Isotretinoin treatment for acne and risk of depression

18 Pages·2012·0.66 MB·English

Isotretinoin treatment for acne and risk
of depression: A systematic review and
meta-analysis
Yu-Chen Huang, MD,a,b and Ying-Chih Cheng, MDc,d
Taipei and New Taipei City, Taiwan
Background: The relationship between isotretinoin treatment for acne and depression is controversial.
Quantitative analysis has not yet been conducted.
Objective: To conduct a meta-analysis, evidence-based examination of the relationship between
isotretinoin and depression.
Method: Asystematicreviewandmeta-analysisoftheliteraturepublishedfrominceptiontoSeptember30,
2016,wasconducted.Controlledorprospectivenon-controlledtrialson$15acnepatientsreceivingisotretinoin
treatmentwereincluded.Theprevalenceofdepressionandchangeindepressionscoreswerecalculated.
Result: Thirty-one studies met the inclusion criteria. In the controlled studies, the change in depression
scores from baseline was not significantly different between patients receiving isotretinoin treatment and
those receiving an alternative treatment (standardized mean difference [SMD] (cid:1)0.334, 95% confidence
interval [CI] (cid:1)0.680 to 0.011). The prevalence of depression after isotretinoin treatment significantly
declined(relativerisk[RR]0.588,95%CI0.382e0.904).Themeandepressionscoressignificantlydecreased
from baseline (SMD (cid:1)0.335, 95% CI (cid:1)0.498 to (cid:1)0.172).
Limitations: No randomized controlled trials were reviewed; a large inter-study variation was observed.
Conclusions: Isotretinoin treatment for acne does not appear to be associated with an increased risk for
depression. Moreover, the treatment of acne appears to ameliorate depressive symptoms. (J Am Acad
Dermatol 2017;76:1068-76.)
Keywords:acne;depression;isotretinoin;meta-analysis;psychologicalimpact;systemicreview.
A
cneisacommon,chronicskinconditionthat
Abbreviationsused:
affects nearly all adolescents. Isotretinoin is
the most effective treatment available for CI: confidenceinterval
recalcitrant nodulocystic acne.1 The possible RCT: randomizedcontrolledtrial
RR: riskratio
induction of depressive symptoms by isotretinoin SD: standarddeviation
treatment for acne was first reported in 1983.2 In SMD: standardizedmeandifference
1998,theUSFoodandDrugAdministrationissueda
warning regarding the possible associations of
isotretinoin with depression, psychosis, suicidal based studies in 20003 and 2003,4 as well as several
ideation, and suicide. However, 2 largepopulation- controlled5-8andnoncontrolledstudies,9-14failedto
FromtheDepartmentofDermatology,WanFangHospital,Taipei Reprintsnotavailablefromtheauthors.
Medical Universitya; Department of Dermatology, School of Correspondence to: Yu-Chen Huang, MD, Department of
MedicineandCollegeofMedicine,TaipeiMedicalUniversityb; Dermatology, Wan Fang Hospital, Taipei Medical University,
Department of Psychiatry, Cardinal Tien Hospital, New Taipei 111,Hsing-LongRoadSec3,WenshanDistrict,TaipeiCity116,
Cityc; and Department of Public Health and Institute of Taiwan.E-mail:[email protected].
Epidemiology and Preventive Medicine, College of Public PublishedonlineMarch10,2017.
Health,NationalTaiwanUniversity,Taipei.d 0190-9622/$36.00
Fundingsources:None. (cid:1)2016bytheAmericanAcademyofDermatology,Inc.
Conflictsofinterest:Nonedeclared. http://dx.doi.org/10.1016/j.jaad.2016.12.028
AcceptedforpublicationDecember20,2016.
