Conductas suicidas y trastornos neuropsiquiátricos post corticoides

7/31/2019 Conductas suicidas y trastornos neuropsiquitricos post corticoides

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Article

Am J Psychiatry 169:5, May 2012 ajp.psychiatryonline.org 491

medical disease are unknown. Moreover, some authors

have asserted that a single glucocorticoid-induced distur-

bance should not be regarded as a contraindication for fu-

ture glucocorticoid treatment, but some case reports have

described individuals who experienced recurrent psychi-

atric disturbances when challenged with glucocorticoids

(15, 16). The evidence base for adverse events such as de-

lirium, panic disorder, and suicidal behavior is poorly de-

veloped and limited to case reports (8).Our aim in this study was to assess the incidence rates of

depression, mania, delirium, panic disorder, and suicide

or suicide attempt in people treated with glucocorticoids

and the risk factors for developing these outcomes in U.K.

primary care.

Mthod

Data Source

Approximately 98% of the population in the United Kingdomis registered with a general practitioner (17). The Health Improve-

(Am J Psychiatry 2012; 169:491497)

Sucda Bhavo and Sv Nuopsychatc ;sods

Foowng Gucocotcod Thapy n Pmay Ca

Laurence Fardet, M.D., Ph.D.

Irene Petersen, Ph.D.

Irwin Nazareth, M.D., Ph.D.

Objective: The incidence and the risk

of suicidal behaviors and severe neuro-psychiatric disorders in people treated

withsystemicglucocorticoidsarepoorly

known. The authors assessed the inci-

denceratesofdepression,mania,deliri-

um,panicdisorder,andsuicidalbehaviors

inpatientstreatedwithglucocorticoidsin

primarycaresettingsandtheriskfactors

fordevelopingtheseoutcomes.

Method:Datawereobtainedforalladult

patients registered between 1990 and

2008atU.K.generalpracticescontribut-

ingtoTheHealthImprovementNetwork

(THIN) primary care database. The inci-

denceratesfortheoutcomesofinterest

were assessed inpatientswho received

prescriptionsfororalglucocorticoidsand

compared with those in patients who

did not receive such prescriptions. The

predictorsoftheseoutcomesinexposed

patientswereascertainedusingCoxpro-

portionalhazardsmodels.

Results: Overall, 786,868 courses of

oral glucocorticoids were prescribed for

372,696patients. Theauthors identied

109 incident casesof suicideor suicide

attemptand10,220incidentcasesofse-

vere neuropsychiatric disorders in these

patients. The incidence of any of theseoutcomeswas22.2per100person-years

at risk for rst-course treatments. Com-

pared topeoplewith thesameunderly-

ingmedicaldiseasewhowerenottreated

withglucocorticoids,thehazardratiofor

suicideorsuicideattemptinexposedpa-

tientswas6.89 (95%CI=4.5210.50);for

depression,1.83 (95%CI=1.721.94); for

mania, 4.35 (95%CI=3.675.16); forde-

lirium,confusion,or disorientation,5.14

(95%CI=4.545.82);andfor panic disor-

der,1.45 (95%CI=1.151.85).Oldermen

wereathigherriskofdelirium/confusion/

disorientationandmania,whileyoungerpatientswereathigherriskofsuicideor

suicideattempt.Patientswithaprevious

historyofneuropsychiatricdisordersand

thosetreatedwithhigherdosagesofglu-

cocorticoidswereatgreaterriskofneuro-

psychiatricoutcomes.

Conclusions: Glucocorticoids increase

therisk of suicidalbehaviorandneuro-

psychiatric disorders. Educatingpatients

and their families about these adverse

eventsandincreasingprimarycarephysi-

cians awareness about theiroccurrence

shouldfacilitateearlymonitoring.

