Mortality Rates in Patients With Nervosa and Other Disorders A Meta-analysis of 36 Studies

Jon Arcelus,l.MS, MSc, FRCPsych. PhD; Alex]. Mitchell, MRCPsych;]adzie Wales, BA; S"ren Nielsen, MD

Context: Morbidity and mortality rates in patients with to adjust for study size using the OerSimonian-Laird eating disorders are thought to be high, but exact rates to allow for heterogeneity inclusion in the analysis remain to be clarified.

Data Synthesis: From 143 potentially relevant ar Obiactive: r 0 systematically compile and analyze the ticles, we found 36 quantitative studies with sufficient mortality rates in individuals with anorexia nervosa (AN), data for extraction. The studies reported outcomes of AN hulimia nervosa (BN), and not other­ during 166 642 person-years, BN during 32 798 person­ wise specified (FDNOS) years, and EDNOS during 22 644 person-years. The weighted mortality rates (ie, deaths per 1000 person Data Sources: A systematic literature search, ap­ years) were 5.1 for AN, 17 for BN, and 3.3 for EONO� praisal, and meta-analysis were conducted of the The standardized mortality ratios were 5.86 for AN, I.\)3 MFDUNElPuhMed. PsycINFO, and Embase databases for BN, and 1.92 for FONOS. One in 5 individuals wllh and 4 full-text collections (ie, ScienceOirect, lngenta Se­ AN who died had committed lect, Ovid, and Wiley-Blackwell Interscience).

Conclusions: Study Selection: Fnglish-Ianguage, peer-reviewed ar­ Individuals with eating disorders have Slg tides published between January 1, 1966, and Septem­ nificantly elevated mortality rates, with the highest rates her 30. 2010, that reported mortality rates in patients with occurring in those with AN. The mortality rates for BN eating disorders and EONOS are similar. The study found age at assess­ ment to be a Significant predictor of mortality for pa­ Data Extraction: Primary data were extracted as raw tients with AN. Further research is needed to identify pre numbers or confidence intervals and corrected for years dictors of mortality in patients with BN and EDNOS. of observation and sample size (ie, person-years of ob­ servation) Weighted proportion meta-analysis was used Arch Gen . 2011;68(7)724-731

ATlN(; DISORDERS ARE IN­ a common presentation in eating disor­ creaSingly recognized as an ders services, few published data exist re important cause of morbid­ garding mortality rates in patients givcII Author Affiliations: ity and mortality in young this diagnosis. 1 5 Anorexia nervosa is a Sl'­ lOllghhorollgh Univt'fsily E individuals. The lifetime risk rious illness in the young population, and ( enlre for ({t'search into Eating of anorexia nervosa (AN) in women is es­ outcome is often poor 5teinhausen" Disordt'rs I ollghhorough 46% n: UllIvnslly (Dr Arcclus) timated to be 0.3% to 1%. with a greater showed that only of patients fully Brandon Unit. Eating Disorders number of patients having bulimia ner­ covered from AN, a third improved with Service (Dr An:elus and vosa (BN)1 2 Anorexia nervosa is a seri­ only partial or residual features of the dis­ Ms Wales) and Department of ous psychiatric illness characterized by an order, and 20% remained chronically ill P�ycho-Oncology (Dr Mitchell) inability to maintain an adequate, healthy for the long term. A low I ei( ester Partnership Trust body weight. is charac­ (BMI), a greater severity of social and psy­ l.el(Tsler (.eneral Hospital. and terized by recurrent episodes of binge chological problems, self-induced vomit Departmenl of C.ancer and eating in combination with some form ing, and purgative abuse have been iden­ Molecular Medicine. l.eicesler of unhealthy compensatory behavior. Eat­ tifiedas predictors of poor outcome in tlll� Royal Infirmary. Univnslly of ing disorder not otherwise specified disorder 7 1.('i(Tslcr (Dr Mitl'hell) I.cltt·sln Fngland. and Region (FDNOS) is a caKhall DSM-IV diagnOSis Most mortality research in the eating Sja'lIand. ( hild and Adolescent for patients with significant featuresof eat­ disorders literature has focused on AN Psychiatric Services. Na'stved. ing disorders that do not meet the crite­ Some authors have suggested that the mor­ [knmark (Dr Nielsen) ria for AN or BN.l Despite EONOS being tality risk for BN is 10wN This conclusion

