A r t ic le

S u ic id a l B e h a v io r a n d S e v e re N e u ro p sy c h ia tric ; iso rd e rs F o llo w in g G lu c o c o rtic o id T h e ra p y in P rim a ry C a re

Laurence Fardet, M.D., Ph.D. Irene Petersen, Ph.D. Irwin Nazareth, M.D., Ph.D.
O b je c tiv e : The incidence and the risk of suicidal behaviors and severe neuropsychiatric disorders in people treated w ith system ic glucocorticoids are poorly know n. The authors assessed the incidence rates of depression, m ania, delirium , panic disorder, and suicidal behaviors in patients treated w ith glucocorticoids in prim ary care settings and the risk factors for developing these outcom es. M e th o d : D ata w ere obtained for all adult patients re gistered betw een 1990 and 2008 at U.K. general practices contributing to The Health Im provem ent Netw ork (THIN) prim ary care database. The incidence rates for the outcom es of interest w ere assessed in patients w ho received prescriptions for oral glucocorticoids and com pared w ith those in patients w ho did not receive such prescriptions. The predictors of these outcom es in exposed patients w ere ascertained using Cox proportional hazards m odels. R e s u lts : O verall, 786,868 courses of oral glucocorticoids w ere prescribed for 372,696 patients. The authors identifed 109 incident cases of suicide or suicide attem pt and 10,220 incident cases of severe neuropsychiatric disorders in these patients. The incidence of any of these outcom es w as 22.2 per 100 person-years at risk for frst-course treatm ents. Com pared to people w ith the sam e underlying m edical disease w ho w ere not treated w ith glucocorticoids, the hazard ratio for suicide or suicide attem pt in exposed patients w as 6.89 (95% CI=4.5210.50); for depression, 1.83 (95% CI=1.721.94); for m ania, 4.35 (95% CI=3.675.16); for delirium , confusion, or disorientation, 5.14 (95% CI=4.545.82); and for panic disorder, 1.45 (95% CI=1.151.85). O lder m en w ere at higher risk of delirium /confusion/ disorientation and m ania, w hile younger patients w ere at higher risk of suicide or suicide attem pt. Patients w ith a previous history of neuropsychiatric disorders and those treated w ith higher dosages of glucocorticoids w ere at greater risk of neuropsychiatric outcom es. C o n c lu s io n s : Glucocorticoids increase the risk of suicidal behavior and neuropsychiatric disorders. Educating patients and their fam ilies about these adverse events and increasing prim ary care physicians aw areness about their occurrence should facilitate early m onitoring. (A m J P sy c h ia try 2 0 1 2 ; 1 6 9 :4 9 1 4 9 7 )

atural glucocorticoids such as cortisol affect behavior, mood, and other CNS-related processes (1). Abnormalities of the hypothalamic-pituitary-adrenal axis, notably hypercortisolemia and specifc dysfunction in glucocorticoid negative feedback, have been demonstrated in people with mood disorders (15). Additionally, some 50%80% of patients with endogenous hypercortisolemia (Cushings syndrome) meet DSM-IV criteria for major depression (6), and about 10% experience psychosis or mania (7). The association of exogenous glucocorticoids 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 retrospective studies indicate prevalence rates of glucocorticoid-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

medical disease are unknown. Moreover, some authors have asserted that a single glucocorticoid-induced disturbance should not be regarded as a contraindication for future glucocorticoid treatment, but some case reports have described individuals who experienced recurrent psychiatric disturbances when challenged with glucocorticoids (15, 16). The evidence base for adverse events such as delirium, panic disorder, and suicidal behavior is poorly developed 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.

