Rogers, M. Et Al (2013) Depression, Antidepressant Medications, And Risk of Clostridium Difficile Infection. BMC Medecine

8/18/2019 Rogers, M. Et Al (2013) Depression, Antidepressant Medications, And Risk of Clostridium Difficile Infection. BMC M…

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Depression, antidepressant medications, and risk

of Clostridium difcile infection

Mary A M Rogers1*, M Todd Greene1, Vincent B Young1, Sanjay Saint12, Kennet M

!anga12, "on Y Kao1 and Da#id M Arono$ 1

• *Corresponding author: Mary A M Rogers [email protected]

Author Afliations

1Department o !nternal Medicine, "ni#ersity o Michigan, $1%&''$( )CRC, Ann Aror, M!

'+1$&2+$$, "-A

2Ann Aror eterans A/airs Medical Center, Ann Aror, M!, "-A

(mail: Mary A M Rogers [email protected] & M 0odd reene [email protected] & incent

3oung young#[email protected] & -an4ay -aint [email protected] & 5enneth M [email protected] &

8ohn 3 5ao [email protected] & Da#id M Arono/ darono/@umich.edu

BMC Medicine 2$19, %%:121 doi:1$.11+%1;'1&;$1


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0he population&ased rate o CD! in older Americans =as 2+2.1$$,$$$ person&years B>!s and histamine&2 receptor antagonists BL2RAs I'J. Anti&depressants ha#e also een

implicated in this inection I


3/14

Study %e conducted a longitudinal study to determine population rates o CD! in indi#iduals =ith and

=ithout depression, and to e#aluate the association et=een depression and CD!. -u4ects =ere

participants in the nationally representati#e Lealth and Retirement -tudy BLR-, =hich is an

ongoing longitudinal study o older Americans. Details o the study design o the LR- and su4ect

characteristics ha#e een pulished pre#iously I19J. Louseholds =ere selected using multistagearea proaility sampling rom the )ational -ample rame, =ith random selection o eligile

indi#iduals =ithin the household. -u4ects =ere inter#ie=ed e#ery 2 years data rom inter#ie=s

during years 12P2$$% =ere used in the present in#estigation. Data rom the inter#ie=s =ere

lin7ed to les rom the Centers or Medicare and Medicaid -er#ices BCM- co#ering the period

11P2$$;, or ee&or&ser#ice eneciaries. 0he CM- -tandard Analytical Oiles used =ere the

!npatient, utpatient, -7illed )ursing Oacility, Carrier B>art , Lome Lealth Agency, and

Denominator les.

CD! =as ased on diagnosis y a physician o CD! B!CD&&CM code $$+.'


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Study A hospital&ased casePcontrol study =as conducted to e#aluate the association et=een

antidepressant medications and hospital&acKuired CD!. -u4ects =ere all adult patients B1+ years or

older hospitaliGed in the "ni#ersity o Michigan Lealth -ystem B"ML- during the period August

2$1$ to Oeruary 2$12, =ho had their stools tested or C. difcile. -tool =as tested or C. difciley

the "ML- Clinical Microiology 6aoratory. 0esting =as perormed on stools or glutamatedehydrogenase BDL antigen and toTins A or BC. D!OO V"!5 CL(5 CM>6(0(W test 0echla, !nc.,

lac7surg, A, "-A. All antigentoTin discordant stool tests =ere su4ected to analysis or the

tcd gene y real&time >CR BD enehmX Cdi/ Assay Oran7lin 6a7es, )8, "-A. ecause

hospital&acKuired inection =as o interest, patients admitted or reason o C. difcile Bprincipal

diagnosis o CD! =ere eTcluded. Cases =ere patients =ho tested positi#e or CD! at '+ hours or

longer ater admission and controls =ere patients =ho tested negati#e or CD! at '+ hours or

longer ater admission. ecause CD! testing is usually ordered or symptomatic patients Bor

eTample, those =ith antiiotic&associated diarrhea, cases and controls =ere suspected a priori to

e airly concordant on these general characteristics. Oor indi#iduals =ith multiple C. difcile tests,

the rst test result =as used or the purposes o this study. Data regarding patient demographics,

comoridities and medications Bprior to the date o stool collection or CD! testing =ere eTtracted

rom the electronic hospital data system. Detailed inormation =as a#ailale or the dosages anddates in =hich medications =ere gi#en to each patient.