ARCH GEN PSYCHIATRY/VOl 68 (NO 7) JUI Y 2011 WWW ARCHGENPSYCHIATRY( OM 724 is surprising, given the medical complications associ­ lional decline only. and those that looked at other aspeos "I ated with self-induced , abuse, and other prognosis, such as hospitalization. without informatiol] purging behaviors. The ratio of observed to expected regarding mortality rate. Mantel-Haenszel pooled risk rallO, deaths (ie, the standardized mortality ratio [SMR]) for were estimated, with a Xl test for heterogeneity (Il) used It) assess between-study differences in effect 17 Random dfeth AN has been reported to be between 0.719 and ]2.8. III Also, models were fined if heterogeneity existed, and risk rallo.' it often has been reported that suicide is a particularly were presented as a forest plOI I" The forest plot shows study common cause of death in AN .11 12 Muir and Palmer'l sug· specific risk ratios (and their 95% lIs) and the relall\'" gested that official death certification may underesti­ weighted contribution of each study, as well as the risk rallo mate the incidence of suicide associated with this disor­ estimate pooled across all studies. The analyses wen' P(I­ der The wide variation of SMRs for eating disorders partly formed with StatsDirect statistical software. version 2. 7 7 may depend on the length of follow-up. For example, (StatsDirect Ltd, Cheshire, England) 4 Nielsen1 reported an SMR of 9.6 after approximately 10 for the analysis, we collected data regarding the number of years of follow-up, as opposed to 3.7 in 4 studies with a participants, the number of participants at follow.. up, mean age mean follow-up period ranging from 20 to 36 years. Other of the population studied at first assessment, sex, mean BMI at first assessment. whether the population studied was inpa factors that correlate with a higher estimate of mortality tient or outpatient, SMR, the percentage of dead case individu are age, case severity, study period, and whether other als, diagnosis. and predictors of death, if availahle. We discu,,, eating disorders with a lower mortality rate were evalu­ findings for AN, UN, and EDNOS separalely The outcome ,)[ ated separately." interest was mortality rate. Given this debate, the primary aim of our study was systematically to compile and to analyze mortality INCLUDED AND EXCLUDED STUDIFS rates in individuals with eating disorders, taking into account variations in sampling, diagnosis, and length Two independent assessors Ok and lW ) identified 143 rel­ of follow up of the study. Our hypothesis was that evant articles that were sneened in detail (Figure 1) In SOIl1[' mortality rates would be devated in all types of eating cases. Ihe aUlhors of those articles were contacted 10 gather fill disorders. We also aimed to explore factors associated ther information. '4 12 After doing so, we excluded 78 arlitil" with mortality among individuals with AN, BN, and because of inadequate duration of the study « I year fIll FDNOS. low-up or case series) or inadequate sample size (<' 15 pa lients) Review articles also were excluded from Ihe analy,i, Of the 6'5 articles retrieved for more detailed evaluation. 29 WI'I ,. ------1."'''00'4.------excluded because of lack of description of cases resulting ill death, same database used in other studies, or lack of diagn". SEARCH STRATEGY sis of death in cases. When investigators conducted multiplt: analyses reported in separate articles. we only se\eoed Ihe al A systematic literature search. appraisal, and meta-analysis weTe tide with a longer follow-up; 7 studies were excluded for Ihi ... conducted. The MFDUNFJPubMed, PsycINFO, and Embase reason ahslract datahases were searched from 1966 through Septem­ her 30. 2010 Also, 4 full-text collections, "cienceDirect. In­ SUMMARY OF RELEVANT STUDIES genta Select. Ovid Full text. and Wiley Blackwell Inter science, were searched, and an article published online ahead Thirty-six relevant empirical quantitative studies of monal of print was included. 10 A broad range of subject headings was ity in eating disorders were published between January I used to identify the relevant disorders and diagnoses For each 1966, and September 30, 2010. All but 1 study21 provided dalabase search. 7 main search components (eating disorders, data regarding mortality rate in patients with AN Twell't' anorexia nervosa, bulimia nervosa, eating disorder not otherwise studies prOVided information regarding patients with BN spedJiI'd mortality, death, and survival) were cre [FDNOS/, and 6 studies desrribed mortality rate in patients with a ated by combining subjecI headings with the "OR" operator. diagnosis of EDNOS. Twenty-five studies provided sufficient and Ihe same components then were combined by using the data for analysis of SMR in AN. Across 36 studies, 17 2i 2 "AND" operator Studies that followed up patients for a mini­ unique patienls had eating disorders Reponed death� mum of 1 year and included 15 or more participants at the time totalled 755. Considerable differences existed among 11ll' of analysis were included. Relevance was determined by screen­ studies regarding deSign, group size, and methods Few ing titles and abstracts. Reference lists of relevant articles were studies were prospectively organized. Diagnostic categoric ... s('feened for further potentially relevant studies, and citation changed considerably during the period of the studies In searches were conducted. The results arc reported for the ex­ some cases, duration of follow-up also was difficult to COli' posure groups for AN, BN, and EDNOS (eTable 1: http://www pute from the original studies. Besides missing data. thi' archgenpsychiatry .com) problem occurred due to variations in the definition of the slarting point or the general practice of providing onl) STATISTICAL ANALYSIS ranges instead of precise group parameters A general lack of control conditions and a scardty of pI!' Primary data were eXlracted as raw numbers or confidence rise information regarding treatment was observed in these stlld intervals « Is) and corrected for years of observation and ies. Different treatment and psychotherapeutic approaches were sample size (ie, person-years of observation) Weighted pro­ used. The diversity of interventions precluded any definite eval Ll portion meta-analysis was used to adjust for study size using ation of trealment effects. 24 Most outcome studies for AN I,' Ihe DerSimonian-Laird model to allow for heterogeneity ported crude mortality rates and SMRs. The crude mortalit � inclusion in the analysis We excluded artkles without rates may have been inflated slightly: not all studies reported adequale data such as those in which no raw number was pre­ the cause of death, so causes other than the eating disorder might sented (or calculable), those that examined predictors of func- have led to palient death

AR( H GFN PSY( HIA fRYIVOL 08 (NO 71 JUI Y 2011 WWW ARCHGFNPWCHIATRYCOM 725 532 Related to all eating disorders including EDNOS 1450 Excluded Not relevant to eating disorders • Not relevant to literature review 43Pat;�tiaIlY;�i;���; identified and screentld for -----' retrieval ;;;�;�I�;J 78 Excluded ---F--==------Ineligible population L Short-term study InadeQuate samPle ze _ 65 Retrieved for more � ______detailed evaluation 1 - 9 9 c � ���t�n of de in case] ------, : No diagnosis of death in cases Using the same database 35 Related to AN U 12 Related to BN 6 Related to EDNDS r- [18 AN] [ 1f-BN]

