse outcome independent of other risk factors that may vary over time.

Several limitations merit discussion. The retrospective collection of risk factors

is subject to recall bias and other biases. However, our data showed proportions of

current smokers and diabetes in schizophrenia that were similar to other studies. We

also lack data concerning potential differences in the time course of hospital evaluation,

and whether the diagnosis of schizophrenia impeded progression of the diagnostic

process. We also lack sufficient data to define the effects of neuroleptics, antipsychotics

or benzodiazepines and other medications on pain sensitivity.

In conclusion, schizophrenia patients are at high risk for perforation and other

complications of appendicitis, due in part to delayed presentation with more advanced

inflammation. Further work may reveal strategies to improve outcomes in these

vulnerable patients.

Acknowledgement

Katsumi Oyafuso, Koichiro Gibo, Kensuke Nakanishi, Yoshihiko Raita, Eitaro Jiroku,

Shinichiro Ueda, Tsuyoshi Morimoto, Miori Sakuma, Lisa M Rucker

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Thomas Lynn Hurt, Lawrence Tierney

A. Contributorship statement:

Dr. Nishihira contributed to study design, extracted clinical data from medical

documents, analyzed and wrote final document.

Dr. McGill analyzed data and wrote final document.

Dr. Kinjo contributed the research, and the final document.

B. Competing interests: none

C. Funding: none

D. Data sharing statement: No additional data available

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References

1. Von Titte SN, McCabe CJ, Ottinger LW. Delayed appendectomy for appendicitis: causes

and consequences. The American journal of emergency medicine 1996;14(7):620-2.

doi: 10.1016/s0735-6757(96)90074-1 [published Online First: 1996/11/01]

2. Lee SL, Ho HS. Acute appendicitis: is there a difference between children and adults? The

American surgeon 2006;72(5):409-13.

3. Pieper R, Kager L, Näsman P. Acute appendicitis: a clinical study of 1018 cases of

emergency appendectomy. Acta Chirurgica Scandinavica 1982;148(1):51-62.

4. McGrath J, Saha S, Chant D, et al. Schizophrenia: a concise overview of incidence,

prevalence, and mortality. Epidemiologic reviews 2008;30:67-76. doi:

10.1093/epirev/mxn001 [published Online First: 2008/05/16]

5. Bleuler E. Dementia praecox or the group of schizophrenias. 1950

6. Kraepelin E. Dementia praecox and paraphrenia: Krieger Publishing Company 1971.

7. Bickerstaff LK, Harris SC, Leggett RS, et al. Pain insensitivity in schizophrenic patients:

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8. Farasatpour M, Janardhan R, Williams CD, et al. Breast cancer in patients with

schizophrenia. The American Journal of Surgery 2013;206(5):798-804.

9. Cooke BK, Magas LT, Virgo KS, et al. Appendectomy for appendicitis in patients with

schizophrenia. American journal of surgery 2007;193(1):41-8. doi:

10.1016/j.amjsurg.2006.06.034 [published Online First: 2006/12/26]

10. Tsay J-H, Lee C-H, Hsu Y-J, et al. Disparities in appendicitis rupture rate among

mentally ill patients. BMC Public Health 2007;7(1):331.

11. Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia:

a systematic quantitative review. Biological psychiatry 2008;63(8):801-08.

12. Fillman S, Cloonan N, Catts V, et al. Increased inflammatory markers identified in the

dorsolateral prefrontal cortex of individuals with schizophrenia. Molecular

psychiatry 2013;18(2):206-14.

13. Sadr Azodi O, Lindström D, Adami J, et al. Impact of body mass index and tobacco

smoking on outcome after open appendicectomy. British journal of surgery

2008;95(6):751-57.

14. Tsai S-H, Hsu C-W, Chen S-C, et al. Complicated acute appendicitis in diabetic patients.

The American Journal of Surgery 2008;196(1):34-39.

15. Buchman T, Zuidema G. Reasons for delay of the diagnosis of acute appendicitis. Surgery,

gynecology & obstetrics 1984;158(3):260-66.

16. Dickerson F, Brown C, Kreyenbuhl J, et al. Obesity among individuals with serious

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mental illness. Acta Psychiatrica Scandinavica 2006;113(4):306-13.

17. Bushe C, Holt R. Prevalence of diabetes and impaired glucose tolerance in patients with

schizophrenia. The British Journal of Psychiatry 2004;184(47):s67-s71.

18. McCREADIE RG. Use of drugs, alcohol and tobacco by people with schizophrenia:

case—control study. The British Journal of Psychiatry 2002;181(4):321-25.

19. Bickell NA, Aufses AH, Rojas M, et al. How time affects the risk of rupture in

appendicitis. Journal of the American College of Surgeons 2006;202(3):401-06.

20. Singh MK, Giles LL, Nasrallah HA. Pain insensitivity in schizophrenia: trait or state

marker? Journal of Psychiatric Practice® 2006;12(2):90-102.

21. Marghand WE. Occurrence of painless myocardial infarction in psychotic patients. New

England Journal of Medicine 1955;253(2):51-55.