M e th o d
D a ta S o u rc e
Approximately 98% of the population in the United Kingdom is registered with a general practitioner (17). The Health Improve-

This article is featured in this m onths AJP A u d io , is discussed in an e d ito ria l by D r. Brow n (p. 447), is an article that provides C lin ic a l G u id a n c e (p. 497), and is the subject of a C M e course (p. 547) A m J Psych ia try 1 6 9 :5 , M ay 2 0 1 2 a jp.p sych ia tryo n lin e.o rg Downloaded From: http://ajp.psychiatryonline.org/ by a WORLD HEALTH ORGANIZATION User on 05/22/2012

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S U iC i; A l B e H A V iO r A N ; N e U r O P S Y C H iA T r iC ; iS O r ; e r S A F T e r G lU C O C O r T iC O i; T H e r A P Y

ment Network (THIN) is a database of anonymized electronic medical records from general practices across the country. Participating general practitioners systematically and prospectively retrieve and enter clinical information on patients, including demographic data, diagnoses, and prescriptions. The database thus provides a longitudinal medical record for each patient. The consultation and prescription data recorded in THIN compare favorably with national data (18). THIN has been validated through audits, comparisons with external statistics, and independent studies and has been shown to have a high level of completeness of clinical diagnostic and prescribing data (1921). To minimize any bias on disease occurrence or prescriptions issued, we restricted our analyses to high-quality data by using quality indicators as defned elsewhere (18, 22), and we excluded entries made within 6 months after registration with the general practice as this may represent retrospective recording of a past history rather than a new episode of a problem (23). We used data from January 1, 1990, to December 31, 2008, from 424 general practices.

that occurred within the frst 3 months of the drug being prescribed.

G lu c o c o rtic o id -E x p o se d G ro u p
We identifed all patients age 18 and older who received at least one oral glucocorticoid prescription. For multiple consecutive prescriptions, the treatment duration was defned as the time from the frst to the last prescription plus the duration of the last prescription. Patients who received a new prescription for an oral glucocorticoid after a period of 3 months or more without were considered to have started a new treatment course. We calculated the prescribed daily dose for each course by multiplying the number of pills prescribed by the dose per pill (calculated in prednisone equivalents) and dividing this result by the number of days for which the drug was prescribed. We took into account the daily dose recorded at the beginning of the course to analyze the effect of drug dosage on outcome. The medical diagnosis recorded on the date that glucocorticoids were started was used as the indication 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 this prescription.

Id e n tif c a tio n o f G lu c o c o rtic o id P re sc rip tio n s

In THIN, each drug is encoded using Multilex codes that are associated 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 prescriptions (18). We selected all oral glucocorticoids prescribed, which included prednisolone, prednisone, hydrocortisone, dexamethasone, triamcinolone, betamethasone, methylprednisolone, and defazacort. Patients treated exclusively with topical, inhaled, or parenteral glucocorticoids were not included in the analyses.

U n e x p o se d G ro u p s
Unexposed groups were patients who did not receive prescriptions for oral glucocorticoids. From the pool of eligible individuals, two comparison groups were identifed. The frst was a selection of a random sample of patients who did not receive glucocorticoid prescriptions, and the second was a random sample of patients who did not receive glucocorticoid prescriptions but who had diagnoses of the same underlying medical diseases as the exposed patients. We selected up to four unexposed individuals from each of these groups for every exposed individual. When selecting the unexposed groups, we stratifed the sample to ensure that they had the same distribution of sex and age (within 10-year age bands) as the glucocorticoid-exposed group. We accounted for the clustering effect within general practices by selecting exposed and unexposed patients from within the same practice. For each unexposed patient, a randomly selected index date was defned at least 6 months after his or her registration.

Id e n tif c a tio n o f N e u ro p sy c h ia tric D iso rd e rs

All diagnoses and symptoms are recorded in THIN using the Read classifcation system (24). The Read classifcation and the Multilex codes were used to create medical and drug code lists that enabled us to identify cases of suicide or suicide attempt; depression; mania; delirium, confusion, or disorientation; and panic disorder in the database. We compiled lists for Read codes and for drug codes by conducting relevant word and code searches in the Read code and drug code dictionaries, as previously described (25). For instance, patients were defned as depressed if they had a Read code entry for unipolar depression, for symptoms of depression (e.g., low mood), or for a prescription for an antidepressant on a given consultation date. Diagnoses were considered frst; prescriptions of antidepressants were used in defning the outcome only when there was no recorded diagnosis of a neuropsychiatric illness and no other recorded indication for the prescription. To exclude patients who may have received prescriptions for antidepressants for anxiety rather than for depression, we eliminated those who had an entry for anxiety or panic disorder but had no entry for depression in their entire computerized medical record. For Read code searches, depression was identifed, with bipolar disorders and depression with psychosis excluded. We applied similar methods to defne mania (diagnosis or symptoms of mania or prescription of antimanic medication), delirium/confusion/disorientation (diagnosis or symptoms of delirium, confusion, or disorientation or prescription of antipsychotic medication), panic disorder (diagnosis of panic disorder or panic attack but excluding codes for anxiety), and suicidal behavior (diagnosis of suicide or suicide attempt). Death certifcates for people who died during the study period were also reviewed to identify those who died from suicide. A glucocorticoid-induced outcome was defned as one that was recorded after glucocorticoid initiation and with a preceding interval of at least 6 months with no similar entry (i.e., no coded entries for diagnosis or for symptoms or medications linked to the diagnosis). For long-term glucocorticoid therapies (i.e., lasting more than 3 months [26]), we arbitrarily defned a glucocorticoid-induced outcome as one