Figure 1. Literature review method used. AN indicates anorexia nervosa; BN, bulimia ner'losa; EDNOS, eating disorder not otherwise specified.

assumed that interstudy differences in age at assess· mt'nt, sex, BM!, and comorbid conditions. such as alco· hoI intake. could be related to mortality in AN Not ANOREXIA NERVOSA enough studies reported comorbid conditions, and no studies observed male patients. Therefore, meta Mortality Rate per Person-years regression analysis only could be conducted for age and BMI. This analysis showed Significant positive correia r hirty-five studies described the mortality rates of pa­ tion with age (r=O.l, P= .01) and nonSignificant corre· tients with AN (eTable 2) The mean (SD) follow-up pe­ lation with BMI on assessment (r=0 9, P= ll ) Results nod of the studies was 12-82 (7_ 39) years, with a maxi­ of the literature review regarding mortality in AN are pre mum mean time of follow-up period of 36.2 years. IS The sented in e Table 2- mean (SD) sample size was 360.7 (954.1), with a maxi­ mum sample size at follow-up of 6009 cases.In The 35 stud­ ies subjected to bias assessment (eFigure 1) followed up a total of 12 808 individuals and reported 639 total deaths. BULIMIA NERVOSA The total follow-up time was 166 642 person-years. Over­ all. the weighted annual mortality for AN was 5.10 deaths Mortality Rate per Person-years (95°,t, Cl, 399-6 14) per 1000 person-years (Figure 2), of which l. 3 deaths resulted from suicide. We analyzed14 Since the first study was reported in 1988, 12 studies de <;tlIdies that included only female patients with AN and scribed the mortality rates of patients with this diagnosis found that the weighted annual mortality rate was 5_ 39 (95% (eFigure"3 and eTable 3) Twelve studies followed up 2585 ( L 3 57 7 59) per 1000 person-years. The weighted mor­ individuals with BN and reported 57 deaths. The mean (�D) tality rate was lower for studies (n= II) that selected in­ sample size was 200.7 (252.6), and the mean (SD) fol­ palients (4 55; 95% CI, 3_09-6.28) low-up period was 9.34 (3.8) years. The total person years of follow-up was 32 798 years The mean follow·up Standardized Mortality Ratio period was 9.74 years. The mortality rate for BN was lower than that reported for AN, with a relative risk of mortality I wenty-five studies involving 12 189 patients with AN of LII (95% 0, 1.40- 3.20) The weighted mortality rate examined SMRs compared with a reference population was 1.74 (95% 0, 1.09-2.44) per 1000 person-years. We (ehgure 2) The mean follow-up period was 14.2 years examined separately 5 studies that reported on a female Hnerogeneity was high (11= 91.2%; 95% CI, 88.9%­ population only. The analysis found a weighted mortality t)L9%) The overall SMR using random-effects meta­ rate of 2.22 (95% CI, 0.73-4.72) per 1000 person years of analysis was 5.86 (95% n, 4. 17-8.26) follow-up. No male-only studies were found.

Predictors of Mortality Standardized Mortality Ratio

Meta-regression analysis was used to identify risk fac­ All 12 studies reported SMRs (although 3 studies re­ Inl<; of death in AN. A priori (based in the literature), we ported no deaths) (Figure 3). Heterogeneity was low

ARC H GEN PSYCHIATRY/VOL b8 (NO. 7) JULY 2011 WWW ARCHGENPSYClUA TRY COM 716 Proportion mela-analysis plot (random effects)

Joergensen21 (1992) • 0.0169 (0.009!Hl.0269) Tanaka el al" (2001) • 0.0138 (0.0056-{).0283)

Pagsberg and Wang" (1994) 0.0108 (0.0013 -0.0383)

Crow el al" (1999) • 0.0107 (0.0029 -0.0271) Rosling el al" (2011) - ... .. 0.0104 (0.0064-0.0158) Dancyger el al" (1997) • 0.0096 (0.0031-0.0223)

Deler and Herzog" (1994) • 0.0091 (0.0042-0.0172) Keel el al" (2003) 0.0082 (0.0039-0.0150)

Lowe el aF (2001) 0.0078 (0.0043-0.0131) Moller·Madsen el al" (1996) �-­ 0.0075 (0.0056-{).0099) Birmingham et al" (2005) +---- 0.0071 (0.0042-0.0114) Theander" (1970) �- 0.0071 (0.0045--0.0105) Eckert el al" (1995) : - 0.0069 (0.0022--0.0159) Fichler el al" (2006) 0.0067 (0.0027 -0.0138)

Ben-Tovim el al" (2001) 0.0065 (0.0013--0.0189)

Herzog el ai' (2000) 0.0058 (0.0023-0.0119)

Crisp el al" (1992) 0.0057 (0.0025--{).0113)

Crisp el al" (2006) 0.0051 (0.0038--0.0067)

Tolslrup el ai" (1985) 0.0048 (0.0022·-0.0090)

Hebebrand el al'" (1997) 0.0046 (0.0024-0.0081)

Patton" (1988) 0.0042 (0.0023-0.0071)

Button el al" (2010) I 0.0040 (0.0019-0.0073) Lee el al" (2003) '---117 0.0038 (0.0008--0.0110) Franko et al" (2004) � 0.0034 (0.0009-{).0087) Papadopoulos et al" (2009) • � 0.0033 (0.0029-0.0037) Korndorfer et ai' (2003) .� 0.0030 (0.0018--0.0048) Signorini et al" (2007) ----=-- 0.0027 (0.0006-{).0079) Crow et al" (2009) 1 ___1 0.0022 (0.0009-0.0045) Morgan et al" (1983) 0.0021 (5.41E-05-o.0118) Millar et al" (2005) rrr-:. � 0.0013 (0.0008-0.0020) Sullivan et al" (1998) : 0.0012 (5.0IE -05--0.0066) Lindblad el al" (2006) . 0.0010 (0.0004--0.0020)

Strober et al" (1997) � : 0.0000 (0.0000--0.0039) Halvorsen et al" (2004) � • 0.0000 (0.0000--0.0082) Wentz et al" (2009) ••- ....;...- 0.0000 (0.0000--0.0072) Combined 'I � 0 0050 (0.0040--0.0061) L T 0,00 0.01 0.02 0.03 0.04

Proportion (95% Confidence Interval)

Figure 2. Annual mortality rate per 1000 person-years in anorexia nervosa. Studies include male and female patients.