22. Daumit GL, Pronovost PJ, Anthony CB, et al. Adverse events during medical and

surgical hospitalizations for persons with schizophrenia. Archives of General

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Table 1: Baseline Characteristics of Patients with Appendicitis,

by Presence or Absence of Schizophrenia

Schizophrenia Controls P

(N=62) (N=200)

Age, mean (std) 43.5 11.6 40.2 17.1 0.16

n % n %

Female n (%) 25 40 93 49 0.5

BMI>25 21 38 53 27 0.3

Current tobacco 45 74 93 47 0.0004

Diabetes 8 13 6 3 0.006

Medications

Neuroleptic 62 100 0 0 <0.0001

Benzodiazepine 38 73 4 2 <0.0001

Anticholinergic 45 85 0 0 <0.0001

SSRI 0 0 1 1 1

TCA 2 4 1 1 0.14

NSAID 2 4 3 2 0.3

Glucocorticoids 0 0 4 2 0.6

Abbreviations: Standard deviation (std), Body Mass Index (BMI),

selective serotonin reuptake inhibitors (SSRI), tricyclic

antidepressants (TCA), Non-steroidal Anti-Inflammatory Drugs

(NSAID)

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Table 2: Preoperative Findings in Patients with and without Schizophrenia

Schizophrenia Controls

N % N % P

Temp> 38.0 C 25 40 38 19 0.001

Abdominal pain 61 98 199 100 1.0

Nausea/vomiting 32 65 129 70 0.07

Pulse>100/min 37 61 31 16 <0.0001

Rebound tenderness 48 83 175 73 0.07

Guarding 35 65 37 32 <0.0001

WBC > 10,000/µL 48 77 153 78 1.0

Delayed presentation* 28 47 50 25 0.004

*Delayed presentation defined as more than 48 hours of symptoms prior to

presentation for care.

Abbreviations: Temperature (temp), white blood count (WBC)

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Table 3. Odds of Perforated Appendicitis by clinical factors

Characteristics Unadjusted Odds Ratio (95%CI) Fully Adjusted Odds Ratio (95%CI)*

Age＞＞＞＞55 2.93 (1.51-5.70) 3.69 (1.62-8.43)

Male sex 1.16 (0.67-2.02) 1.31 (0.66-2.55)

Diabetes Mellitus 2.95 (0.92-9.50) 1.18 (0.30-4.66)

Body mass index>25 1.70 (0.92-3.14) 1.59 (0.80-3.18)

Current smoker 1.61 (0.91-2.84) 1.38 (0.69-2.76)

Schizophrenia 5.66 (3.02-10.6) 4.73 (2.23-10.0)

Time of presentation

>48 hours 3.13 (1.74-5.63) 2.19 (1.11-4.30)

*Age, Gender, Diabetes, Smoking, Body Mass Index, Time of presentation, Schizophrenia

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Table 4: Characteristics of perforated appendicitis and hospitalization, by presence or

absence of schizophrenia


N % N % P

Perforation 33 55 35 18 <0.0001

Hospital length of stay > 7 days 43 69 72 36 <0.0001

Death 0 0 1 1 1

Wound healing by secondary intention 35 56 45 23 <0.0001

Wound infection 0 0 7 4 0.2

Appendiceal tear at operation 2 3 8 4 1

Suppurative ascites 27 44 25 13 <0.0001

Intra-abdominal abscess 19 31 15 8 <0.0001

Bacteremia/sepsis 5 8 4 2 0.04

Re-operation 3 5 0 0 0.01

Respiratory arrest 1 2 0 0 0.2

Gangrenous or necrotic appendicitis 27 43 29 15 <0.0001

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Increased Perforated Appendicitis in Patients with

Schizophrenia

Journal: BMJ Open

Manuscript ID bmjopen-2017-017150.R1


Date Submitted by the Author: 16-Jun-2017

Complete List of Authors: Nishihira, Masafumi McGill, Rita Kinjo, Mitsuyo; Okinawa Chubu Hospital, Rheumatology


Emergency medicine


Keywords: appendectomy, Schizophrenia & psychotic disorders < PSYCHIATRY, Adult surgery < SURGERY


BMJ Open on A

pril 25, 2021 by guest. Protected by copyright.

http://bmjopen.bm

j.com/

BM

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1

Increased Perforated Appendicitis in Patients with Schizophrenia

Yoshimasa Nishihira1, Rita L. McGill

2, Mitsuyo Kinjo

3



3. Department of Medicine, Division of Rheumatology, Okinawa Chubu Hospital,

Japan


Mailing address:



Phone: 81-98-973-4111

Fax: 81-98-973-2703

Email:




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ABSTRACT

Objective


schizophrenia. We aimed to compare the prevalence of perforation in appendicitis

between patients with and without schizophrenia.

Design

Retrospective cohort study with random matching.

Setting

A single tertiary medical center in Japan.

Participants

From 1985-2013, 1,821 cases of appendicitis requiring appendectomy were collected.

Schizophrenic patients and a cohort of randomly selected control subjects without

schizophrenia who underwent appendectomy were identified.


The primary outcome was the rate of perforated appendicitis in patients with and

without schizophrenia. Secondary outcome was the odds of perforated appendicitis by

different clinical factors.

Results

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compared. The prevalence of perforation was 53% in patients with schizophrenia vs

17% in controls (P<0.0001). The adjusted odds ratio (OR) for perforation were 4.87

(95% CI: 2.33-10.2) for schizophrenia, 3.35 (95% CI: 1.51-7.45) for age >55 years, and

2.18 (95% CI: 1.12-4.27) for delayed presentation.