S ta tistic a l A n a ly sis
For each participant, follow-up time was accrued from glucocorticoid initiation or index date until the date of the outcome, the end date of glucocorticoid exposure (up to 3 months after glucocorticoid initiation), a date up to 3 months after the index date, the date of leaving the practice, the date of death, or the end of the study period. We calculated incidence rates by dividing the number of newly diagnosed cases of suicide or suicide attempt, depression, mania, delirium/confusion/disorientation, and panic disorder by the total follow-up time in the study cohort. This was frst done as a total for all outcomes and then for each one in turn. Incidence rates were estimated for all glucocorticoid courses and then separately for the frst, second, and third or later courses. We assessed risk factors for each outcome using Cox proportional hazards models. We initially compared the exposed and unexposed groups to assess hazard ratios associated with the frst prescription issued for glucocorticoids, and we performed a sensitivity analysis that excluded prescriptions for antidepressants, antipsychotics, or antimanic agents as a defnition of a neuropsychiatric 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 outcomes in patients treated with glucocorticoids. In those who received multiple courses, only one course was randomly selected to avoid a clustering effect within patients. We selected a random mixture of frst and later exposures to glucocorticoids to examine

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FA r ; e T, P e T e r S e N , A N ; N A Z A r e T H TA B l e 1 . C h a ra c te ristic s o f S tu d y P o p u la tio n s in a n A n a ly sis o f S u ic id a l B e h a v io r a n d S e v e re N e u ro p sy c h ia tric ; iso rd e rs F o llo w in g G lu c o c o rtic o id T h e ra p y in P rim a ry C a re First Unexposed Population, Stratifed by Age and Sex (N=1,224,984) Mean 55.2 N 717,840 296,777 SD 19.1 % 58.6 24.2 Exposed Patients With an Identifed Indication for Prescription (N=261,272) Mean 55.3 N 155,979 65,862 SD 18.9 % 59.7 25.2 Second Unexposed Population, Stratifed by Age, Sex, and Underlying Disease (N=660,776) Mean 53.5 N 393,162 174,386 SD 18.8 % 59.5 26.4

Characteristic Age (years)a Female Previous history of neuropsychiatric disorder Underlying disease Lower respiratory tract infection Asthma Chronic obstructive pulmonary disease Polymyalgia rheumatica or giant cell arteritis Other

All Exposed Patients (N=372,696) Mean 57.5 N 220,272 89,396 SD 18.8 % 59.1 24.0

100,720 78,924 20,329 19,250 42,049

38.5 30.2 7.8 7.4 16.1

309,177 229,746 43,916 1,206 76,731

46.8 34.8 6.6 0.2 11.6

a Age at frst glucocorticoid prescription for exposed patients or age at randomly selected index date (see text) for unexposed patients.

whether previous exposure to glucocorticoid therapy was associated with the risk of developing a neuropsychiatric illness. Models were ftted sequentially, adjusting for each individual potential confounderage (classifed into four categories), sex, past history of glucocorticoid use (yes or no), past history of any neuropsychiatric disorder (yes or no), daily dose of glucocorticoids (classifed into fve categories), and underlying medical disease. The initial daily dose of glucocorticoids was missing for 11% of glucocorticoid courses and was then addressed through multiple imputation, which assumed that the missing covariate values were missing at random. The proportional hazard assumption was checked graphically and by analyzing Schoenfeld residuals. For continuous variables, we checked linearity by comparing two models, one with the linear term and the other with the categories using the log-likelihood ratio test. We examined for differences in the effect of glucocorticoid daily dose between men and women and according to age by testing the dose-by-sex and doseby-age interaction terms. These were not signifcant and hence were excluded from the fnal model. Incidence rates are reported per 100 person-years at risk. All analyses were conducted using Stata, version 11.1 (StataCorp, College Station, Tex.). The study was approved by the University College London THIN steering committee and by the THIN scientifc review committee.