Natural glucocorticoids such as cortisol affect be-havior, mood, and other CNS-related processes (1). Ab-

normalities of the hypothalamic-pituitary-adrenal axis,

notably hypercortisolemia and specic dysfunction in

glucocorticoid negative feedback, have been demon-

strated in people with mood disorders (15). Additionally,

some 50%80% of patients with endogenous hypercor-

tisolemia (Cushings syndrome) meet DSM-IV criteria for

major depression (6), and about 10% experience psycho-sis or mania (7). The association of exogenous glucocorti-

coids with depressive and manic syndromes is relatively

well documented (8). In view of the frequency and severity

of such disturbances in various clinical populations who

receive prescriptions for glucocorticoids, there is a need

for population-based prevalence studies. Data from ret-

rospective studies indicate prevalence rates of glucocor-

ticoid-induced neuropsychiatric disorders ranging from

below 1% to 50% (912). While drug dosage is a known risk

factor (13, 14), the effects of age, sex, and the underlying

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492 ajp.psychiatryonline.org Am J Psychiatry 169:5, May 2012

SUiCi;Al BeHAViOr AN; NeUrOPSYCHiATriC ;iSOr;erS AFTer GlUCOCOrTiCOi; THerAPY

that occurred within the rst 3 months of the drug being pre-scribed.

Glucocorticoid-Exposed Group

We identied all patients age 18 and older who received at leastone oral glucocorticoid prescription. For multiple consecutiveprescriptions, the treatment duration was dened as the timefrom the rst to the last prescription plus the duration of the lastprescription. Patients who received a new prescription for an oral

glucocorticoid after a period of 3 months or more without wereconsidered to have started a new treatment course. We calculatedthe prescribed daily dose for each course by multiplying the num-ber of pills prescribed by the dose per pill (calculated in predni-sone equivalents) and dividing this result by the number of daysfor which the drug was prescribed. We took into account the dailydose recorded at the beginning of the course to analyze the effectof drug dosage on outcome. The medical diagnosis recorded onthe date that glucocorticoids were started was used as the indica-tion for the glucocorticoid prescription. If no medical diagnosis

was recorded on that date, we searched for 12 relevant chronic

conditions entered in the records 3 months before or after thisprescription.

Unexposed GroupsUnexposed groups were patients who did not receive pre-

scriptions for oral glucocorticoids. From the pool of eligible in-dividuals, two comparison groups were identied. The rst wasa selection of a random sample of patients who did not receiveglucocorticoid prescriptions, and the second was a random sam-ple of patients who did not receive glucocorticoid prescriptions

but who had diagnoses of the same underlying medical diseasesas the exposed patients. We selected up to four unexposed indi-viduals from each of these groups for every exposed individual.

When selecting the unexposed groups, we stratied the sample toensure that they had the same distribution of sex and age (within10-year age bands) as the glucocorticoid-exposed group. We ac-counted for the clustering effect within general practices by se-lecting exposed and unexposed patients from within the same

practice. For each unexposed patient, a randomly selected indexdate was dened at least 6 months after his or her registration.

Statistical Analysis

For each participant, follow-up time was accrued from gluco-corticoid initiation or index date until the date of the outcome,the end date of glucocorticoid exposure (up to 3 months afterglucocorticoid initiation), a date up to 3 months after the indexdate, the date of leaving the practice, the date of death, or theend of the study period. We calculated incidence rates by divid-ing the number of newly diagnosed cases of suicide or suicideattempt, depression, mania, delirium/confusion/disorientation,and panic disorder by the total follow-up time in the study cohort.

This was rst done as a total for all outcomes and then for each

one in turn. Incidence rates were estimated for all glucocorticoidcourses and then separately for the rst, second, and third or latercourses. We assessed risk factors for each outcome using Cox pro-portional hazards models. We initially compared the exposed andunexposed groups to assess hazard ratios associated with the rstprescription issued for glucocorticoids, and we performed a sensi-tivity analysis that excluded prescriptions for antidepressants, an-tipsychotics, or antimanic agents as a denition of a neuropsychi-atric disorder. The estimated hazard ratios were adjusted for age,sex, past history of neuropsychiatric disorders, and the underlying