Conclusion




� This is one of few retrospective cohort studies with random matching using

real-world clinical data to evaluate ruptured appendicitis and its complications

among schizophrenic patients.

� Detailed clinical parameters correlated with surgical outcome during three decades

of clinical practice allow us to address the magnitude of schizophrenia on excess

adverse outcome independent of other risk factors that may vary over time.


biases.

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diagnostic process.

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INTRODUCTION



appendicitis has been estimated at 2.4 per million and the morbidity has been estimated

at 7.7 to 17.8 per million2 3

.





pain. Pain insensitivity (hypoalgesia) has been described in psychotic disorders since

the early 20th

century 5,6

. Kraepelin noted that patients often become less sensitive to

body discomfort: “They endure uncomfortable positions, pricks of needles, injuries,

without thinking much of it.”6 Bleuler observed unusual self-mutilation such as eye

enucleation and auto-castration and noted the “complete analgesia” in patients with

schizophrenia5. Prior studies indicated diagnostic and surgical delay of somatic

problems may often be encountered among schizophrenia patients7,8

. Schizophrenic

patients who require appendectomy have a high rate of perforation and other adverse

outcomes9. Tsay and his colleagues reported that the rate of appendiceal perforation was

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46.7% among schizophrenic cohort and 25.1% among patients without major

psychiatric disorders, suggesting that schizophrenia was associated with a 2.83 times

higher risk of having a ruptured appendix10

. Cooke et al reported a 66% perforation rate

in a case series of appendicitis in schizophrenic patients9. Smoking and comorbid

conditions such as diabetes and obesity are commonly seen in schizophrenia, and may

partly explain the higher rates of appendiceal rupture. The increased rate of

complications in schizophrenia has been consistent, but the contributions of pain

insensitivity and delayed access to medical care have not been defined.

This retrospective cohort study was designed to examine the clinical

characteristics of appendicitis in schizophrenic subjects, and to compare the rate of

complications to patients without schizophrenia.

METHODS

Study Subjects




schizophrenia was present, defined as a diagnosis rendered by a psychiatrist with the

confirmation an antipsychotic medication prescription. In no cases, were antipsychotic

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medications prescribed for any control subjects. The diagnosis of schizophrenia

corresponded to DSM-4 text revision (DSM4-TR) criteria. Sixty-two schizophrenic

patients and 1,759 control subjects without schizophrenia who underwent

appendectomy during the observation period were identified. Two hundred patients

were randomly selected as controls. This study was approved by the Institutional Ethics

Committee of Okinawa Chubu Hospital.


Data collected included the presenting history and physical examination findings, and

the results of computed tomography (CT) or ultrasound studies performed prior to

surgery. Most appendectomy was performed as open surgery and only a few patients

underwent laparoscopic intervention in our cohort. Appendicitis was confirmed by

surgical and pathological findings, and the presence of rupture or abscess was noted.

Perforated appendicitis was defined either intraoperatively or post-operatively, based

upon pathological findings. Patient characteristics were recorded including age, gender,

smoking, body mass index (kg/m2), history of diabetes, and date of appendectomy.

Tobacco use was reported by patients and was dichotomized as current vs. former/never.

Diabetes was self-reported. Clinical characteristics of appendicitis that were collected

included abdominal pain, nausea, vomiting. The duration of abdominal symptoms at the

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time of emergency department presentation was categorized as either 2 days or longer

vs. less than 2 days; The duration from ED presentation to operating room was

categorized as either 12 hours or longer vs. less than 12 hours; vital signs including

temperature of 38°C or higher and tachycardia >100 beats per minute; signs of

peritoneal irritation including guarding and rebound tenderness; leukocytosis (white

blood cell count > 10,000/µl). Ultrasound or CT findings were recorded, with note of

whether appendicitis was reported to be likely. Medication use was ascertained,

including antipsychotic drugs (clozapine, olanzapine, risperidone, chlorpromazine

hydrochloride, levomepromazine, haloperidol, perospirone, zotepine), benzodiazepine,

serotonin selective reuptake inhibitors (SSRI), tricyclic antidepressants, anticholinergics,

corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs).




schizophrenia 10

. Detecting differences of this magnitude with 80% or 90% power

yielded sample sizes of 29 and 39 patients per group. Controls were selected randomly

from all non-schizophrenic patients, using a table of random numbers. Continuous

variables were compared using Student’s t-test and categorical variable by a two-sided

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Fisher’s exact test, as appropriate; all tests were performed at a 5% level of significance.


between schizophrenic and non-schizophrenic patients, controlling for age, gender,

body mass index, diabetes, smoking, and time of presentation. In sensitivity analysis, a

second cohort of age matched controls was selected from the base non-schizophrenic

population, with three controls for each schizophrenic subject, and a conditional logistic

regression was performed.

All analyses were performed using R with no additional packages installed (R

Foundation for Statistical Computing, Vienna, Austria https://www.R-project.org/),

using the EZR statistical interface, version 2.13.0. The same analysis was replicated

using STATA version 14.2, Texas, USA.