r e su lts
In total, 786,868 courses of oral glucocorticoids, representing 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 identifed for 560,472 courses prescribed in 261,272 patients. The characteristics of both the exposed and the unexposed patients are summarized in Table 1. In c id e n c e a n d A sso c ia tio n W ith G lu c o c o rtic o id E x p o su re In patients exposed to glucocorticoids, we identifed 19 incident cases of completed suicide, 90 incident cases of suicide attempt, 6,918 incident cases of depression, 2,030
A m J Psych ia try 1 6 9 :5 , M ay 2 0 1 2

incident cases of delirium/confusion/disorientation, 898 incident cases of mania, 266 incident cases of panic disorder, 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 personyears at risk for frst 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 all neuropsychiatric disorders (all exposed patients, hazard 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 frst prescription of glucocorticoids issued. Compared with the unexposed populations, the risk of suicide or suicide attempt increased fve- to sevenfold in people treated with glucocorticoids (all exposed patients, hazard ratio=5.27, 95% CI=3.827.29; exposed patients with an indication 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/disorientation (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 exposed patients, hazard ratio=5.66, 95% CI=5.096.60; exposed patients with an indication for prescription, hazard 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 prescription, 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 prescription, hazard ratio=1.45, 95% CI=1.151.85).
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S U iC i; A l B e H A V iO r A N ; N e U r O P S Y C H iA T r iC ; iS O r ; e r S A F T e r G lU C O C O r T iC O i; T H e r A P Y F iG U r e 1 . A sso c ia tio n B e tw e e n F irst C o u rse o f G lu c o c o rtic o id s a n d r isk o f N e u ro p sy c h ia tric O u tc o m e s in e x p o se d C o m p a re d W ith U n e x p o se d P a tie n ts

All Exposed Patients Compared With Unexposed Patientsa All Depression Delirium, Confusion, or Disorientation Mania Panic Disorder Suicidal Behavior Psychiatric Referralc 0 2 4 6 Hazard Ratio (95% CI) 8 0 2 4 6 8 10 Hazard Ratio (95% CI) Exposed Patients With an Identified Indication for Prescription Compared With Unexposed Patientsb

a Model adjusted for sex, age, and past history of neuropsychiatric disorders. Unexposed patients (N=1,224,984) were a random sample of b Model adjusted for sex, age, underlying medical disease, and past history of neuropsychiatric disorders. Unexposed patients (N=660,776)

patients who did not receive glucocorticoid prescriptions, frequency-matched for age and sex with the exposed group (N=372,696).

were a random sample of patients who did not receive glucocorticoid prescriptions but who had diagnoses of the same underlying medical diseases as the exposed patients, frequency-matched for age, sex, and underlying medical disorder with the exposed group (N=261,272). c Record of psychiatric referral without any details of the symptoms experienced.

Sensitivity analysis excluding patients for whom medication was used to determine diagnoses of depression, mania, and delirium/confusion/disorientation revealed qualitatively similar fndings. 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 patients with an identifed indication for prescription were compared with unexposed patients with the same underlying medical disease. R isk F a c to rs Larger daily doses of glucocorticoids and a prior history of neuropsychiatric disorders were associated with a greater risk of all incident outcomes, whereas prior treatment with glucocorticoids was associated with a lower risk (Table 2). Women were at higher risk of depression and at lower 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 considering 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).