([1=0%). and the overall SMR using random-effects meta­ tality rate for FDNOS was 331 deaths (95% (1,1.41-\ analysis was 1.93 (95% Cl, 1.44-2. 59), a significant dif­ 5 75) per 1000 person-years ferences from 1.00 (P= 002) Standardized Mortality Ratio

EDNOS Mortality Rate Only 4 studies involving 1812 individuals with EONO" reported SMRs with CIs (e1able 4) The mean fol Mortality Rate per Person-years low up period was 10.9 years. Heterogeneity was 10\\ (12=0%), and the overall SMR using random--effects meta­ Only 6 studies described the mortality rate of patients analYSis was 1.92 (95% Cl, 1.46-2.52), a signifkant dtl with FDNOS (Figure4) The difficulties defining FDNOS 1 (P< .00l) makes it more complicated to study this group Despite ference from the relatively small number of studies, the examination Because of the small number of studies, multiregrrc,­ of this group is important to the indusivity of the study, sion analysis was not used to explore prognostic factors 101 given that these patients represent such a large propor­ mortality rate in patients with BN and EONOS No differ­ 1000 tion of patients observed in prat'lice. The mean (SD) ence in observed mortality (per person-years of foHm\­ sample size was 313 (391. 7) patients, and the mean fol­ up) between BN and EDNOS was found, but AN had a 2.7- low-up period of the studies was 9.1 (7 7) years. A total fold higher mortality rate than BN Time series analysl� of 1879 individuals were followed up, and the reported showed no statistically significant effectfor AN and BN but total number of deaths was 59. The total person-years of a negative correlation for FDNOS (adjusted R1=06b. follow-up was 22 644. Overall, the weighted annual mor- P= .01), suggesting a smaller effect in more recent studic�

ARCH GFN PSYCHIATRY/VOl 68 (NO 7) JIll Y 2011 WWW AR( HGENPSY( HIA TRY (OM 727 Proportion meta-analySis plot (random effects)

Patton" (1988) 0.548 (0.505-0.590)

Joergensen" (1992) 0.530 (0.457-0.603)

Button el al" (2010) 0.352 (0.313-0.393)

Crow el al" (1999) 0.317 (0.266-0.372) Crow el al" (2009) 0.205 (0.199-0.211) _ • Fichler and Quadflieg" (2004) • 0.165 (0 150-0.180) Birmingham el al" (2005) • 0.143 (0.134-0.154) Keel el al" (2003) • � 0.106 (0.087-0 127) Button el aI" (2010) I • 0.072 (0.065-0.081) Pagsberg and Wang" (1994)..­ 0.000 (0.000-0.058) Herzog el aP (2000). 0.000 (0.000-0.003) Ben-Tovlm el al" (2001), 0.000 (0.000-0.008) Combined +- 0.157 (0.096-0.229) I - 0.0 0.2 0.4 0.6 0.8 Proportion (95% Confidence Interval) l. __ Figure 3. Standardized mortality ratios (95% confidence Intervals) in patients with bulimia nervosa

Proportion meta-analysis plot (random effects)

Joergensen" (1992) I • 0.0119 (0.003:Hl.0302)

Ben· Tovim el al" (2001) �--- -11.1------0.0108 (0.001:Hl.0385)

Crowel al" (1999) I'-�-----�------'---'-­ 0.0067 (0.0002--0.0366)

Crow el al" (2009) 0.0030 (0.0022-0.0041)

Button et al22 (2010) 0.0013 (0.0006--0.0024)

Birmingham et al" (2005) 0.0009 (2.35E-05�J.0052) Combined I 0.0033 (0.0015-0.0058) c , , 0.00 0.01 0.02 0.03 0.04 Proportion (95% Confidence Interval)

Figure 4. Mortality rates per person-years in patients with eating disorder not otherwise specified.