1068
JAMACADDERMATOL Huang and Cheng 1069
VOLUME76,NUMBER6
demonstrate an increased risk for depression or English. The search parameters included the
suicide associated with isotretinoin. In 2008, a case terms ‘‘depression’’ combined with ‘‘isotretinoin,’’
cross-overstudybyAzoulayetal15revealedastatis- ‘‘accutane,’’or‘‘13-cis-retinoicacid.’’
tically significant association between isotretinoin
anddepression.However,alargepopulation-based Study selection
study16 found acne alone to be significantly associ- We primarily focused our literature search on
ated with depression and suicidal ideation. Despite randomized controlled trials (RCTs). However,
the controversy surrounding in the absence of an RCT,
isotretinoin, the potential in- we included large-scale
CAPSULE SUMMARY
creaseintheriskforpsycho- population-based studies,
logical problems associated non-RCT, and prospective
withsevereacneshouldalso d The relationship between isotretinoin open-label studies with $15
treatment for acne and depression is
be considered. Multiple patients with acne who had
controversial.
studies on the relationship received isotretinoin therapy.
between isotretinoin and d Meta-analysis did not show a positive Onlystudiesthatprovidedthe
depression have been con- associationbetweenisotretinoinuseand prevalence of depression or
ducted, some of which depression. In fact, incidence of depression scores were
demonstrated that treating depression declined after isotretinoin included.Articlesfromadverse
acne with isotretinoin use. event reporting systems, re-
improved depressive symp- Although individual susceptibility to viewarticles,casereports,cor-
d
toms.17-23 Considering depression during isotretinoin use respondence, and conference
whether sex, isotretinoin cannot be ruled out, the available reportwereexcluded.Quality
dose, treatment time, and evidence suggests that patients with assessmentwasperformedus-
the patient baseline psycho- nodulocystic acne can safely be treated ing methodological index for
logic condition affected the withisotretinoinwithoutincreasingtheir nonrandomizedstudies.27The
results of these studies is risk for depression. studieswithqualityscores\12
crucial. However, with only werealsoexcluded.
limited data and small sam-
ple sizes, assessing these confounding factors is Outcomes
difficult. Further, 3 systematic reviews by Strahan Theprimaryoutcomesofthepresentstudywerethe
et al in 2006,24 Marqueling et al in 2007,25 and prevalenceofdepressionandchangeinthedepression
Bremner et al in 201226 did not achieve consistent scorefollowingisotretinointherapy.
results. Strahan et al24 and Marqueling et al25
concluded that the current literature does not sup- Data extraction
port a causative association between isotretinoin Data were independently extracted by 2 authors
and depression. However, Bremner et al26 (Dr Huang and Dr Cheng). Any disagreement was
concluded that isotretinoin has a causal link with resolved by consensus. Data on the following
depression. Here we sought to determine the measures were extracted: study design, inclusion
relationship between isotretinoin and depression criteria, sample size, treatment regimen, study
by providing a thorough, evidence-based meta- results, and quality scores (Supplemental Table I;
analysis of this controversy. available at http://www.jaad.org). For population-
based studies, we extracted the outcome (relative
METHODS risk[RR])(SupplementalTableII;availableathttp://
Thismeta-analysiswascarriedoutinaccordance www.jaad.org). Age, the proportion of male
with the Preferred Reporting Items for Systematic patients, follow-up time, cumulative isotretinoin
Reviews and Meta-Analyses (http://www.prisma- dose, depression scale, and depression score with
statement.org/). standard deviation (SD) before, during, and after
treatmentwerealsoextracted(SupplementalTables
Data source and search strategy III and IV; available at http://www.jaad.org). We
We identified studies indexed in PubMed, extracted the number ofdepression cases (Table I),
MEDLINE, EmBase, and the Cochrane Library data- ifprovidedbythestudy.Thenon-RCTsconsistedof
bases from inception of isotretinoin treatment to 2 groups of patients with acne who received
September 30, 2016, (last literature search day isotretinoin or alternative therapy within the same
October4,2016).Allarticlesincludedinthepresent study.Depressionwasdefinedbytheoriginalstudy.