medical disease. We then ascertained the predictors of the out-comes in patients treated with glucocorticoids. In those who re-ceived multiple courses, only one course was randomly selectedto avoid a clustering effect within patients. We selected a randommixture of rst and later exposures to glucocorticoids to examine

ment Network (THIN) is a database of anonymized electronicmedical records from general practices across the country. Par-ticipating general practitioners systematically and prospectivelyretrieve and enter clinical information on patients, includingdemographic data, diagnoses, and prescriptions. The databasethus provides a longitudinal medical record for each patient. Theconsultation and prescription data recorded in THIN compare fa-vorably with national data (18). THIN has been validated throughaudits, comparisons with external statistics, and independent

studies and has been shown to have a high level of completenessof clinical diagnostic and prescribing data (1921). To minimizeany bias on disease occurrence or prescriptions issued, we re-stricted our analyses to high-quality data by using quality indica-tors as dened elsewhere (18, 22), and we excluded entries made

within 6 months after registration with the general practice asthis may represent retrospective recording of a past history ratherthan a new episode of a problem (23). We used data from January1, 1990, to December 31, 2008, from 424 general practices.

Identifcation o Glucocorticoid Prescriptions

In THIN, each drug is encoded using Multilex codes that areassociated with data from the British National Formulary(http://bnf.org/bnf). Prescribing is particularly well recorded in THIN

since physicians use the practice computers to issue prescrip-tions (18). We selected all oral glucocorticoids prescribed, whichincluded prednisolone, prednisone, hydrocortisone, dexametha-sone, triamcinolone, betamethasone, methylprednisolone, anddeazacort. Patients treated exclusively with topical, inhaled, orparenteral glucocorticoids were not included in the analyses.

Identifcation o Neuropsychiatric Disorders

All diagnoses and symptoms are recorded in THIN using theRead classication system (24). The Read classication and theMultilex codes were used to create medical and drug code liststhat enabled us to identify cases of suicide or suicide attempt;depression; mania; delirium, confusion, or disorientation; andpanic disorder in the database. We compiled lists for Read codesand for drug codes by conducting relevant word and code search-

es in the Read code and drug code dictionaries, as previouslydescribed (25). For instance, patients were dened as depressedif they had a Read code entry for unipolar depression, for symp-

toms of depression (e.g., low mood), or for a prescription for anantidepressant on a given consultation date. Diagnoses were con-sidered rst; prescriptions of antidepressants were used in den-ing the outcome only when there was no recorded diagnosis ofa neuropsychiatric illness and no other recorded indication forthe prescription. To exclude patients who may have received pre-scriptions for antidepressants for anxiety rather than for depres-sion, we eliminated those who had an entry for anxiety or panicdisorder but had no entry for depression in their entire comput-erized medical record. For Read code searches, depression was

identied, with bipolar disorders and depression with psychosis

excluded. We applied similar methods to dene mania (diagnosisor symptoms of mania or prescription of antimanic medication),delirium/confusion/disorientation (diagnosis or symptoms ofdelirium, confusion, or disorientation or prescription of antipsy-chotic medication), panic disorder (diagnosis of panic disorder orpanic attack but excluding codes for anxiety), and suicidal behav-ior (diagnosis of suicide or suicide attempt). Death certicates forpeople who died during the study period were also reviewed toidentify those who died from suicide. A glucocorticoid-inducedoutcome was dened as one that was recorded after glucocorti-

coid initiation and with a preceding interval of at least 6 monthswith no similar entry (i.e., no coded entries for diagnosis or forsymptoms or medications linked to the diagnosis). For long-termglucocorticoid therapies (i.e., lasting more than 3 months [26]),

we arbitrarily dened a glucocorticoid-induced outcome as one



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FAr;eT, PeTerSeN, AN; NAZAreTH

incident cases of delirium/confusion/disorientation, 898

incident cases of mania, 266 incident cases of panic disor-

der, and 108 incident cases of psychiatric referral without

any details of the symptoms experienced. The incidence

rate of all outcomes varied depending on the order of the

glucocorticoid courses. It was 15.7 per 100 person-years

at risk for all glucocorticoid courses, 22.2 per 100 person-

years at risk for rst courses, 14.0 per 100 person-years at

risk for second glucocorticoid courses, and 11.7 per 100

person-years at risk for third and later courses.