ders. Indeed, it is equally useful to present the actual death ------I.iiJi§i¥' .------rate per person-year. The issue of diagnostic crossover also is important A rhe aim of this study was to measure mortality rate in range of rates have been reported in the literature. For patients with eating disorders using meta-analysis. The 20% ('xisting literature regarding mortality rate from eating individuals with AN, it has been suggested that to 50% disorders has several limitations. First, length of fol­ will develop BN over time.lO.ll.50 A study by Eddy et low-up has varied considerably. A second and probably a1"l showed that one-third of patients with an intake di­ 7 more important limItation is low ascertainment rates. ror agnosis of AN crossed over to BN during years of follow example, in the BN studies reviewed by Keel and Mitch­ up. This finding did not prevent patients from crossing el!, 4� some had ascertainment rates as low as 50%. Other back (ie, relapsing) into AN. Movement from an initial limitations include the relatively small numbers of study diagnosis of BN to AN is less common. A review by Keel 10%; patients with BN or EDNOS, the classification used in and Mitchell4Q put this figure at less than Eddy et 14.06% 7 the study, and the population studied. A further limita­ aPI found this rate to be during a -year fol­ tion is that many studies have focused on indirect SMRs. low-up period. This finding is important when examin­ Two major approaches to standardization, direct and in­ ing SMRs for the eating disorder groups because pa­ direct, have been used. Direct standardization is used when tients who had been diagnosed as haVing AN on the study population is large enough that age-specific rates assessment may have had BN by the time they died Di­ within the population are stable When the population agnostic crossover may have occurred; therefore, we can­ is small (or the outcome IS rare), the number of events not imply stability of diagnosis ohserved can be smalL In that drcumstam·e. indirect stan­ As hypotheSized. we found an overall elevated mor­ dardization methods can be used to produce an SMR. The tality rate for patients with all types of eating disorders. indirect �MR presents a comparison with the general This risk of death was highest for those with AN, with a population, but it is unclear whether this population is weighted annual mortality rate of 5 per 1000 person­ comparable with that of individuals with eating disor- years (slightly higher in studies of females only), fol-

--_._------'--'------ARCH GEN PSYCHIATRY/VOl 68 (NO 7). lUi Y 2011 WWWAR( HGfNPSYCHIATRYCOM 728 lowed by patients with EDNOS at 3 per 1000 person­ could be explained by the assertion that FDNOS some· years of follow-up and BN at 1.7 per 1000 person-years times reflected the earlier stages of AN. Further studic.., of follow-up. The mortality rate, particularly for AN, was are required before firm conclusions ('an be drawn. considcrably lower for those studies that had a long fol­ Our study found that thc mortality rates in patients low-up period, such as that by Korndorfcr et al,9 which with eating disorders are high. In some cases (ie, thosl' showed an SMR for AN of 0.71 and had 27.1 ycars of fol­ involving AN), they are much higher than for other psy­ low-up, or the study by Crow et aL21 with an SMR of 1.7 chiatric disordcrs. Studies in other psychiatric disorders . and a follow-up of 18.13 years. Studiesl';,IQ 40 with fewer have found SMRs of 2.8 and 2.5 in males and females with years of follow-up gencrally showed a high SMR. Given , ';4 1. 9 and 2. 1 in males and females with the cros,,'iover observedbetween diagnoses, the actual du­ , and 1.5 and 1.6 in males and females ration of follow-up may be less important than the du­ with unipolar disorder, respectively 'j'j ration of illness. The causes of patient deaths were not always avail­ PREDICTION OF DEATH able, and it is likely that many of the people who died may not havc had AN or an eating disorder at thc time Our secondary objective was to cxamine the fanors ;I.., of death. However, the rates of suicide were examined socia ted with mortality rate among the different diagno· separately because this was mentioned in a number of ses. Information rcgarding factors that predict out­ studies. fwclve studies described deaths from suicide in comes was drawn from only a handful of studies and patients with AN, and analysis showed that the weighted occasionally was conflicting.We anticipated that we would annual mortality due to suicide in AN was 1.39, which analyzc predictors of