study involved human clinical studies written in The cumulative isotretinoin dose was calculated
1070 Huang and Cheng JAMACADDERMATOL
JUNE2017
Table I. The prevalenceofdepression before, during,and aftertreatment
Casesofdepression Casesofdepressionduring Casesofdepressionatfinal Definitionof
Study atbaseline,n(%) treatment,n(%) follow-up,n(%) depression
Brunoet al,198428 1(1.1)major depression 10 (11)minordepression N/A Nodefinition
Kellettet al,199910 6(18) N/A 0(0) HADS-D[10
Hullet al,200029 1(0.5)had history of 4(4.4) 2(4) Self-reported
depression
Strauss et al,200114 N/A, 15(5)had history of 10(3.3) N/A BDI[13
psychiatric medication
Kellettet al,200511 8(25.81) 4(19.05) 4(18.19) BDI[13
Chiaet al,20055 9(15.3) N/A 5(8.2) CES-D[16
Kaymak etal, 20069 0(0) 1(1) 0(0) HSRD[13
Cohenetal, 20076 1(1) N/A 2(2) CES-D[15
Kaymark etal, 200930 12(33.3) 7(19.4) 4(11.1) BDI[13
Rehnetal, 200922 9(7.1) 7(5.6) 4(3.2) BDI$ 10
Ergun etal, 201117 5(7.9)had depression 5(7.9) 2(40)nofollow-up, Self-reported
history, 4 ofthem 3(60)improved
taking antidepressants
Marron etal, 201320 12(3.5) N/A 6(1.7) HADS-D[10
Webster et al,201431 N/A 4(0.9) 0(0) Self-reported
Suarez etal, 201632 1(2.8) 3(8.3) 3(8.3) Zungscale[50
BDI, Beck Depression Inventory; CES-D, Center for Epidemiological Studies Depression; HADS-D, Hospital Anxiety Depression Scale-
Depression;HRSD,HamiltonRatingScaleforDepression;N/A,notavailable.
accordingtothedoseprovidedintheoriginalstudy. groups.Wecomputedthemeanchangeinthescores
If the follow-up time was provided in weeks, we from baseline and SD for both the isotretinoin and
calculatedaweektobe7days;ifgiveninmonths,we controlled groups. The data were combined in the
calculatedamonthtobe30days.Thedetailsofthe same analysis as the studies that reported only the
depression scales are shown in Supplemental final scores of the 2 groups. This computation
TableV(availableathttp://www.jaad.org). requires the preepost correlation value to be input.
However, no studies reported the preepost
Data analysis correlation values necessary to conduct an
For the controlled trials, we produced a pooled appropriately paired analysis. We used a preepost
estimate of the mean difference in the depression correlation of 0.5.33 The same computations were
score change for patients treated with isotretinoin conducted for all meta-analyses in prospective
compared with patients who received alternative open-label studies with before and after data.
therapy. For all studies that provided depression Sensitivity analyses were conducted for each case
scores,weperformedapooledestimateforthechange by using preepost correlations of 0.2 and 0.8. If
indepressionscore.Iftherewere$3studiesusingthe studieslackednecessarydata,theywerenotpooled
same depression scales, a pooled estimate was also in the meta-analysis. Similarly, none of the
performed. Data were then stratified by follow-up uncontrolled studies that measured dichotomous
timeinto3groups:1)1-2months;2)3-4months;and outcomes before and after treatment reported
3) past 4 months. Separate meta-analyses were then data in a matched format; therefore, these
conducted for each subgroup, as well as a pooled outcomeswereanalyzedasunmatcheddata,shown
analysis of the prevalence of depression before and to be similar and easier to interpret than
after treatment for studies with a clear definition of matched analyses.34 Homogeneity testing was
depression and a depression case number. performed using the I2 test. A fixed-effects
Continuous data were analyzed using the weighted modelwasusediftherewasalackinheterogeneity.
mean difference when comparing grouped studies WhenI2was[60%,arandom-effectmodelwasused.
usingthesamescaleorstandardizedmeandifference A meta-regression was performed to determine
(SMD) when comparing variable and non- the effect of the cumulative isotretinoin dose, pro-
standardizedoutcomescalesreportedacrossstudies. portion of male patients, high baseline depression
DichotomousanalyseswereconductedusingRR. scores (studies with baseline scores exceeding
For meta-analyses of controlled trials, some the definition of depression, categorical variable),
studies reported the baseline and final scores for 2 and quality scores on the change of depression
JAMACADDERMATOL Huang and Cheng 1071
VOLUME76,NUMBER6
Fig1. Selectionofstudiesincludedinthepresentsystematicreviewandmeta-analysis.