Figure 1 presents the adjusted hazard ratios for allneuropsychiatric disorders (all exposed patients, haz-

ard ratio=3.26, 95% CI=3.143.37; exposed patients with

an indication for prescription, hazard ratio=2.26, 95%

CI=2.152.37) and for each individual disorder associated

with the rst prescription of glucocorticoids issued. Com-

pared with the unexposed populations, the risk of suicide

or suicide attempt increased ve- to sevenfold in people

treated with glucocorticoids (all exposed patients, hazard

ratio=5.27, 95% CI=3.827.29; exposed patients with an in-

dication for prescription, hazard ratio=6.89, 95% CI=4.52

10.50), even though the overall risk was low. The increased

risk was most marked for delirium/confusion/disorienta-

tion (all exposed patients, hazard ratio=6.35, 95% CI=5.92

6.81; exposed patients with an indication for prescription,

hazard ratio=5.14, 95% CI=4.545.82) and mania (all ex-

posed patients, hazard ratio=5.66, 95% CI=5.096.60; ex-

posed patients with an indication for prescription, haz-

ard ratio=4.35, 95% CI=3.675.16) when compared with

depression (all exposed patients, hazard ratio=2.60, 95%

CI=2.492.70; exposed patients with an indication for pre-

scription, hazard ratio=1.83, 95% CI=1.721.94) and panic

disorder (all exposed patients, hazard ratio=1.97, 95%

CI=1.602.43; exposed patients with an indication for pre-

scription, hazard ratio=1.45, 95% CI=1.151.85).

whether previous exposure to glucocorticoid therapy was associ-

ated with the risk of developing a neuropsychiatric illness.Models were tted sequentially, adjusting for each individual

potential confounderage (classied into four categories), sex,past history of glucocorticoid use (yes or no), past history of anyneuropsychiatric disorder (yes or no), daily dose of glucocorti-coids (classied into ve categories), and underlying medicaldisease. The initial daily dose of glucocorticoids was missing for11% of glucocorticoid courses and was then addressed throughmultiple imputation, which assumed that the missing covariatevalues were missing at random. The proportional hazard assump-

tion was checked graphically and by analyzing Schoenfeld residu-

als. For continuous variables, we checked linearity by comparingtwo models, one with the linear term and the other with the cat-egories using the log-likelihood ratio test. We examined for differ-ences in the effect of glucocorticoid daily dose between men and

women and according to age by testing the dose-by-sex and dose-by-age interaction terms. These were not signicant and hence

were excluded from the nal model. Incidence rates are reportedper 100 person-years at risk. All analyses were conducted usingStata, version 11.1 (StataCorp, College Station, Tex.). The study

was approved by the University College London THIN steering

committee and by the THIN scientic review committee.

rsuts

In total, 786,868 courses of oral glucocorticoids, rep-resenting 89,298 years of glucocorticoid exposure, were

prescribed in 372,696 adult patients (age 18 or older). The

clinical indication for the glucocorticoid prescription was

identied for 560,472 courses prescribed in 261,272 pa-

tients. The characteristics of both the exposed and the un-

exposed patients are summarized in Table 1.

Incidence and Association With Glucocorticoid

Exposure

In patients exposed to glucocorticoids, we identied 19

incident cases of completed suicide, 90 incident cases of

suicide attempt, 6,918 incident cases of depression, 2,030

TABle 1. Chaactstcs of Study Popuatons n an Anayss of Sucda Bhavo and Sv Nuopsychatc ;sodsFoowng Gucocotcod Thapy n Pmay Ca

CharacteristicAllExposedPatients

(N=372,696)

FirstUnexposedPopulation,Strati-

fedbyAgeandSex(N=1,224,984)

ExposedPatientsWithanIdentifedIndica-tionorPrescription

(N=261,272)