RESULTS


were compared with 200 controls. Among schizophrenic patients, the mean age was

43.5 years and 40% were female; in controls, mean age was 40.2 years and 46% were

female (P>0.15 for both comparisons). Baseline characteristics of both groups are

shown in Table 1. Compared to controls, the patients with schizophrenia were more

likely to be current smokers and have diabetes. Most patients with schizophrenia

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reported abdominal pain. Consistent with their underlying psychiatric diagnosis, the use

of neuroleptics, anxiolytics, and anti-cholinergic drugs was higher in the schizophrenic

group, but the use of anti-depressants was infrequent in both groups.






schizophrenia were significantly more likely to report that the duration of symptoms

was greater than 48 hours prior to ED presentation (47% vs 25%, P=0.002). Time from

ED to operating room was not different between groups (31% vs 24%, P=0.3)


patients aged 55 or older, 2.99 times higher for delayed presentation, and 5.56 times

higher in patients with schizophrenia (Table 3). Schizophrenia remained the strongest

risk factor for perforation, even after adjustment for age, gender, body mass index,

diabetes, or tobacco use (OR=5.42, 95%CI 2.66, 11.1). However, adjusting for delayed


perforation (OR=4.87, 95% CI 2.33-10.2). Among schizophrenic patients, the odds of

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Once diagnosed, schizophrenic patients were more likely to have longer hospital lengths




for the diagnosis of appendicitis became more readily available, with better image

quality.

Sensitivity Analysis

In our sensitivity analysis using a cohort of matched controls and adjusting for the same

demographic and clinical factors (including time of presentation), age >55 was no

longer a risk for perforation (OR=0.77, 95% CI 0.14, 4.22). However, schizophrenia

remained a significant risk factor (OR=2.96, 95% CI 1.39, 6.27) as well as delayed

presentation (OR=4.46, 95% CI 2.30, 8.64).

DISCUSSION

This retrospective cohort study described the features of appendicitis in

patients with schizophrenia and demonstrated that patients with schizophrenia had

substantially greater odds of having perforation. Increased risk at the time of operation

was independent of known risk factors such as age, smoking or diabetes, compared to

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non-schizophrenics. Most patients with schizophrenia reported classic abdominal

symptoms. This study provided insights into the poor outcomes experienced by this

vulnerable patient group.




schizophrenia presented with classic symptoms of appendicitis including abdominal

pain as reported previously9. In our study, some clinical signs such as fever, tachycardia,

and abdominal guarding were more pronounced in schizophrenics. About half (47%) of




schizophrenia.

Diabetes and tobacco use have been associated with increased risk of

perforation in appendicitis13-15


schizophrenic patients are more likely to be overweight, diabetic, and less likely to

adhere to a healthy lifestyle16

. Bushe reported the prevalence of diabetes was

approximately 15% in a sample of schizophrenic patients17

. In another study, 65-79% of

schizophrenic patients were reported to be smokers18

. Despite this, our data showed that

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adjustment for traditional risk factors did not attenuate the association of schizophrenia

with increased appendiceal rupture. Schizophrenia was more strongly associated with

ruptured appendicitis than any other variable we evaluated.


model was adjusted for delayed presentation, suggesting that schizophrenic patients

may be systematically less likely to seek medical care in response to abdominal pain.

Delayed presentation has been associated with the risk of perforation in other

populations19

. Nearly all of our schizophrenic patients reported abdominal pain,

contradicting the notion that they don’t experience pain. However, patients with

schizophrenia may have abnormal perception and reporting of pain, which may be

related to medications or the underlying psychiatric disorder20

. Delay in seeking medical

attention may be partially attributable to altered pain sensitivity in schizophrenia. Our

data contrast with those of Marchand, who reported that 37% of schizophrenia patients

with appendicitis reported no pain21

. Lack of insurance and financial restrictions are

minimized under the universal health care system in Japan, which confers support for

living costs and medical expenditures for patients diagnosed with schizophrenia.

However, our data do not permit us to speculate upon non-financial factors such as

perceptions of stigma in the health care setting.

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Our data are consistent with those of Daumit et al, who noted that schizophrenic

patients have a greater than 2-fold risk of major avoidable in-hospital complications22

.

Patients with schizophrenia suffered from more medical complications and longer

lengths of stay, partially reflecting later presentation with more advanced inflammatory

deterioration of the appendix and surrounding tissues. Regardless of the timing of

presentation, however, our data indicate that there is still substantial excess risk of

perforation associated with schizophrenia. We cannot rule out the possibility that the

pathophysiology of appendicitis may be different in schizophrenic patients, due to

alterations in the microbiome or altered inflammatory responses11,12

.


antipsychotic medication use, or severity of schizophrenia, and appendiceal perforation.

Schizophrenic patients tended to have more severe psychiatric symptoms in the

inpatient setting, and often required increased medications. However, our results show

that the rate of perforation did not differ between hospitalized and non-hospitalized

schizophrenic patients (50% vs 71% p=0.11), suggesting that schizophrenia itself, rather

than the medications for schizophrenia, is a risk factor for perforated appendicitis.

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There are several strengths in this study. First, this is one of a few cohort

studies that has evaluated ruptured appendicitis and its complications among

schizophrenic patients. Second, detailed clinical parameters with surgical outcome

during three decades of clinical practice allow us to address the magnitude of

schizophrenia on excess adverse outcome independent of other risk factors that may

vary over time.


is subject to recall bias and other biases. However, our data showed proportions of

current smokers and diabetes in schizophrenia that were similar to other studies. We did

not have data concerning potential differences in dietary habits, the time course of

hospital evaluation, and whether the diagnosis of schizophrenia impeded progression of

the diagnostic process. We also lacked sufficient data to define the effects of

neuroleptics, antipsychotics or benzodiazepines and other medications on pain

sensitivity.