death in the varying diagnoses. How­ means that 1 in 5 individuals with AN who died had com­ ever, bccause an insufficient number of studics identi­ mitted suicide. fied risk factors by meta-regrcssion analysisfor the FDNOS rhe SMR values for BN and FDNOS are lower than and BN groups, this was examined for the AN studies only. for AN (ie, 5.86), giving individuals with FDNOS and Few studies specifically examined predictors of mortal­ BN SMRs of 1.92 and 1.93, respectively. It can be ar­ ity; instead, many examined predictors of poorer out­ gued that rcviews of SMR in BN can be highly selective come. Based on the information from different studil's, because they only may include those studies that have factors highlighted for poorer outcome, including mor­ found deaths at follow-up. In the present meta-analysis, tality, in patients with AN includcd older age at first prc­ we included all follow-up studies of patients with BN sentation,3U6.40 alcohol misuse ,22 34.55 and low BMI at pre­ Three of the studies did not find any case individuals who sentation.25.3446 Other strong predictors of mortalil y died, and 4 studies gave an SMR higher than 2. The low involved comorbid disorders, such as affective disorder, SMR suggests that a diagnosis of BN per se does not ren­ suicidal behavior or self-harm, alcohol abuse, and a his­ der an individual at increased risk of premature death, tory of hospitalization for such mental hcalth problcms. but this finding does not necessarily justify compla­ Button et aP2 found that only BMI at assessment and al­ cency, given that comorbid affective disorder and re­ cohol misuse reliably predicted mortality status, al­ lated behaviors may often accompany bulimic symp­ though evidence of an affective disorder almost was sig­ toms nificant Some studies24 46 also have found evidence of an Little has been reported regarding the morbidity or association betwcen alcohol misuse and increased mor­ mortality associatcd with EDNOS because this was not tality in AN. One of them1b found that youngcr age and an accepted diagnosis until the DSM-IV criteria were pub­ longer hospital stay at first hospitalization were associ­ lished, although atypical eating disorders were noted be­ ated with better outcome, and psychiatric and somatIC fore thcn. Our results for EDNOS suggesta possibly higher comorbidily worsened the outcome of patients with ea!· mortality risk than in BN. The SMR (ie, 192) reported ing disorders in this meta-analysis is higher that that reported in the Unfortunately, because of the small number of stud­ study by Birmingham et al,32 which found that SMR for ies that recorded different prognostic factors (such as so­ patients with EDNOS was only 1.1. Eating disorder not matic , alcohol and drug abuse, and psychi­ otherwise specified is a mixture of atypical AN and atypi­ atric comorbidity), meta-regression analYSis for these cal BN in International Statistical ClaSSification of Dis­ factors was not possible. However, the studies sclected eases, 1 Otlt Revision (ICD-l 0)';2terms; therefore, those find­ in this meta-analysis allow examination of the influenct' ings can bc difficult to interpret The question also cxists of weight and age at presentation on the SMR. One study of whcthcr patients with EDNOS had previously been or included in the meta-analysis11 found that when SMR is were likely to become patients with AN. Bascd on thc used as an index of mortality, an inverse trend scems to study by Eddy et al,';1 this would appear to be so. Thc occur, namely, higher SMR with lower weight at presen authors' depiction of the longitudinal course and cross­ tation. In view of this, some studies have suggested low over diagnoses for patients with an intake diagnosis of BMI on assessment as a predictor of death. However, meta· AN highlighted that some patients could be classified as regression analysis of the studies did not show a signifi­ having partial recovery. These figures ranged from 7'5% cant correlation between mortality and BMI on asscss to 85% during the 7-year follow-up period, depending ment. Because age at presentation is known, this POilll on subtype. Agras et aP3 examined the course of EDNOS frequently is used as a proxy variable for age at illness and found that only 18% of this group had never had or onset. Age at onset is difficult to determine with any prl' did not develop another diagnosed ED during the 4-year cision in most cases, Most of the studies included in this study. Thus, any elevated mortality risk of EDNOS partly meta-analysis indicated effectof age at presentation, which