scores for patients who received isotretinoin. after depression scores. A summary of the trial
Publication bias was tested by the Egger test. All of characteristicsispresentedinTableI.
the above analyses were performed using the Ofthe31studies,1population-basedstudyfound
Comprehensive Meta-Analysis software version 3 that isotretinoin significantly increased the risk of
(Biostat,Inc,Englewood,NJ). depression, while 2 open-label studies found
increased depression scores following isotretinoin
RESULTS therapy (1 significantly and the other nonsignifi-
Search results and trial characteristics cantly increased). The other 10 controlled studies
Ofthe172studiesscreened,theinclusioncriteria and 15 open-label studies found no association
were met in 31 studies (Fig 1): 3 population-based betweenisotretinoinuseandtheriskfordepression.
studies, 8 controlled studies, and 20 prospective Eleven out of 25 studies (2 controlled5,30 and 9
open-label studies, of which 4 provided only the open-label studies10,11,17,19-23,35) found a significant
prevalence of depression without before and improvement in the depression scores or a
1072 Huang and Cheng JAMACADDERMATOL
JUNE2017
4 151111 reduced frequency of depression following
6 030080
P .0 \.0.0.0.0.0.0 isotretinointherapy.Theimproveddepressionscore
wassignificantlygreaterthanthecontrolgroupin1
6 971946
2I 83. 93.93.92.93.95.93. ce. controlled study and nonsignificant in the other
n controlled study. The remaining 3 studies only pro-
5%CI) 029) 0.170)0.074)1.028)0.167)0.021)0.152) ndiffere vdiedperdestshioenpraefvtearlen1cemoofndtheproesfsiothne:ra1p)y1;1%2)m4il%d
Correlation0.8 estimatemean(9 (cid:1)0(0.103to0. (cid:1)(cid:1)6(0.461to(cid:1)(cid:1)8(2.041to(cid:1)(cid:1)6(4.005to(cid:1)(cid:1)5(0.643to(cid:1)(cid:1)4(0.369to(cid:1)(cid:1)0(0.589to D,weightedmea TpcreoarsembovllpeavlleIee;dntiacovwena;iiotlhafabndlcedeopnar3ttei)hnstsut0ipeo.9d:n/%/twfrreowdamuwtmri.tnjehagneatdst.t(hoaSerrugrtap)t.ppoylethmweerhnaiptcahyl
Effect (cid:1)0.50 (cid:1)0.31(cid:1)1.05(cid:1)2.51(cid:1)0.40(cid:1)0.17(cid:1)0.37 e;WM Cishoatrreatcitneoriiznatuisoen of patients with acne and
c
n
5 192315 e Clinical and outcome data for patients with acne
1 040080 er
es P .0 \.0.0.0.0.0.0 diff aresummarized(TableI,SupplementalTablesII-IV;
r n available at http://www.jaad.org). Excluding the 3
sco 2I 0.9 1.37.58.86.96.47.8 mea population-based studies, 2932 acne patients
on-controlledstudiesaboutdepression Correlation0.2 2Effectestimatemean(95%CI)IP (cid:1)(cid:1)(cid:1)62.4.0580.257(0.465to0.049)4olledandopen-labelstudies)\(cid:1)(cid:1)(cid:1)87.2.0010.342(0.512to0.169)8(cid:1)(cid:1)(cid:1)85.6.0461.087(2.169to0.006)7(cid:1)(cid:1)(cid:1)80.4.0012.337(3.809to0.864)6(cid:1)(cid:1)(cid:1)85.4.0020.386(0.639to0.134)7(cid:1)(cid:1)(cid:1)90.6.0780.210(0.446to0.026)8(cid:1)(cid:1)(cid:1)84.2.0020.328(0.555to0.101)7 DepressionScale-Depression;SMD,standardizedw-upaftercompletionofisotretinointreatment. wcwdckeodSTscouxtgoweaeaoammcb.csTsrntreerleIiehpuee0esnsseall.dtcIcae5ositI4eahtrcrt-e.fiee1edlaavdFes0dsaneltmo..utbut1geahirTledgs-tetdneh0thsol/ishoe.eekat2oerdwsflgwe2rf,aye6/sotfitstftidmtttmhhnhiuciehnaseoeoegdryint/ibirdsmniemkiiotacesnesrgdeosnoseo.f/eiatourtalnadrelllTosnlieel-ianettahfdtissyiinesnortendcuascaanowotenrdlnuieyirppgisneddeeasoorer,isisseest2deiernsebsedoasfmnt,xretirfoiooitceifgnnhnoetnm/oewpprtks1hier1uitndghgee5ssf/eitsnotcir-d3peunr1eihraefnrdg5aoiye2gctt0yte.smiah2twmsmdhTna6eieoneihet1rgtnilsinndhnye1/rt.