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Acknowledgement

Koichiro Gibo, Yoshihiko Raita for assistance with data analysis, Eitaro Jiroku, Naoko

Hentona for data collection, Katsumi Oyafuso, Shinichiro Ueda, Tsuyoshi Morimoto,

Mio Sakuma for advice about study design, as well as Lisa M Rucker, Thomas Lynn

Hurt, and Lawrence Tierney for advice on manuscript content.




Dr. McGill analyzed data and assisted with composition of the final document.

Dr. Kinjo contributed to the research question, study design, and the final document.

B. Competing interests: None Declared

C. Funding: none


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References






















11. Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia:

a systematic quantitative review. Biological psychiatry 2008;63(8):801-08.



psychiatry 2013;18(2):206-14.



2008;95(6):751-57.






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Psychiatry 2006;63(3):267-72.

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(N=62) (N=200)

Age, mean (std) 43.5 11.6 40.2 17.1 0.17

N % n %

Female n (%) 25 40 92 46 0.48

BMI>25 21 38 52 27 0.13


Diabetes 8 13 6 3 0.006

Medications

Neuroleptic 62 100 0 0 <0.0001



SSRI 0 0 1 1 1

TCA 2 4 1 1 0.11

NSAID 2 4 3 2 0.28





(NSAID)

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N % N % P

Temp> 38.0 C 25 40 38 19 0.001

Abdominal pain 61 98 199 100 0.24


Pulse>100/min 37 61 31 16 <0.0001


Guarding 35 65 37 32 0.0001

WBC > 10,000/µL 48 77 152 77 1.0


Delayed ED to OR ** 18 31 45 24 0.3



**Delayed Emergency Department (ED) to Operating Room (OR) defined as

greater than 12 hours of ED stay prior to appendectomy


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Age＞＞＞＞55 2.7 (1.42-5.23) 3.35 (1.51-7.45)

Female sex 1.09 (0.63-1.91) 1.16 (0.60-2.23)


Body mass index>25 1.57 (0.87-2.72) 1.41 (0.71-2.81)

Current smoker 1.54 (0.87-2.72) 1.23 (0.62-2.46)

Schizophrenia 5.56 (2.99-10.3) 4.87 (2.33-10.2)


>48 hours 2.99 (1.66-5.63) 2.18 (1.12-4.27)

*Age, Gender, Diabetes, Smoking, Body Mass Index, Schizophrenia, Time of presentation

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N % N % P

Perforation 33 53 34 17 <0.0001


Death 0 0 1 1 1




Suppurative ascites 1 1 2 1 0.56






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Perforated Appendicitis in Patients with Schizophrenia: a

retrospective cohort study

Journal: BMJ Open

Manuscript ID bmjopen-2017-017150.R2


Date Submitted by the Author: 28-Jun-2017

Complete List of Authors: Nishihira, Masafumi; Okinawa Chubu Hospital, Department of Psychiatry McGill, Rita; University of Chicago Medical Center, Department of medicine, Division of nephrology Kinjo, Mitsuyo; Okinawa Chubu Hospital, Rheumatology


Emergency medicine


Keywords: appendectomy, Schizophrenia & psychotic disorders < PSYCHIATRY, Adult

surgery < SURGERY


BMJ Open on A

pril 25, 2021 by guest. Protected by copyright.

http://bmjopen.bm

j.com/

BM

J Open: first published as 10.1136/bm

jopen-2017-017150 on 25 Septem

ber 2017. Dow

nloaded from



1

Perforated Appendicitis in Patients with Schizophrenia: a retrospective cohort

study

Yoshimasa Nishihira1, Rita L. McGill

2, Mitsuyo Kinjo

3



3. Department of Medicine, Division of Rheumatology, Okinawa Chubu Hospital, Japan


Mailing address:



Phone: 81-98-973-4111

Fax: 81-98-973-2703

Email:




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ABSTRACT

Objective


schizophrenia. We aimed to compare the prevalence of perforation in appendicitis

between patients with and without schizophrenia.

Design

Retrospective cohort study with random matching.

Setting

A single tertiary medical center in Japan.

Participants

From 1985-2013, 1,821 cases of appendicitis requiring appendectomy were collected.

Schizophrenic patients and a cohort of randomly selected control subjects without

schizophrenia who underwent appendectomy were identified.


The primary outcome was the rate of perforated appendicitis in patients with and without

schizophrenia. Secondary outcome was the odds of perforated appendicitis by different

clinical factors.

Results

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compared. The prevalence of perforation was 53% in patients with schizophrenia vs 17%

in controls (P<0.0001). The adjusted odds ratio (OR) for perforation were 4.87 (95% CI:

2.33-10.2) for schizophrenia, 3.35 (95% CI: 1.51-7.45) for age >55 years, and 2.18 (95%

CI: 1.12-4.27) for delayed presentation.

Conclusion




� This is one of few retrospective cohort studies with random matching using

real-world clinical data to evaluate ruptured appendicitis and its complications

among schizophrenic patients.

� Detailed clinical parameters correlated with surgical outcome during three decades

of clinical practice allow us to address the magnitude of schizophrenia on excess

adverse outcome independent of other risk factors that may vary over time.


biases.