0o assess di/erences in patient characteristics y casePcontrol status, >earsonSs Y2 test or

categorical data, -tudentSs t &test or di/erences in mean age, and the 5rus7al&allis test or

di/erences in length o stay prior to stool collection =ere used. "nconditional logistic regression

=as used to assess the association et=een antidepressant use and CD!, =ith and =ithout

ad4ustment or age, gender, race, antiacterial medications, >>!s, L2RAs, statins, irritale o=el

syndrome, celiac disease, CrohnSs disease and ulcerati#e colitis.

Oinally, =e conducted a sensiti#ity analysis or the casePcontrol study using di/erent controls. e

conducted a case&crosso#er study in =hich each patient ser#ed as hisher o=n control, to e#aluate

di/erences in anti&depressants =hile controlling or any history o depression. 0his analysis

incorporates a =ithin&person comparison in =hich the use o medications is compared o#er

di/erent time periods or the same patient and thereore, it can e used to separate the e/ects othe anti&depressants rom the e/ects o the disease itsel Bpathophysiology o depression. -uch an

approach also controls or actors that are difcult to capture, such as genetic prole and past

dietary haits. "ML- hospitaliGations in =hich hospital&acKuired CD! occurred Bn F '$% =ere

compared =ith suseKuent hospitaliGations Bn F ' or the same patient in =hich CD! did not

occur B8uly 2$$ to 8une 2$12. dds ratios BRs =ere calculated using a conditional logit model

or panel data Bclogit, o/set y the natural log o the time at ris7 or inection Blength o stay or

hospitaliGations =ithout CD! length o time rom admission to stool collection or positi#e C.

difcile or hospitaliGations =ith CD!. -tatistical analyses =ere perormed y using -tataM> 11.2

B-tataCorp 6>, College -tation, 0Z, "-A. Alpha =as set at $.$


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Ta&'e %- Rate of Clostridium difcile infection &y pre#ious diagnosis of major depression

in Medicare &ene.ciaries

Ater ad4usting or demographic characteristics, comoridities and reKuency o medical #isits,

there =as a 9%H increase in the odds o de#eloping CD! or indi#iduals =ith ma4or depression

compared =ith those =ithout ma4or depression B0ale 2. 0he ndings =ere similar or depressi#edisorders BR F 1.9


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!n a sensiti#ity analysis using a case&crosso#er design in =hich patients Bn F '$% ser#ed as their

o=n controls, the interaction et=een mirtaGapine and traGodone remained signicant BP F $.$1$

ater ad4ustment or antiacterial medications, statins, immunosuppressant medications, red lood

cell transusions, >>!s, and L2RAs B0ale


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person&years in the youngest age group o patients =ith depression, =hereas it =as 9$1.$1$$,$$$

person&years in the oldest age group or those =ithout depression. ! CD! =ere a crude indicator o

gut health, it =ould seem that the microiota o people =ith depression may e more similar to

that o the #ery aged. -tudies o the microiota o older adults generally sho= less di#ersity,

particularly in those =ho li#e in long&term residential care compared =ith community d=ellers I2


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adeKuately assess the similarity o results across hospitals. !n -tudy 1, the use o a nationally

representati#e sample that captured oth outpatient #isits and inpatient stays o#er an eTtended

period B1; years maTimum =as a strength or the assessment o depression, =ido=hood, and

other actors in =hich randomiGation is not possile.

A limitation o -tudy 1 =as the use o physician diagnoses to detect depression, =hich may

underestimate the true reKuency o this disease. Lo=e#er, data rom the LR- contain additional

inormation eyond physician diagnoses. !normation =as a#ailale rom sel&report y participants

during iennial inter#ie=s. 0he #ariales sho=n in 0ale 2 relate to depression measured in

di/erent =ays and the Rs all tended to sho= a similar pattern. Oor eTample, patient sel&report o

eeling sad Birrespecti#e o a physicianSs diagnosis =as signicantly associated =ith CD!. 0he R

=as 1.'1 BP F $.$$+ =hich parallels the ndings or a physician diagnosis o ma4or depression BR

F 1.9%, P F $.$1%. Moreo#er, i underestimation o depression is present through missed

diagnoses, it is li7ely to e non&di/erential misclassication that is, the under&reporting o

depression could occur in oth people =ho ha#e and people =ho do not ha#e CD!. 0here is

currently no estalished lin7 et=een depression and CD! in the medical literature y =hich

physicians across the country =ould lin7 these t=o conditions. hen such non&di/erential

misclassication occurs, the R tends to e pulled to=ards the null. 0hus, i under&diagnosis o

depression does occur, =e =ould eTpect that the true Breerence population R =ould e greaterthan 1.9%.