ARCfI GEN PSYCHIATRY/VOl 68 (NO. 7) JUI Y lOll WWWARCHGENPSYC.HIATRY.COM 719 for most studies was a highly significant effect. Most stud­ Nielsen. Drafting of the manuscript Arcelus, Mitchell. ies report too few deaths in the younger age groups and Wales, and Nielsen. Critical revision oj the manuscript for t no many deaths in those presenting for treatment at age important intellectual wntent: Arcelus, Mitchell, Wales, 20 years or older A dear pattern can be observed across and Nielsen. Statistical analysis: Mitchell and Nielsen. Ad­ ages. an SMR of approximately 3 in the youngest, ap­ ministrative, technical, and material support: Arcelus and proxJnlately 10 in those aged 15 to 19 years, dose to 18 Wales. Study supervision: Arcelus in those aged 20 to 29 years, and approximately 6 in those Financial Disclosure: None reported. IV 110 present for treatment at age 30 years or older [Q 47.55.'56 Online-Only Material: The eTables and eFigures are avail­ able at http://www .archgenpsychiatry.com. lIMITA nONS AND FUTURE STUDIES

r his analysis has a number of limitations. Notably, we re lied on the quality and nonrepetition of primary publica Hoek HW. van Hoeken 0 Review olthe prevalence and incidence of eating disorders. 11011S. We sought to ensure data integrity by excluding small Int J Eat Disord. 2003;34(4):383-396. studies with less than I year of follow-up and fewer than 2. Preti A. de Girolamo G. Vilagut G. Alonso J. Graaf R, Bruffaerts R. Demyttenaere l'i patients. The possibility exiSL'i of counting some indi­ K. Pinto-Meza A, Haro JM, Morosini P. ESEMeD-WMH Investigators The epi· viduals twice, especially when several related publica­ demiology of eating disorders In SIX European countries results of the ESEMeD tions are derived from 1 group. We attempted to deal with WMH project. J Psychiatr Res, 2009;43(14):1125-1132 3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental duplicate data from the same authors by excluding stud­ Disorders. ed 4 Washington. DC American Psychiatric Association. 1994 ies in which the population characteristicswere nearly iden­ 4. Button EJ, Benson E. Nollett C. Palmer Rl. Don't forget EDNOS (eating disorder tical to those already entered. The study is limited by the not otherwise specified): patterns of service use in an eating disorders service. number of available published data for these diagnoses,and Psychiatr Bull. 2005;29 134-136 :llthough these were reasonably robust for AN, fewer were 5. Fairburn CG. Cooper Z. Bohn K, O'Connor ME. Doll HA. Palmer RL The severity and status of eating disorder NOS: implicationsfor DSM-V Behav Res Ther.2oo7. available for the other diagnoses Through the years, in­ 45(8):1705-1715 vestigators used many diagnostic and outcome assess­ 6. Steinhausen H-C. Outcome of eating disorders Child Adolesc Psychiatr Clin N ment measures; these measures reflected numerous defi­ Am. 2009;18(1):225-242. nitions (ie, diagnoses) of illness. The lack of consistency 7 Lowe B, Zipfel S, Buchholz C, Dupont Y. Reas DL. Herzog W Long-term out­ come of anorexia nervosa in a prospective 21-year follow-up study. PsycholMel/. of measures makes comparisons across studies difficult 2001;31 (5):881 -890. ( onsolidalion of measures, standardized definitions, and 8. Herzog DB, Greenwood ON, Dorer OJ, Flores AT. Ekeblad ER. Richards A, Blais reporting guidelines are critical to the further advance­ MA, Keller MB. Mortalityin eating disorders: a descriptive study Int J Eat Disord. ment of the field. In addition, although we have used the 2000;28(1 ):20-26. values published in the relevant studies,it is possible that 9. Korndorter SR, Lucas AR, Suman VJ. Crowson CS, Krahn LE, Melton LJ III. Long-term survivalof patients with anorexia nervosa: a population-based study not all deaths reported were due to the eating disorder it­ in Rochester. Minn. Mayo Clin Proc. 2003;78(3):278-284 <;elf because comorbid physical conditions were not re­ 10. Eckert ED. Halmi KA, Marchi P. Grove W. Crosby R. Ten-year follow-up of an­ ported. Despite the number of studies examined, it is im­ orexia nervosa: clinical course and outcome Psychol Med. 1995;25(1).143- possible to conclude whether patient death is a direct result 156. Strober M, Freeman R, Morrell W The long-term course of severe anorexia ner­ of eating disorders. Future studies only will be able to in­ 11 vosa in adolescents: survival analysis of recovery. relapse. and outcome predic­ vestigate cause and predictive factors of death in patients tors over 10-15 years in a prospective study. Int J Eat Disord. 1997;22(4) with eating disorders by developing large national or in­ 339-360. ternational databases containing information that should 12 Pompili M, Mancinelli I, Girardi P. Ruberto A. TatareUi R. Suicide in anorexia ner­ tnclude psychiatric and physical comorbidity,drug and al­ vosa: a meta-analysis. Int J Eat Disord. 2004;36(1):99-103. 13. Muir A, Palmer RL An audit of a British sample of death certificates in which cohol abuse, and personality factors,as well as the psycho­ anorexia nervosa is listed as a cause of death. Int J Eat Disord. 2004;36(3) pathologic features of eating disorders. The study showed 356-360. that mortality rates in individuals with eating disorders are 14 Nielsen S. Epidemiology and mortality of eating disorders. Psychiatr ClinNorth high not only for those with AN but also for those with Am. 2001;24(2):201-214. 15. Keel PK. Dorer OJ. Eddy KT. Franko 0, Charatan DL. Herzog DB. Predictors of FDNOS and BN,which highlights the seriousness of these mortality in eating disorders. ArchGen Psychiatry. 2003;60(2): 179-183 conditions. Future, robust studies should inform physi­ 16. Rosling AM, Sparen P. Norring C, von Knorring A-L Mortality of eating disor­ nans of the predictive factors associated with mortality rate ders a follow up study oltreatment in a specialist unit 1974-2000. Int J Eat Disord. in patients with EDNOS and BN; so far, late presentation 2011;44(4):304-310. of AN appears to be the only clear predictor of death among 17 Mantel N, Haenszel W Statistical aspects olthe analysis of data from retrospec· tive studies of disease. J Natl Inst. 1959;22(4)719-748 55.56 lhese disorders 18. Egger M, Smith GO. Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997;315(7121): 1533-1537 Submitted for Publication: July 22, 2010; final revision 19. Mlllier-MadsenS, Nystrup J. Nielsen S. Mortality in anorexia nervosa in Denmark received October 1,2010; accepted December 28,2010. during the period 1970-1987. Acta PsychiatrScand. 1996;94(6):454-459. 20. Crow S, Praus B. Thuras P Mortality from eating disorders a 5- to 10-year rec· (orrespondence: Jon Arcelus, lMS, MSc, MRCPsych, ord linkage study Int J Eat Disord. 1999;26(1)97-101 PhD, Brandon Unit, Eating Disorders Service, Leicester 21 Crow SJ, Peterson CB, Swanson SA, Raymond NC. Specker S. Eckert ED, Mitch· Partnership Trust,Leicester General Hospital,Gwendo­ ell JE. Increased mortality in bulimia nervosa and other eating disorders. Am J len Road, l.eicester LE5 4PW, England Q.Arcelus@lboro Psychiatry. 2009; 166(12) 1342-1346. :lc.uk) 22 Button EJ, Chadalavada B, Palmer RL Mortality and predictors of death in a co­ hort of patients presenting to an eating disorders service Int J Eat Disord. 2010: Author Contributions: Study concept and design: Arce­ 43(5):387-392. Ius A((luisition of data: Arceius, Mitchell, Wales, and 23. Fichter MM, Quadflieg N. Twelve-year course and outcome of bulimia nervosa Nielsen Analysis and interpretation of data: Mitchell and Psychol Med. 2004;34(8):1395-1406.