ultsofmeta-analysisofcontrolledstudiesandn Correlation0.5Noofstudy/EffectpatientmeasureEffectestimatemean(95%CI) (cid:1)(cid:1)(cid:1)6/210vs158SMD0.334(0.6800.011)beforeandafterisotretinointreatment(includecontr(cid:1)(cid:1)(cid:1)19/1411SMD0.335(0.498to0.172)(cid:1)(cid:1)(cid:1)8/812WMD1.068(2.120to0.017)(cid:1)(cid:1)(cid:1)4/132WMD2.422(3.897to0.948)(cid:1)(cid:1)(cid:1)8/544SMD0.399(0.647to0.152)(cid:1)(cid:1)15/1002SMD0.199(0.420to0.022)(cid:1)(cid:1)(cid:1)5/645SMD0.347(0.571to0.123) Inventory;CI,confidenceinterval;HADS-D,HospitalAnxiety3618d2studies(SimicetalandGnanaraietal)withoutfollo 0i0pdl9sBDuTodw(cid:1)sic..5nepfioheoe050ifo%tpefcsemTtp18.hrer3tkare18hr-remrea3teteCs),eteeisl4igsesenIansw1s,soDat9ittl-oiaopsr(cid:1)tho25(es9r-doipnabenn%recp05letrmonostes.i%reig4eictesrngSvothir9ensosCmrocnean8ssetoricaIislsimietpanefiooflfshtesot(unicntpnoms0ocehrsatco,fr.oiniei3eenoniDrg(cid:1)desa8ntvrgcnIoeefln0e2natyoefiintp.dav-finvrdr1co0dcreerecsi)70ee.feeetaifan9a2.iagsolcnl5nn0atls)menrltoit.oti4tleendcoiliodro)fiy0ioraotTynnw.etnen.csnrh,dh0preaarg-t1aeveeFvrru(tdnti0eetcaHlaoHvphtarw7saalmllreAteyeusot,ihhmiapeo[eDspo9Citsteapanghd5ehan(SeInnsiSh%nt]eee-dt(tiMDaacFetrdp,f(cid:1)al4slniC)Dripegfrpst,noto0hIoeprsymem2(cid:1)A.leeps0fr6ltd)os-oeron.o08.(me0eblswnx.Sr0ld0as3aotaiMe(tiiit1e3hsRnoownebat5et5DsRddnonngyy---.,
TheresTableII. ControlledstudyDepressionscoresTotalBDIHADS-D1-2months3-4months[4months* BDI,BeckDepression*Thisgroupcontaine 00ssdpic..eug02opbn14rrlie90iefcs93isc.a;,satPiinoT9o=tn5hnly%e.0br2sieafcC2lusoa)Intr(aeenEn0dseg.d0lgto6aeip3nrhl8letio-ges0ts1sh.t94d,(q1FePu0cisag8=rtle;uit.md35yP)1iese5ncs=8foto)ri.rens.0h(d0coch7eow6pae)enrfefdgiswcesiieeonrninnoet
JAMACADDERMATOL Huang and Cheng 1073
VOLUME76,NUMBER6
Study name Statistics for each study Std diff in means and 95% CI
Std diff Standard Lower Upper
in means error Variance limit limit Z-Value p-Value
Chia et al, 2005 -0.080 0.199 0.040 -0.470 0.311 -0.400 0.689
Kaymak et al, 2009 -0.836 0.260 0.068 -1.346 -0.326 -3.215 0.001
Simie et al, 2009 -0.195 0.218 0.047 -0.622 0.231 -0.898 0.369
McGrath et al, 2010 0.110 0.271 0.074 -0.421 0.642 0.407 0.684
Suarez et al, 2016 -0.744 0.272 0.074 -1.277 -0.210 -2.733 0.006
-0.334 0.176 0.031 -0.680 0.011 -1.899 0.058
-1.00 -0.50 0.00 0.50 1.00
Isotretinoin Control
Fig 2. Forest plot. Standardized mean difference in depression score change from baseline
(post-score minus pre-score) between the isotretinoin group and the control group
(isotretinoingroupminuscontrolgroup).Themorenegativeastandardizedmeandifference
is the greaterthe improvement in depression scores in theisotretinoin group in comparison
withthecontrolgroup.