SecondUnexposedPopulation,Stratifed

byAge,Sex,andUnderlyingDisease

(N=660,776)

Mean SD Mean SD Mean SD Mean SD

Age(years)a 57.5 18.8 55.2 19.1 55.3 18.9 53.5 18.8

N % N % N % N %

Female 220,272 59.1 717,840 58.6 155,979 59.7 393,162 59.5

Previoushistoryoneuropsychiatricdisorder

89,396 24.0 296,777 24.2 65,862 25.2 174,386 26.4

Underlyingdisease

Lowerrespiratorytractinection 100,720 38.5 309,177 46.8

Asthma 78,924 30.2 229,746 34.8

Chronicobstructivepulmonarydisease

20,329 7.8 43,916 6.6

Polymyalgiarheumaticaorgiantcellarteritis

19,250 7.4 1,206 0.2

Other 42,049 16.1 76,731 11.6aAgeatfrstglucocorticoidprescriptionorexposedpatientsorageatrandomlyselectedindexdate(seetext)orunexposedpatients.



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neuropsychiatric outcomes. We found a high incidence of

neuropsychiatric adverse events in the rst 3 months of

treatment with glucocorticoids. Overall, the incidence was

15.7 per 100 person-years at risk, and for patients on their

rst course of glucocorticoids, it was 22.2 per 100 person-

years at risk. Despite a low incidence, the risk of suicide

or suicide attempt increased up to sevenfold in patientstreated with glucocorticoids after adjustment for known

confounders, including the underlying medical disease.

Depression was more common than mania, delirium/

confusion/disorientation, or panic disorder, although the

increase in risk was most marked for delirium/confusion/

disorientation and mania. The risk factors differed for

each outcome except for higher daily doses of glucocorti-

coids, which consistently remained a risk factor.

At any given time in the United Kingdom, about 1% of

the general adult population receives oral glucocorticoids

(2628). Psychiatric symptoms are among the most dis-

tressing adverse events experienced by this patient group

(29), and yet only limited data are available on their inci-

dence and predisposing risk factors (8, 30). A 1983 litera-

ture review (13) reported a weighted average incidence of

5.7% for severe neuropsychiatric adverse events in people

treated with glucocorticoids, but the interval over which

these occurred was not specied. We observed a twofold

increase in risk of depression in people exposed to glu-

cocorticoids, which is consistent with results reported a

decade ago by Patten (31). The study, based on a general

population sample, showed that the prevalence of major

depression was approximately three times as high in pa-

tients treated with glucocorticoids as in those not exposed

Sensitivity analysis excluding patients for whom medi-

cation was used to determine diagnoses of depression,

mania, and delirium/confusion/disorientation revealed

qualitatively similar ndings. The adjusted hazard ratios

were 1.39 (95% CI=1.291.51) for depression, 3.94 (95%

CI=3.524.44) for delirium/confusion/disorientation, and

3.48 (95% CI=2.964.09) for mania when exposed patientswith an identied indication for prescription were com-

pared with unexposed patients with the same underlying

medical disease.

Risk Factors

Larger daily doses of glucocorticoids and a prior history

of neuropsychiatric disorders were associated with a great-

er risk of all incident outcomes, whereas prior treatment

with glucocorticoids was associated with a lower risk (Ta-

ble 2). Women were at higher risk of depression and at low-

er risk of mania and delirium/confusion/disorientation.

The risk of depression, mania, and delirium/confusion/

disorientation rose with age, but the reverse was observed

for suicidal behavior and panic disorder. When consider-

ing only patients who received multiple glucocorticoid

courses, a previous history of a glucocorticoid-induced

neuropsychiatric disorder was associated with a greater

risk of having a recurrence of the same disorder after a

subsequent course (hazard ratio=1.32, 95% CI=1.001.74).