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diagnostic process.

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5

INTRODUCTION



appendicitis has been estimated at 2.4 per million and the morbidity has been estimated at

7.7 to 17.8 per million2 3

.





pain. Pain insensitivity (hypoalgesia) has been described in psychotic disorders since the

early 20th

century 5,6

. Kraepelin noted that patients often become less sensitive to body

discomfort: “They endure uncomfortable positions, pricks of needles, injuries, without

thinking much of it.”6 Bleuler observed unusual self-mutilation such as eye enucleation

and auto-castration and noted the “complete analgesia” in patients with schizophrenia5.

Prior studies indicated diagnostic and surgical delay of somatic problems may often be

encountered among schizophrenia patients7,8

. Schizophrenic patients who require

appendectomy have a high rate of perforation and other adverse outcomes9. Tsay and his

colleagues reported that the rate of appendiceal perforation was 46.7% among

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schizophrenic cohort and 25.1% among patients without major psychiatric disorders,

suggesting that schizophrenia was associated with a 2.83 times higher risk of having a

ruptured appendix10

. Cooke et al reported a 66% perforation rate in a case series of

appendicitis in schizophrenic patients9. Smoking and comorbid conditions such as

diabetes and obesity are commonly seen in schizophrenia, and may partly explain the

higher rates of appendiceal rupture. The increased rate of complications in schizophrenia

has been consistent, but the contributions of pain insensitivity and delayed access to

medical care have not been defined.

This retrospective cohort study was designed to examine the clinical

characteristics of appendicitis in schizophrenic subjects, and to compare the rate of

complications to patients without schizophrenia.

METHODS

Study Subjects




schizophrenia was present, defined as a diagnosis rendered by a psychiatrist with the

confirmation an antipsychotic medication prescription. In no cases, were antipsychotic

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medications prescribed for any control subjects. The diagnosis of schizophrenia

corresponded to DSM-4 text revision (DSM4-TR) criteria. Sixty-two schizophrenic

patients and 1,759 control subjects without schizophrenia who underwent appendectomy

during the observation period were identified. Two hundred patients were randomly

selected as controls. This study was approved by the Institutional Ethics Committee of

Okinawa Chubu Hospital.


Data collected included the presenting history and physical examination findings, and the

results of computed tomography (CT) or ultrasound studies performed prior to surgery.

Most appendectomy was performed as open surgery and only a few patients underwent

laparoscopic intervention in our cohort. Appendicitis was confirmed by surgical and

pathological findings, and the presence of rupture or abscess was noted. Perforated

appendicitis was defined either intraoperatively or post-operatively, based upon

pathological findings. Patient characteristics were recorded including age, gender,

smoking, body mass index (kg/m2), history of diabetes, and date of appendectomy.

Tobacco use was reported by patients and was dichotomized as current vs. former/never.

Diabetes was self-reported. Clinical characteristics of appendicitis that were collected

included abdominal pain, nausea, vomiting. The duration of abdominal symptoms at the

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time of emergency department presentation was categorized as either 2 days or longer vs.

less than 2 days; The duration from ED presentation to operating room was categorized as

either 12 hours or longer vs. less than 12 hours; vital signs including temperature of 38°C

or higher and tachycardia >100 beats per minute; signs of peritoneal irritation including

guarding and rebound tenderness; leukocytosis (white blood cell count > 10,000/µl).

Ultrasound or CT findings were recorded, with note of whether appendicitis was reported

to be likely. Medication use was ascertained, including antipsychotic drugs (clozapine,

olanzapine, risperidone, chlorpromazine hydrochloride, levomepromazine, haloperidol,

perospirone, zotepine), benzodiazepine, serotonin selective reuptake inhibitors (SSRI),

tricyclic antidepressants, anticholinergics, corticosteroids and nonsteroidal

anti-inflammatory drugs (NSAIDs).




schizophrenia 10

. Detecting differences of this magnitude with 80% or 90% power yielded

sample sizes of 29 and 39 patients per group. Controls were selected randomly from all

non-schizophrenic patients, using a table of random numbers. Continuous variables were

compared using Student’s t-test and categorical variable by a two-sided Fisher’s exact test,

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as appropriate; all tests were performed at a 5% level of significance.


between schizophrenic and non-schizophrenic patients, controlling for age, gender, body

mass index, diabetes, smoking, and time of presentation. In sensitivity analysis, a second

cohort of age matched controls was selected from the base non-schizophrenic population,

with three controls for each schizophrenic subject, and a conditional logistic regression

was performed.

All analyses were performed using R with no additional packages installed (R

Foundation for Statistical Computing, Vienna, Austria https://www.R-project.org/), using

the EZR statistical interface, version 2.13.0. The same analysis was replicated using

STATA version 14.2, Texas, USA.