Another concern may e testing ias, =hich =ould occur i the ordering o a test or C.

difcileoccurs at di/erent rates in persons =ith and =ithout depression. !n -tudy 2, participants

=ere all patients =ho =ere tested or C. difcile during a gi#en time period ecause o symptoms

e#idenced during hospitaliGation that is, antiiotic&associated diarrhea. ecause depression has

not een pre#iously correlated =ith CD! in the medical literature or in general clinical practice, =e

do not suspect that there =as di/erential testing ased on this specic diagnosis.

"nortunately, Kuestions regarding dietary inta7e =ere not as7ed o all participants in the LR- as a

part o the ongoing iennial inter#ie=, nor did =e ha#e dietary inta7e inormation on the

hospitaliGed patients in -tudy 2. 0hereore, the inNuence o haitual diet on oth depression and

CD! cannot e assessed in our studies. 0here =as one aspect o our in#estigation, ho=e#er, in

=hich =e =ere ale to control or past dietary inta7e. !n the sensiti#ity study o the hospitaliGedpatients B-tudy 2, =e conducted a case&crosso#er study =herey each person =as compared =ith

himhersel. !n this instance, past dietary haits Bprior to 8uly 2$$ =ere held constant such haits

are the same ecause the person is the same. hen diet =as held constant, patients recei#ing

mirtaGapine =ith traGodone =ere at greater ris7 o de#eloping CD!. Lo=e#er, i some o these

patients egan eating di/erently ater 8uly 2$$, such di/erences could not e measured. #erall,

the e/ect o diet on oth depression and CD! =ould e an interesting area or urther study.

(onc'usions

i#en the rise o CD!, especially among older indi#iduals I91J, elucidating the modiale ris7

actors or this oten&atal illness is an important patient saety issue. ur complementary studiesre#eal that adults =ith depression and those that use specic anti&depressants seem to e more

li7ely to eTperience CD!. ido=hood and li#ing alone are also associated =ith CD!. Clinicians

prescriing antimicroials to patients =ith depression should e a=are o the possile increased

ris7 o CD! in this patient population.

A&&re#iations

M!: ody mass indeT CD!: Clostridium difcile inection C!: Condence inter#al CM-: Centers or

Medicare and Medicaid -er#ices !: astrointestinal LR-: Lealth and Retirement -tudy L2RAs:

histamine&2 receptor antagonists >>!s: proton&pump inhiitors --R!: selecti#e serotonin reupta7e

inhiitor "ML-: "ni#ersity o Michigan Lealth -ystem.

http://www.biomedcentral.com/1741-7015/11/121/table/T2http://www.biomedcentral.com/1741-7015/11/121/table/T2http://www.biomedcentral.com/1741-7015/11/121#B31http://www.biomedcentral.com/1741-7015/11/121/table/T2http://www.biomedcentral.com/1741-7015/11/121#B31


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(ompeting interests

0he authors declare that they ha#e no competing interests.

Autors8 contri&utions

MAMR, M0 and DMA participated in designing the studies, and MAMR generated the hypotheses.

3, 5M6 and DMA pro#ided resources. MAMR and M0 eTtracted the data. MAMR had ull access

to all o the data, conducted the analyses, and =rote the rst drat o the report. MAMR, M0, 3,

--, 5M6, 835 and DMA participated in interpretation o the data, =riting o the manuscript, and

critically re#ie= o the paper. All authors appro#ed the nal manuscript.

Autors8 information

0he authors are part o the )ational !nstitutes o Lealth&sponsored (nterics Research

!n#estigational )et=or7 Cooperati#e Research Centers that =ere unded to conduct research to

ridge the gaps et=een asic, translational, and clinical research on enteric disease agents. As apart o this net=or7, =e are eTploring contriutors to C. difcile pathogenesis.