;scusson

To our knowledge, this is the largest study to date exam-

ining the effects of glucocorticoid treatment on adverse

FiGUre 1. Assocaton Btwn Fst Cous of Gucocotcods and rsk of Nuopsychatc Outcoms n exposd Com-pad Wth Unxposd Patnts

All

Depression

Delirium, Confusion,

or Disorientation

Mania

Panic Disorder

Suicidal Behavior

Psychiatric Referralc

0 2 4 6 8

Hazard Ratio (95% CI) Hazard Ratio (95% CI)

All Exposed Patients

Compared With

Unexposed Patientsa

Exposed Patients With an Identified

Indication for Prescription

Compared With Unexposed Patientsb

0 2 4 6 8 10

aModeladjustedorsex,age,andpasthistoryoneuropsychiatricdisorders.Unexposedpatients(N=1,224,984)werearandomsampleo

patientswhodidnotreceiveglucocorticoidprescriptions,requency-matchedorageandsexwiththeexposedgroup(N=372,696).bModeladjustedorsex,age,underlyingmedicaldisease,andpasthistoryoneuropsychiatricdisorders.Unexposedpatients(N=660,776)werearandomsampleopatientswhodidnotreceiveglucocorticoidprescriptionsbutwhohaddiagnosesothesameunderlyingmedicaldiseasesastheexposedpatients,requency-matchedorage,sex,andunderlyingmedicaldisorderwiththeexposedgroup(N=261,272).

cRecordopsychiatricreerralwithoutanydetailsothesymptomsexperienced.



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illness was associated with an increased risk of developing

further neuropsychiatric disorders after glucocorticoid

therapy. Our results indicate that a previous vulnerability

to a specic neuropsychiatric disorder places a patient at

risk of developing the same disorder when next exposed to

glucocorticoids, hence reducing their chances of develop-

ing a new neuropsychiatric problem. This would explain

why a past history of a given neuropsychiatric disorder

may seem to protect against other neuropsychiatric dis-

orders. We also found that previous treatment with gluco-

corticoids was associated with a lower risk of developing

a neuropsychiatric outcome. The most likely explanation

for this nding is that patients known to have had a psy-

chiatric adverse event after starting treatment with a glu-

cocorticoid may be less likely to receive a prescription for

the drug again. Finally, we found that people with asthma

and those with polymyalgia rheumatica or giant cell ar-

teritis may be less likely to develop neuropsychiatric dis-

to glucocorticoids. Although the risk factors were differ-

ent for the outcomes examined, some distinct patterns

associated with age and sex were observed. First, women

were more likely to develop depression after receiving a

glucocorticoid prescription, and men were more likely

to develop mania or delirium/confusion/disorientation.

Second, the risk of depression, mania, and delirium/con-

fusion/disorientation increased with age, while the risk of

panic disorder and suicide or suicide attempt was more

pronounced in younger people. We found that the initial

daily dose of glucocorticoid was predictive of neuropsy-

chiatric adverse disorders, which is consistent with pre-

vious research (13, 14). In the Boston Collaborative Drug

Study, severe psychiatric symptoms were reported in 1.3%

of patients treated with less than 40 mg/day of prednisone,

compared with 18.4% of those receiving more than 80

mg/day (14). Contrary to ndings from previous research

(3234), we found that a prior history of neuropsychiatric

TABle 2. rsk Factos fo Nuopsychatc ;sods n th Gucocotcod-exposd Popuaton

Depressiona(N=3,424)

Delirium,Conusion,orDisorientationa

(N=1,537) Maniaa(N=599)PanicDisorderb

(N=109)SuicidalBehaviorc

(N=51)

RiskFactorHazard

Ratio 95%CIHazard

R atio 95%CIHazard

R atio 95%CIHazard

Ratio 95%CIHazard

Ratio 95%CI

Sex(womenversusmen) 1.26 1.171.35 0.84 0.760.93 0.73 0.620.86 1.13 0.771.68 1.23 0.702.19

Age(years)