RESULTS


were compared with 200 controls. Among schizophrenic patients, the mean age was 43.5

years and 40% were female; in controls, mean age was 40.2 years and 46% were female

(P>0.15 for both comparisons). Baseline characteristics of both groups are shown in

Table 1. Compared to controls, the patients with schizophrenia were more likely to be

current smokers and have diabetes. Most patients with schizophrenia reported abdominal

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pain. Consistent with their underlying psychiatric diagnosis, the use of neuroleptics,

anxiolytics, and anti-cholinergic drugs was higher in the schizophrenic group, but the use

of anti-depressants was infrequent in both groups.






schizophrenia were significantly more likely to report that the duration of symptoms was

greater than 48 hours prior to ED presentation (47% vs 25%, P=0.002). Time from ED to

operating room was not different between groups (31% vs 24%, P=0.3)


patients aged 55 or older, 2.99 times higher for delayed presentation, and 5.56 times

higher in patients with schizophrenia (Table 3). Schizophrenia remained the strongest risk

factor for perforation, even after adjustment for age, gender, body mass index, diabetes,

or tobacco use (OR=5.42, 95%CI 2.66, 11.1). However, adjusting for delayed


perforation (OR=4.87, 95% CI 2.33-10.2). Among schizophrenic patients, the odds of

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Once diagnosed, schizophrenic patients were more likely to have longer hospital lengths




for the diagnosis of appendicitis became more readily available, with better image

quality.

Sensitivity Analysis

In our sensitivity analysis using a cohort of matched controls and adjusting for the same

demographic and clinical factors (including time of presentation), age >55 was no longer

a risk for perforation (OR=0.77, 95% CI 0.14, 4.22). However, schizophrenia remained a

significant risk factor (OR=2.96, 95% CI 1.39, 6.27) as well as delayed presentation

(OR=4.46, 95% CI 2.30, 8.64).

DISCUSSION

This retrospective cohort study described the features of appendicitis in patients

with schizophrenia and demonstrated that patients with schizophrenia had substantially

greater odds of having perforation. Increased risk at the time of operation was

independent of known risk factors such as age, smoking or diabetes, compared to

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non-schizophrenics. Most patients with schizophrenia reported classic abdominal

symptoms. This study provided insights into the poor outcomes experienced by this

vulnerable patient group.




schizophrenia presented with classic symptoms of appendicitis including abdominal pain

as reported previously9. In our study, some clinical signs such as fever, tachycardia, and

abdominal guarding were more pronounced in schizophrenics. About half (47%) of




schizophrenia.

Diabetes and tobacco use have been associated with increased risk of perforation

in appendicitis13-15


schizophrenic patients are more likely to be overweight, diabetic, and less likely to adhere

to a healthy lifestyle16

. Bushe reported the prevalence of diabetes was approximately 15%

in a sample of schizophrenic patients17

. In another study, 65-79% of schizophrenic

patients were reported to be smokers18

. Despite this, our data showed that adjustment for

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traditional risk factors did not attenuate the association of schizophrenia with increased

appendiceal rupture. Schizophrenia was more strongly associated with ruptured

appendicitis than any other variable we evaluated.


model was adjusted for delayed presentation, suggesting that schizophrenic patients may

be systematically less likely to seek medical care in response to abdominal pain. Delayed

presentation has been associated with the risk of perforation in other populations19

.

Nearly all of our schizophrenic patients reported abdominal pain, contradicting the notion

that they don’t experience pain. However, patients with schizophrenia may have

abnormal perception and reporting of pain, which may be related to medications or the

underlying psychiatric disorder20

. Delay in seeking medical attention may be partially

attributable to altered pain sensitivity in schizophrenia. Our data contrast with those of

Marchand, who reported that 37% of schizophrenia patients with appendicitis reported no

pain21

. Lack of insurance and financial restrictions are minimized under the universal

health care system in Japan, which confers support for living costs and medical

expenditures for patients diagnosed with schizophrenia. However, our data do not permit

us to speculate upon non-financial factors such as perceptions of stigma in the health care

setting.

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Our data are consistent with those of Daumit et al, who noted that schizophrenic patients

have a greater than 2-fold risk of major avoidable in-hospital complications22

. Patients

with schizophrenia suffered from more medical complications and longer lengths of stay,

partially reflecting later presentation with more advanced inflammatory deterioration of

the appendix and surrounding tissues. Regardless of the timing of presentation, however,

our data indicate that there is still substantial excess risk of perforation associated with

schizophrenia. We cannot rule out the possibility that the pathophysiology of appendicitis

may be different in schizophrenic patients, due to alterations in the microbiome or altered

inflammatory responses11,12

.


antipsychotic medication use, or severity of schizophrenia, and appendiceal perforation.

Schizophrenic patients tended to have more severe psychiatric symptoms in the inpatient

setting, and often required increased medications. However, our results show that the rate

of perforation did not differ between hospitalized and non-hospitalized schizophrenic

patients (50% vs 71% p=0.11), suggesting that schizophrenia itself, rather than the

medications for schizophrenia, is a risk factor for perforated appendicitis.

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There are several strengths in this study. First, this is one of a few cohort studies

that has evaluated ruptured appendicitis and its complications among schizophrenic

patients. Second, detailed clinical parameters with surgical outcome during three decades

of clinical practice allow us to address the magnitude of schizophrenia on excess adverse

outcome independent of other risk factors that may vary over time.


is subject to recall bias and other biases. However, our data showed proportions of current

smokers and diabetes in schizophrenia that were similar to other studies. We did not have

data concerning potential differences in dietary habits, the time course of hospital


diagnostic process. We also lacked sufficient data to define the effects of neuroleptics,

antipsychotics or benzodiazepines and other medications on pain sensitivity.