; isc u ssio n
To our knowledge, this is the largest study to date examining the effects of glucocorticoid treatment on adverse

neuropsychiatric outcomes. We found a high incidence of neuropsychiatric adverse events in the frst 3 months of treatment with glucocorticoids. Overall, the incidence was 15.7 per 100 person-years at risk, and for patients on their frst course of glucocorticoids, it was 22.2 per 100 personyears at risk. Despite a low incidence, the risk of suicide or suicide attempt increased up to sevenfold in patients treated 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 glucocorticoids, 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 distressing adverse events experienced by this patient group (29), and yet only limited data are available on their incidence and predisposing risk factors (8, 30). A 1983 literature 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 specifed. We observed a twofold increase in risk of depression in people exposed to glucocorticoids, 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 patients treated with glucocorticoids as in those not exposed
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FA r ; e T, P e T e r S e N , A N ; N A Z A r e T H TA B l e 2 . r isk F a c to rs fo r N e u ro p sy c h ia tric ; iso rd e rs in th e G lu c o c o rtic o id -e x p o se d P o p u la tio n Depression a (N=3,424) Risk Factor Sex (women versus men) Age (years) 1830 (reference) 3150 5170 71 Initial daily dose d (mg) 10 1120 2140 4160 61 Past history of glucocorticoid therapy Past medical history Depression Delirium, confusion, or disorientation Mania Panic disorder Suicide attempt Underlying disease Lower respiratory tract infection Asthma Chronic obstructive pulmonary disease Polymyalgia rheumatica/giant cell arteritis Other medical disease. Hazard Ratio 1.26 1.00 1.14 1.27 1.24 1.00 1.08 1.04 1.57 2.03 0.67 95% CI 1.171.35 0.971.35 1.091.49 1.061.46 0.981.19 0.951.14 1.351.82 1.722.39 0.630.73 Delirium, Confusion, or Disorientation a (N=1,537) Hazard Ratio 0.84 1.00 2.06 6.39 10.30 1.00 1.85 1.34 4.88 6.01 0.34 95% CI 0.760.93 1.203.56 3.8210.68 6.1717.20 1.572.17 1.151.56 4.075.86 4.977.28 0.290.39 Panic Disorderb (N=109) Hazard Ratio 1.13 1.00 0.58 0.53 0.39 1.00 3.42 4.01 5.08 2.44 95% CI 0.771.68 0.301.09 0.290.97 0.210.74 1.537.67 1.928.40 1.8414.05 0.5211.49 Suicidal Behaviorc (N=51) Hazard Ratio 1.23 1.00 0.89 0.22 0.27 95% CI 0.702.19 0.411.91 0.080.54 0.110.65

Mania a (N=599) Hazard Ratio 0.73 1.00 1.47 2.55 2.93 1.00 1.17 1.22 3.24 5.18 0.47 95% CI 0.620.86 0.852.53 1.534.24 1.764.88 0.901.53 0.971.54 2.394.38 3.856.97 0.380.57

1.39 0.56 0.80 0.99 1.30 1.00 0.75 1.06 0.60 1.02

1.291.50 0.430.72 0.631.01 0.831.19 1.021.65 0.660.86 0.911.23 0.520.69 0.931.11

0.64 0.92 0.59 0.84 1.09 1.00 0.41 0.59 0.26 1.22

0.560.74 0.691.21 0.370.94 0.581.20 0.621.94 0.310.55 0.450.79 0.200.34 1.071.38

0.83 1.19 1.82 0.68 0.88 1.00 0.60 0.77 0.41 1.05

0.681.03 0.801.79 1.192.77 0.381.21 0.391.98 0.420.86 0.521.14 0.280.61 0.861.29

4.64

2.757.83 9.87 4.7420.53

a Model adjusted for sex, age, initial daily dose, past history of glucocorticoid therapy, past history of neuropsychiatric disorder, and underlying b Model adjusted for sex, age, initial daily dose, and past history of panic disorder. c Model adjusted for sex, age, and past history of suicide attempt. d In prednisone equivalents.

to glucocorticoids. Although the risk factors were different 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/confusion/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 neuropsychiatric adverse disorders, which is consistent with previous 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 fndings from previous research (3234), we found that a prior history of neuropsychiatric
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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 specifc neuropsychiatric disorder places a patient at risk of developing the same disorder when next exposed to glucocorticoids, hence reducing their chances of developing a new neuropsychiatric problem. This would explain why a past history of a given neuropsychiatric disorder may seem to protect against other neuropsychiatric disorders. We also found that previous treatment with glucocorticoids was associated with a lower risk of developing a neuropsychiatric outcome. The most likely explanation for this fnding is that patients known to have had a psychiatric adverse event after starting treatment with a glucocorticoid 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 arteritis may be less likely to develop neuropsychiatric disa jp.p sych ia tryo n lin e.o rg