1830(reerence) 1.00 1.00 1.00 1.00 1.00

3150 1.14 0.971.35 2.06 1.203.56 1.47 0.852.53 0.58 0.301.09 0.89 0.411.91

5170 1.27 1.091.49 6.39 3.8210.68 2.55 1.534.24 0.53 0.290.97 0.22 0.080.54

71 1.24 1.061.46 10.30 6.1717.20 2.93 1.764.88 0.39 0.210.74 0.27 0.110.65

Initialdailydosed(mg)

10 1.00 1.00 1.00 1.00

1120 1.08 0.981.19 1.85 1.572.17 1.17 0.901.53 3.42 1.537.67

2140 1.04 0.951.14 1.34 1.151.56 1.22 0.971.54 4.01 1.928.40

4160 1.57 1.351.82 4.88 4.075.86 3.24 2.394.38 5.08 1.8414.05

61 2.03 1.722.39 6.01 4.977.28 5.18 3.856.97 2.44 0.5211.49

Pasthistoryoglucocor-ticoidtherapy

0.67 0.630.73 0.34 0 .290.39 0.47 0.380.57

Pastmedicalhistory

Depression 1.39 1.291.50 0.64 0.560.74 0.83 0.681.03 Delirium,conusion,ordisorientation

0.56 0.430.72 0.92 0 .691.21 1.19 0.801.79

Mania 0.80 0.631.01 0.59 0.370.94 1.82 1.192.77

Panicdisorder 0.99 0.831.19 0.84 0.581.20 0.68 0.381.21 4.64 2.757.83

Suicideattempt 1.30 1.021.65 1.09 0.621.94 0.88 0.391.98 9.87 4.7420.53

Underlyingdisease

Lowerrespiratorytractinection

1.00 1.00 1.00

Asthma 0.75 0.660.86 0.41 0.310.55 0.60 0.420.86

Chronicobstructivepulmonarydisease

1.06 0.911.23 0.59 0 .450.79 0.77 0.521.14

Polymyalgiarheumati-ca/giantcellarteritis

0.60 0.520.69 0.26 0 .200.34 0.41 0.280.61

Other 1.02 0.931.11 1.22 1.071.38 1.05 0.861.29aModeladjustedorsex,age,initialdailydose,pasthistoryoglucocorticoidtherapy,pasthistoryoneuropsychiatricdisorder,andunderlying

medicaldisease.bModeladjustedorsex,age,initialdailydose,andpasthistoryopanicdisorder.cModeladjustedorsex,age,andpasthistoryosuicideattempt.dInprednisoneequivalents.



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psychotropic medications without entry of a concomi-

tant neuropsychiatric diagnosis in the record since the

clinician would have taken for granted that concomitant

neuropsychiatric dysfunction is a possible effect of gluco-

corticoid therapy. Lastly, suicide and suicide attempt were

pooled because of the low number of completed suicides.

However, it is noteworthy that they may represent two dif-

ferent phenomena that may or may not be related.People treated with glucocorticoids have a twofold high-

er risk of developing depression, a four- to vefold higher

risk of developing mania or delirium/confusion/disorien-

tation, and nearly a sevenfold higher risk of committing or

attempting suicide compared with people unexposed to

glucocorticoids. Physicians must exercise caution in ad-

ministering these drugs, in particular when the reasons

for prescribing are not in accordance with the consensual

clinical recommendations (27). In instances where it is

essential to prescribe a glucocorticoid, patients and their

families should be informed about the possibility of these

severe adverse events (36). Close monitoring of relevantneuropsychiatric adverse events must be undertaken by

patients, their families, and their treating physicians so

that cessation of the drug or reduction of the dosage is

considered for those who develop such adverse reactions.

The effectiveness of such monitoring in primary care re-

quires evaluation.

Received July 6, 2011; revisions received Sept. 27 and Nov. 18, 2011;

accepted Dec. 5, 2011 (doi: 10.1176/appi.ajp.2011.11071009). From

the Medical Research Council General Practice Research Framework,

London; the Department o Internal Medicine, Saint-Antoine Hospi-

tal, Paris; the Faculty o Medicine, University Pierre and Marie Curie,

Paris; and the Research Department o Primary Care and Population

Health, Royal Free Campus, London. Address correspondence to Dr.