ARCH r;EN PSYCHIATRY/VOL 68 (NO 7). JUI Y 2011 WWWARCHGfNPSYCHlATRY COM 730 24 Steinhausen H-C. The outcome of anorexia nervosa in the 20th century. Am J 41 Franko DL. Keel PK. Dorer OJ. Blais MA. Delinsky SS. Eddy Kl Charat V Rnnn Psychiatry 2002: 159(8) 1284-1293 R. Herzog DB. What predicts suicide attempts in women with eating disordn,,;? 25. Theander S Anorexia nervosa a psychiatric investigation of 94 female patients. Psychol Med. 2004;34(5)843-853. Acta PsychiatrScand Suppl. 1970;214:1·194 42. Signorini A. De Filippo E. Panico S. De Caprio C. Pasanisi F. Contaldo F LOflo 26. Papadopoulos FC. Ekbom A. Brandt L. Ekselius L. Excess mortality. causes of death term mortality in anorexia nervosa: a report after an 8-year follow-up and a re and prognostic factors in anorexia nervosa. Br J Psychiatry. 2009;194(1) 10-17 view of the most recent literature Eur J Clin Nutr. 2007;61(1)119-122 27 Joergensen J. The epidemiology of eating disorders in Fyn County. Denmark. 43. Morgan HG. Purgold J. Wei bourne J. Management and outcome In anorexia nm 1977 1986. Acta PsychiatrScand 1992:85(1 ):30-34 vosa: a standardized prognostic study. Br J Psychiatry 1983.143:282-287 28 Tanaka H. Kiriike N. Nagata T. Riku K Outcome of severe anorexia nervosa pa­ 44 Millar HR. Wardell F. Vyvyan JP. Naji SA. Prescott GJ. Eagles JM Anorexia nero tients receiving inpatient treatment in Japan an 8-year follow-up study. Psy­ vosa mortality in Northeast Scotland. 1965-1999. Am J Psychiatry. 2005.1(;2 chiatry Clin Neurosci. 2001 :55(4)389-396. (4)165-172 29 Pagsberg AK. Wang AR. Epidemiology of anorexia nervosa and bulimia nervosa 45 Sullivan PF. Bulik CM. Fear JL. Pickering A Outcome of anorexia nervosa a C;l°.r in Bornholm County Denmark. 1970-1989. Acta Psychiatr Scand 1994:90 control study Am J Psychiatry. 1998;155(7):939-946. (4) .259-265 46 Lindblad F. Lindberg L. Hjern A. Improved survival in adolescent patients with 30 Dancyger IF. Sunday SR Eckert ED. Halmi A comparative analysiS of Minnesota KA anorexia nervosa. a comparison of two SwediSh national cohorts of female Multiphasic Personality Inventory profiles of anorexia nervosaat hospital admission. inpatients Am J Psychiatry. 2006;163(8):1433-1435. discharge. and 1O-year follow-up Compr Psychiatry. 1997;38(3):185-191 47 Halvorsen I. Andersen A. Heyerdahl S Good outcome of adolescent onset �n 31 Deter H-C. Herzog W Anorexia nervosa in a long-term perspective results of orexia nervosa after systematic treatment intermediate to long-term followtJP the Heidelberg-Mannheim Study. Psychosom Med. 1994;56(1 );20-27 of a representative county-sample Eur Child Adolesc Psychiatry 2004 13(5) 32 Birmingham CL. Su J. Hlynsky JA. Goldner EM. Gao M. The mortality rate from 295-306. anorexia nervosa Int J Eat Disord. 2005;38(2)143-146 48. Wentz E. Gillberg IC. Anckarsater H. Gillberg C. RAstam M. Adolescent·onsel nn 33 Fichter MM. Quadllieg N. Hedlund S. Twelve-year course and outcome predic­ orexia nervosa: 18-year outcome. Br J Psychiatry. 2009:194(2)168-174 tors of anorexia nervosa. Int J fat Disord. 2006;39(2):87-100. 49. Keel PK. Mitchell JE. Outcome in bulimia nervosa. Am J Psychiatry. 1997.154(3) 34 Ben· Tovim 01. Walker K. Gilchrist P. Freeman R. Kalucy R. Esterman A Out­ 313-321. come in patients with eating disorders a 5-year study Lancet. 2001 :357(9264) 50. Bulik CM. Sullivan PF. Fear J. Pickering Predictors of the development of hu 1254-1257 A limia nervosa in women with anorexia nervosa. J Nerv Ment Dis 1997 35 Crisp AH. Callender JS. Halek C. Hsu LK Long-term mortality in anorexia ner­ 18� (11):704-707 vosa;a 20-year follow-up olthe St George's and Aberdeen cohorts.Br J Psychiatry 51. Eddy Dorer OJ. Franko DL. Tahilani K. Thompson-Brenner H. Herzog 1992:161 104 107 KT. DB. Diagnostic crossover in anorexia nervosa and bulimia nervosa: implications fOI 36. Crisp A. Gowers S. Joughin N. McClelland L. Rooney B. Nielsen S. Bowyer C. DSM-V. Am J Psychiatry. 2008;165(2):245-250 Halek C. Hartman D. Tattersall M. Hugo P. Robinson D. Atkinson R. Clifton A. Death. survival and recovery in anorexia nervosa: a thirtyfive year study. fur Eat 52. World Health Organization. InternationalStatistical Classificationof Diseases. 10th Disord Rev. 2006.14(3):168-175. Revision (lCD-tO). Geneva, Switzerland: World Health Organization; 1992 37 Tolstrup K. Brinch M. Isager 1 Nielsen S. Nystrup J. Severin B. Olesen NS. 53. Agras WS, Crow S, Mitchell JE. Halmi KA,Bryson S. A 4-year prospective study Long-term outcome of 151 cases of anorexia nervosa The Copenhagen An­ of Eating Disorder NOS compared with full eating disorder syndromes. Int J tar orexia Nervosa Follow-Up Study Acta PsychiatrScand. 1985;71(4):380-387 Disord. 2009:42(6):565-570 38 Hebebrand J. Himmelmann GW. Herzog W. Herpertz-Dahlmann BM. Steinhau­ 54 Osby U, Correia N. Brandt L, Ekbom A. Spanin P Mortality and causes of de�th sen H·C. Amstein M. Seidel R Deter H-C. Remschmidt H. Schafer H. Prediction In schizophrenia in Stockholm County. Sweden. Schizophr Res. 2000;45( 1). of low body weight at long-term follow-up in acute anorexia nervosaby low body 21-28. weight at referraL Am J Psychiatry. 1997: 154(4):566-569 55 Deter HC. Schellberg 0, Kopp W. Friederich HC, Herzog W Predictability of n 39. Patton GC. Mortality in eating disorders. Psychol Med. 1988:18(4):947-951 favorable outcome in anorexia nervosa. fur Psychiatry. 2005;20(2):165-172 40. Lee S. Chan YYL. Hsu LKG. The intermediate-term outcome of Chinese patients 56. Osby U. Brandt L. Correia N. Ekbom A, Sparen P. Excess mortality in bipolar aml with anorexia nervosa in Hong Kong Am J Psychiatry. 2003:160(5):967-972 unipolar disorder in Sweden. Arch Gen Psychiatry. 2001 ;58(9) 844-850.

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