Fig 3. Funnel plot analysis for potential publication bias. The funnel plot for change in
depressionscoresin19studiesshowednoasymmetry,whichmeansnopublicationbias.Each
dot represents a study; the y-axis represents the standard error of the study and the x-axis
shows the study result (standardized mean difference of pre- and post-treatment depression
scoresineachstudy).
DISCUSSION increase depression-related behavior in mice and
The relationship between isotretinoin treatment ratsinsomestudies39,40butnotinothers.41,42
for acne and depression remains controversial both This meta-analysis found no association between
clinically and scientifically. Because isotretinoin is isotretinoin and depression. Moreover, symptoms of
a fat-soluble compound, it can easily cross the depression improved following isotretinoin treat-
bloodebrain barrier and interact with brain tissue ment, but this effect was not significantly different
whereverintracellularretinoidreceptorsarepresent. from alternative therapy. Among studies that could
It can affect the dopaminergic36 and serotonergic notbeusedinthismeta-analysis,onlythepopulation-
systems,37 hippocampal neurogenesis,38 and basedstudybyAzoulayetal15concludedthatisotret-
frontal orbital activity.8 The chronic administration inoin significantly increased the risk for depression
of 1-mg/kg dose of isotretinoin has been shown to in acne patients. All 3 population-based studies
1074 Huang and Cheng JAMACADDERMATOL
JUNE2017
underestimatedtheincidenceofdepressionbecause In our study, similar to that in the study by
diagnostic codes and antidepressant prescriptions Halvorsen et al,16 the patients with acne had high
were used as inclusion criteria and patients with baseline depression scores, which exceeded the
inadequate data were excluded. Moreover, this un- depression cut-off points of 4 studies. However,
derestimation might be particularly problematic for meta-regression results revealed that high baseline
thestudybyAzoulayetal15becausetheRRestimate scores did not affect depression score changes and
wasbasedonasmallsubsetofpatientswhometstrict male patients were as capable of improving
depressionanddataavailabilitycriteria;therefore,the depressionscoresasfemalepatients.
results might not be applicable to a general popula- From the view of prevalence of depression, the
tionofpatientstreatedwithisotretinoin.43 risk was significantly decreased after treatment.
The systematic review by Bremner et al26 However, some studies described newly developed
concluded that isotretinoin had a causal link with depression during treatment. In the controlled trial
depression. Despite their finding that multiple conductedbySuarezetal,32newonsetofdepression
studies demonstrated no association between was noted in both the isotretinoin and antibiotic
isotretinoin and depression or an improvement in groups, implying that depression is associated with
depressive symptoms following isotretinoin acne,independentlyofisotretinoin.Thus,physicians
treatment, they concluded that the sample sizes shouldconsiderthepossibilityofdepressionamong
were too small to confirm that most patients allacnepatientsregardlessofthetreatmentmethod.