Acknowledgement

Koichiro Gibo, Yoshihiko Raita for assistance with data analysis, Eitaro Jiroku, Naoko

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Hentona for data collection, Katsumi Oyafuso, Shinichiro Ueda, Tsuyoshi Morimoto,

Mio Sakuma for advice about study design, as well as Lisa M Rucker, Thomas Lynn Hurt,

and Lawrence Tierney for advice on manuscript content.




Dr. McGill analyzed data and assisted with composition of the final document.

Dr. Kinjo contributed to the research question, study design, and the final document.

B. Competing interests: None Declared

C. Funding: none


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References






















11. Potvin S, Stip E, Sepehry AA, et al. Inflammatory cytokine alterations in schizophrenia: a

systematic quantitative review. Biological psychiatry 2008;63(8):801-08.



psychiatry 2013;18(2):206-14.



2008;95(6):751-57.






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Psychiatry 2006;63(3):267-72.

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(N=62) (N=200)

Age, mean (std) 43.5 11.6 40.2 17.1 0.17

N % n %

Female n (%) 25 40 92 46 0.48

BMI>25 21 38 52 27 0.13


Diabetes 8 13 6 3 0.006

Medications

Neuroleptic 62 100 0 0 <0.0001



SSRI 0 0 1 1 1

TCA 2 4 1 1 0.11

NSAID 2 4 3 2 0.28





(NSAID)

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N % N % P

Temp> 38.0 C 25 40 38 19 0.001

Abdominal pain 61 98 199 100 0.24


Pulse>100/min 37 61 31 16 <0.0001


Guarding 35 65 37 32 0.0001

WBC > 10,000/µL 48 77 152 77 1.0


Delayed ED to OR ** 18 31 45 24 0.3



**Delayed Emergency Department (ED) to Operating Room (OR) defined as

greater than 12 hours of ED stay prior to appendectomy


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Age＞＞＞＞55 2.7 (1.42-5.23) 3.35 (1.51-7.45)

Female sex 1.09 (0.63-1.91) 1.16 (0.60-2.23)


Body mass index>25 1.57 (0.87-2.72) 1.41 (0.71-2.81)

Current smoker 1.54 (0.87-2.72) 1.23 (0.62-2.46)

Schizophrenia 5.56 (2.99-10.3) 4.87 (2.33-10.2)


>48 hours 2.99 (1.66-5.63) 2.18 (1.12-4.27)

*Age, Gender, Diabetes, Smoking, Body Mass Index, Schizophrenia, Time of presentation

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N % N % P

Perforation 33 53 34 17 <0.0001


Death 0 0 1 1 1




Suppurative ascites 1 1 2 1 0.56






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STROBE Statement—Checklist of items that should be included in reports of cohort studies

Item

No Recommendation

Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract

Page1.3.

(b) Provide in the abstract an informative and balanced summary of what was done

and what was found

Page3

Introduction

Background/rationale 2 Explain the scientific background and rationale for the investigation being reported

Page 5,6

Objectives 3 State specific objectives, including any prespecified hypotheses

Page 6

Methods

Study design 4 Present key elements of study design early in the paper

Page 6

Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment,

exposure, follow-up, and data collection

Page 6, 7

Participants 6 (a) Give the eligibility criteria, and the sources and methods of selection of

participants. Describe methods of follow-up

Page 6,7

(b) For matched studies, give matching criteria and number of exposed and

unexposed

Page 9

Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect

modifiers. Give diagnostic criteria, if applicable

Page 7,8

Data sources/

measurement

8* For each variable of interest, give sources of data and details of methods of

assessment (measurement). Describe comparability of assessment methods if there is

more than one group

Page 7,8

Bias 9 Describe any efforts to address potential sources of bias

Page 15

Study size 10 Explain how the study size was arrived at

Page 8

Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable,

describe which groupings were chosen and why

Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding

Page 9

(b) Describe any methods used to examine subgroups and interactions

Page

(c) Explain how missing data were addressed

Page 8

(d) If applicable, explain how loss to follow-up was addressed

(e) Describe any sensitivity analyses

Page 9

Results

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Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially

eligible, examined for eligibility, confirmed eligible, included in the study,

completing follow-up, and analysed

Page 9

(b) Give reasons for non-participation at each stage

(c) Consider use of a flow diagram

Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and

information on exposures and potential confounders

Page 9, 10

(b) Indicate number of participants with missing data for each variable of interest

(c) Summarise follow-up time (eg, average and total amount)

Outcome data 15* Report numbers of outcome events or summary measures over time

Page 10

Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and

their precision (eg, 95% confidence interval). Make clear which confounders were

adjusted for and why they were included

Page 10 and Table 3

(b) Report category boundaries when continuous variables were categorized

(c) If relevant, consider translating estimates of relative risk into absolute risk for a

meaningful time period

Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and

sensitivity analyses

Page 11

Discussion

Key results 18 Summarise key results with reference to study objectives

Page 11-12

Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or

imprecision. Discuss both direction and magnitude of any potential bias

Page 15

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations,

multiplicity of analyses, results from similar studies, and other relevant evidence

Page 15

Generalisability 21 Discuss the generalisability (external validity) of the study results

Other information

Funding 22 Give the source of funding and the role of the funders for the present study and, if

applicable, for the original study on which the present article is based

*Give information separately for exposed and unexposed groups.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and

published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely

available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is

available at http://www.strobe-statement.org.

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Documents

When an article is published we post the peer reviewers ...This case control study was designed to examine the clinical characteristics of appendicitis in schizophrenic subjects, and