Fardet ([email protected]).

The authors report no fnancial relationships with commercial in-

terests.

Supported by a grant rom the French National Society o Internal

Medicine and the Public Assistance-Paris Hospitals to Dr. Fardet. Dr

Petersen received unding rom the U.K. Medical Research Council

(grant G0601726).

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6. Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F,

ChrousosGP,FavaGA,FindlingJW,GaillardRC,GrossmanAB,

KolaB,LacroixA,ManciniT,ManteroF,Newell-PriceJ,Nieman

orders and that the risk of panic attack decreased at the

highest glucocorticoid dosage. There is no clear explana-

tion for the lower risk of neuropsychiatric outcomes in

people with polymyalgia rheumatica or giant cell arteritis.

People with asthma are chronically exposed to low doses

of glucocorticoids (e.g., inhaled glucocorticoids), and it is

possible that this protects them when they are exposed

to higher dosages. The most likely explanation for the de-creasing risk of panic disorder in people exposed to the

highest dosages of glucocorticoids is that our study was

underpowered to examine this effect.

Our study has several strengths. One of them is its use

of a very large population of patients with a wide range

of conditions affecting both sexes and all age groups. The

large number of incident neuropsychiatric outcomes al-

lowed us to conduct a statistically powerful study. We were

able to assess incidence risk for suicide or suicide attempt

and to examine each subtype of severe neuropsychiatric

disorder. The study had some limitations as well. For ex-

ample, it is known that in the THIN database, symptoms(e.g., low mood) are frequently recorded instead of a de-

nite illness for some common mental illnesses such as

depression (35). Nevertheless, our ndings are relevant

to clinical practice, since we included diagnostic labels

used in general practice rather than strict DSM-IV or ICD-

10 classications. Second, it is likely that the most severe

forms of the underlying medical diseases may require

treatment with glucocorticoids, and it can be argued that

the observed neuropsychiatric outcomes may be associ-

ated with severity of the medical illness rather than the

glucocorticoid treatment. However, the effects of gluco-

corticoids could be separated from those of disease se-verity only in a randomized controlled trial that included

people with similar levels of disease severity receiving

either glucocorticoids or placeboan ethically unaccept-

able design. Third, we chose to use diagnoses and pre-

scribed drugs (i.e., antidepressants, antipsychotics, and

antimanic agents) to dene cases of depression, delirium/

confusion/disorientation, and mania. However, in some

cases, medications may have been prescribed for other

conditions (e.g., antidepressants for neuropathies). It is

possible that this approach led to a slight overestimation

of incidence rates of neuropsychiatric disorders. However,

we also believe that these rates would have been under-

estimated if medication prescriptions had not been taken

into account. Indeed, in our view, physicians are less likely

to record a diagnosis of a neuropsychiatric illness they

attribute to the glucocorticoid exposure and for which

they know that the symptoms will improve once gluco-

corticoids are stopped or reduced. This hypothesis is sup-

ported by the fact that the hazard ratios were lower when

we restricted our analysis to neuropsychiatric diagnoses

only and excluded patients treated with relevant psycho-

tropic drugs but without a relevant diagnosis. This could

mean that patients exposed to glucocorticoids were more

likely than unexposed patients to receive prescriptions for



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Clinical Guidance: Suicide Attempts, Delirium, and Mania From

Steroid Therapy

An epidemiological study by Fardet et al. of British general practice patients who re-ceived oral glucocorticoids showed that patients who received these drugs were seventimes as likely to attempt suicide as were patients with the same illness who did notreceive steroids. The increase was most prominent in younger people. Mania and de-lirium were also signicantly more common, particularly in older men. Neuropsy-chiatric effects were more common in patients receiving higher doses and those withprevious mental disorders. Brown (p. 447) notes in an editorial that this is the rstlarge-scale study of the effects of steroids, with over 300,000 patients exposed to thedrugs.


Conductas suicidas y trastornos neuropsiquiátricos post corticoides

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