receiving isotretinoin did not develop depression. WealsoagreewithBremneretal26thatsomepatients
The systematic reviews by Strahan et al,24 are more susceptible to depression. However, if
Marqueling et al,25 and Bremner et al26 did not there is a link between isotretinoin and depression,
includeapoolinganalysistoderivetheirconclusion. no predictive tests exist for quantifying the level of
In our meta-analysis, we pooled the results of 1411 risk to patients; perhaps it is an idiosyncratic
patients who received depression evaluations at reaction.45
baseline and after treatment, which revealed a Ourstudyhassomelimitations.Thefirstlimitation
significant improvement in the depression scores. was that no RCTs were included; however, we
Bremner et al26 used the study by Meysken et al44 included recent studies with the highest level of
to support a dose-response relationship of up to evidence, all of which demonstrated a weak
3 mg/kg/day isotretinoin for advanced cancer relationship between isotretinoin and depression.
patients, 25% of whom exhibited depression. Thesecondlimitationwashighinter-studyvariability
However,highdosesthatmightcausesymptomsof (eg, different evaluation tools). Therefore, we used
depression are not usually prescribed for acne. In thestandardizedmeandifferenceoutcomemeasure
our study, the typical dose prescribed for acne for the meta-analyses of continuous data and
(0.5-1mg/kg)wasnotfoundtohaveadose-related performed meta-regression for sensitivity analysis.
riskfordepression,consistentwiththeresultsofthe Thequalityscoreaffectedthechangeindepression
studybyAzoulayetal.15 scores: when omitting the studies with the lowest
Bremner et al26 stated that depression usually scores, the improvement in depression score
develops 1-2 months or sometimes around remainedsignificant.
2-4 months after treatment and further emphasized In conclusion, this meta-analysis demonstrated
that challengeerechallenge cases support a causal that isotretinoin treatment for acne at the typical
link.Inourstudy,thedepressionscoressignificantly therapeutic dose is not associated with an
decreased within the first 1-2 months and after increased risk for depression. Moreover, the
4 months and tended to decrease (but not treatmentofacneimprovedsymptomsofdepression
significantly) within 3-4 months. Although 4 studies formostpatients.Somepatientsmightbemoreprone
found increased scores at 3-4 months, 2 of them todepressionregardlessofacneorotherconditions.
foundthatscoresat6monthshaddecreasedbelow Thus,closelymonitoringacnepatientsfordepression
baseline despite continued treatment. The other 2 isessentialtoidentifypatientsatahighrisk.
studies involved follow-up for only 3-4 months.
Webster et al31 found that in all patients who
REFERENCES
reporteddepression,theconditionresolvedwithout 1. WebsterGF.Acnevulgaris.BMJ.2002;325:465-469.
discontinuing isotretinoin. Increased depression 2. Hazen PG, Carney JF, Walker AE, et al. Depressionea side
scores or newly reported depression cases might effect of 13-cis-retinoic acid therapy. J Am Acad Dermatol.
1983;9:278-279.
beexplainedbythepersistenceofacneorotherside
3. JickSS,KremersHM,Vasilakis-ScaramozzaC.Isotretinoinuse
effectsof isotretinoin, which mightresolveoverthe
and risk of depression, psychotic symptoms, suicide, and
courseoftreatment. attemptedsuicide.ArchDermatol.2000;136:1231-1236.
JAMACADDERMATOL Huang and Cheng 1075
VOLUME76,NUMBER6
4. Hersom K, Neary MP, Levaux HP, et al. Isotretinoin and treatment: a 12-week follow-up study of male Finnish
antidepressant pharmacotherapy: a prescription sequence military conscripts. J Eur Acad Dermatol Venereol. 2009;23:
symmetryanalysis.JAmAcadDermatol.2003;49:424-432. 1294-1297.
5. Chia CY, Lane W, Chibnall J, et al. Isotretinoin therapy and 23. Yesilova Y, Bez Y, Ari M, et al. Effects of isotretinoin on
moodchangesinadolescentswithmoderate-to-severeacne: obsessivecompulsivesymptoms,depression,andanxietyin
acohortstudy.ArchDermatol.2005;141:557-560. patients with acne vulgaris. J Dermatolog Treat. 2012;23:
6. CohenJ,AdamsS,PattenS.Noassociationfoundbetween 268-271.
patientsreceivingisotretinoinforacneandthedevelopment 24. Strahan JE, Raimer S. Isotretinoin and the controversy of
of depression in a Canadian prospective cohort. Can J Clin psychiatricadverseeffects.IntJDermatol.2006;45:789-799.