9unding

0his pro4ect =as unded y a grant rom the )ational !nstitute o Allergy and !nectious Diseases

Bgrant numer uMed Astract ] >ulisher Oull 0eTt

- Murphy -6, Zu 8V, 5ochane7 5D: Deats* pre'iminary data for :%:- ;ationa' Vita'

Statistics Reports-

Natl Center Health Stat 2$12, , )otermans D, #an enthem L, raGier 8-, ilcoT ML, Rupni7 M, Monnet D6,

#an Dissel 80, 5ui4per (8, (CD!- -tudy roup: Clostridium difcile infection in +urope*

a ospita'0&ased sur#ey-

ancet 2$11, 1==*%9&;9. >uMed Astract ] >ulisher Oull 0eTt

5- 6eonard 8, Marshall 85, Moayyedi >: Systematic re#ie) of te risk of enteric infection

in patients taking acid suppression-

!m " #astroenterol 2$$;, %:*2$';&2$uMed Astract ] >ulisher Oull 0eTt

http://www.biomedcentral.com/pubmed/21460491http://www.biomedcentral.com/pubmed/21460491http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=21460491http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=21460491http://www.biomedcentral.com/pubmed/21084111http://www.biomedcentral.com/pubmed/21084111http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=21084111http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=21084111http://www.biomedcentral.com/pubmed/17509031http://www.biomedcentral.com/pubmed/17509031http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=17509031http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=17509031http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=17509031http://www.biomedcentral.com/sfx_links?ui=1741-7015-11-121&bibl=B4http://www.biomedcentral.com/sfx_links?ui=1741-7015-11-121&bibl=B4http://www.biomedcentral.com/sfx_links?ui=1741-7015-11-121&bibl=B3http://www.biomedcentral.com/sfx_links?ui=1741-7015-11-121&bibl=B2http://www.biomedcentral.com/sfx_links?ui=1741-7015-11-121&bibl=B1http://www.biomedcentral.com/pubmed/21460491http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=21460491http://www.biomedcentral.com/pubmed/21084111http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=21084111http://www.biomedcentral.com/pubmed/17509031http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&cmd=prlinks&retmode=ref&id=17509031


10/14

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ini&itors increase signi.cant'y te risk of Clostridium difcile infection in a

'o)0endemicity, non0out&reak ospita' setting-

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co'onic morpo'ogy and pysio'ogy in t)o rat mode's of enanced stress0

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Cmp'ications for psyconeuroendocrino'ogy-

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11/14

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inammatory &o)e' disease in a mouse mode' of depression-

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12/14

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Clin Inect 0is 2$12, 66*-%uMed Astract ] >ulisher Oull 0eTt ]


Researc artic'e

(ross0nationa' epidemio'ogy of DSM0CV major depressi#e

episode

+#e'yn Bromet1*, !aura e'ena Andrade2, Cr#ing )ang9, ;ancy A Sampson9, "ordi

A'onso', Gio#anni de Giro'amoierre

!Fpine19, Dapna !e#inson1', er&ert Matscinger1


14/14

MethodsMajor depressive episodes "M#$% as defined by the 0ia%nostic and Statistical Manual o Mental

0isorders, fourth edition "#M!-I&% were evaluated in face-to-face interviews using the World

ealth 'rgani(ation )omposite International #iagnostic Interview ")I#I%. #ata from 18 countries

were analy(ed in this report "n * 8+,%. /ll countries surveyed representative, population-based

samples of adults.

Results0he average lifetime and 1-month prevalence estimates of #!M-I& M#$ were 12.34 and 5.54 in

the ten high-income and 11.14 and 5.+4 in the eight low- to middle-income countries. 0he

average age of onset ascertained retrospectively was 5. in the high-income and 2. in low- to

middle-income countries. 6unctional impairment was associated with recency of M#$. 0he female7

male ratio was about 71. In high-income countries, younger age was associated with higher 1-

month prevalence by contrast, in several low- to middle-income countries, older age was

associated with greater li9elihood of M#$. 0he strongest demographic correlate in high-income

countries was being separated from a partner, and in low- to middle-income countries, was being

divorced or widowed.

ConclusionsM#$ is a significant public-health concern across all regions of the world and is strongly lin9ed to

social conditions. 6uture research is needed to investigate the combination of demographic ris9

factors that are most strongly associated with M#$ in the specific countries included in the WM.

Documents

Rogers, M. Et Al (2013) Depression, Antidepressant Medications, And Risk of Clostridium Difficile Infection. BMC Medecine