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S U iC i; A l B e H A V iO r A N ; N e U r O P S Y C H iA T r iC ; iS O r ; e r S A F T e r G lU C O C O r T iC O i; T H e r A P Y

orders and that the risk of panic attack decreased at the highest glucocorticoid dosage. There is no clear explanation 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 decreasing 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 allowed 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 example, it is known that in the THIN database, symptoms (e.g., low mood) are frequently recorded instead of a defnite illness for some common mental illnesses such as depression (35). Nevertheless, our fndings are relevant to clinical practice, since we included diagnostic labels used in general practice rather than strict DSM-IV or ICD10 classifcations. 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 associated with severity of the medical illness rather than the glucocorticoid treatment. However, the effects of glucocorticoids could be separated from those of disease severity only in a randomized controlled trial that included people with similar levels of disease severity receiving either glucocorticoids or placeboan ethically unacceptable design. Third, we chose to use diagnoses and prescribed drugs (i.e., antidepressants, antipsychotics, and antimanic agents) to defne 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 underestimated 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 glucocorticoids are stopped or reduced. This hypothesis is supported by the fact that the hazard ratios were lower when we restricted our analysis to neuropsychiatric diagnoses only and excluded patients treated with relevant psychotropic drugs but without a relevant diagnosis. This could mean that patients exposed to glucocorticoids were more likely than unexposed patients to receive prescriptions for

psychotropic medications without entry of a concomitant neuropsychiatric diagnosis in the record since the clinician would have taken for granted that concomitant neuropsychiatric dysfunction is a possible effect of glucocorticoid 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 different phenomena that may or may not be related. People treated with glucocorticoids have a twofold higher risk of developing depression, a four- to fvefold higher risk of developing mania or delirium/confusion/disorientation, and nearly a sevenfold higher risk of committing or attempting suicide compared with people unexposed to glucocorticoids. Physicians must exercise caution in administering 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 relevant neuropsychiatric 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 requires evaluation.

R e ce ive d Ju ly 6 , 2 0 1 1 ; re v isio n s re ce ive d Se p t. 2 7 a n d N o v. 1 8 , 2 0 1 1 ; a cce p te d D e c . 5 , 2 0 1 1 (d o i: 1 0 .1 1 7 6 /a p p i.a jp.2 0 1 1 .1 1 0 7 1 0 0 9 ). Fro m th e M e d ica l R e se a rch C o u n cil G e n e ra l P ra ctice R e se a rch Fra m e w o rk, Lo n d o n ; th e D e p a rtm e n t o f In te rn a l M e d icin e , Sa in t-A n to in e H o sp ita l, P a ris; th e F a cu lty o f M e d icin e , U n ive rsity P ie rre a n d M a rie C u rie , P a ris; a n d th e R e se a rc h D e p a rtm e n t o f P rim a ry C a re a n d Po p u la tio n H e a lth , R o y a l Fre e C a m p u s, Lo n d o n . A d d re ss co rre sp o n d e n ce to D r. F a rd e t (la u re n ce .fa rd e t@sa t.a p h p.fr). T h e a u th o rs re p o rt n o fn a n cia l re la tio n sh ip s w ith co m m e rcia l in te re sts. Su p p o rte d b y a g ra n t fro m th e Fre n ch N a tio n a l So cie ty o f In te rn a l M e d icin e a n d th e P u b lic A ssista n ce -P a ris H o sp ita ls to D r. F a rd e t. D r Pe te rse n re ce ive d fu n d in g fro m th e U.K . M e d ica l R e se a rch C o u n cil (g ra n t G 0 6 0 1 7 2 6 ).

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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 received oral glucocorticoids showed that patients who received these drugs were seven times as likely to attempt suicide as were patients with the same illness who did not receive steroids. The increase was most prominent in younger people. Mania and delirium were also signifcantly more common, particularly in older men. Neuropsychiatric effects were more common in patients receiving higher doses and those with previous mental disorders. Brown (p. 447) notes in an editorial that this is the frst large-scale study of the effects of steroids, with over 300,000 patients exposed to the drugs.

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