Pharmacol.2007;14:e227-e233. 25. MarquelingAL,ZaneLT.Depressionandsuicidalbehaviorin
7. NgCH,TamMM,CeliE,etal.Prospectivestudyofdepressive acnepatientstreatedwithisotretinoin:asystematicreview.
symptomsandqualityoflifeinacnevulgarispatientstreated SeminCutanMedSurg.2007;26:210-220.
withisotretinoincomparedtoantibioticandtopicaltherapy. 26. Bremner JD, Shearer KD, McCaffery PJ. Retinoic acid and
AustralasJDermatol.2002;43:262-268. affective disorders: the evidence for an association. J Clin
8. BremnerJD,FaniN,AshrafA,etal.Functionalbrainimaging Psychiatry.2012;73:37-50.
alterations in acne patients treated with isotretinoin. Am J 27. Slim K, Nini E, Forestier D, et al. Methodological index for
Psychiatry.2005;162:983-991. non-randomized studies (minors): development and valida-
9. Kaymak Y, Kalay M, Ilter N, et al. Incidence of depression tionofanewinstrument.ANZJSurg.2003;73:712-716.
related to isotretinoin treatment in 100 acne vulgaris 28. Bruno NP, Beacham BE, Burnett JW. Adverse effects of
patients.PsycholRep.2006;99:897-906. isotretinointherapy.Cutis.1984;33:484-489.
10. KellettSC,GawkrodgerDJ.Thepsychologicalandemotional 29. HullPR,Demkiw-BartelC.Isotretinoinuseinacne:prospec-
impactofacneandtheeffectoftreatmentwithisotretinoin. tiveevaluationofadverseevents.JCutanMedSurg.2000;4:
BrJDermatol.1999;140:273-282. 66-70.
11. Kellett SC, Gawkrodger DJ. A prospective study of the 30. Kaymak Y, Taner E, Taner Y. Comparison of depression,
responsiveness of depression and suicidal ideation in acne anxiety and life quality in acne vulgaris patients who were
patients to different phases of isotretinoin therapy. Eur J treated with either isotretinoin or topical agents. Int J
Dermatol.2005;15:484-488. Dermatol.2009;48:41-46.
12. Rubinow DR, Peck GL, SquillaceKM, et al. Reducedanxiety 31. Webster GF, Leyden JJ, Gross JA. Results of a phase III,
and depression in cystic acne patients after successful double-blind, randomized, parallel-group, non-inferiority
treatmentwithoralisotretinoin.JAmAcadDermatol.1987; studyevaluatingthesafetyandefficacyofisotretinoin-Lidose
17:25-32. in patients with severe recalcitrant nodular acne. J Drugs
13. SchulpisK,GeorgalaS,PapakonstantinouED,etal.Psycho- Dermatol.2014;13:665-670.
logical and sympatho-adrenal status in patients with cystic 32. Suarez B, Serrano A, Cova Y, et al. Isotretinoin was not
acne.JEurAcadDermatolVenereol.1999;13:24-27. associatedwithdepressionoranxiety:atwelve-weekstudy.
14. Strauss JS, Leyden JJ, Lucky AW, et al. Safety of a new WorldJPsychiatry.2016;6:136-142.
micronizedformulationofisotretinoininpatientswithsevere 33. AbramsKR,GilliesCL,LambertPC.Meta-analysisofhetero-
recalcitrant nodular acne: a randomized trial comparing geneously reported trials assessing change from baseline.
micronized isotretinoin with standard isotretinoin. J Am StatMed.2005;24:3823-3844.
AcadDermatol.2001;45:196-207. 34. ZouGY.Onerelativeriskversustwooddsratios:implications
15. AzoulayL,BlaisL,KorenG,etal.Isotretinoinandtheriskof formeta-analysesinvolvingpairedandunpairedbinarydata.
depression in patients with acne vulgaris: a case-crossover ClinTrials.2007;4:25-31.
study.JClinPsychiatry.2008;69:526-532. 35. Bozdag KE, Gulseren S, Guven F, et al. Evaluation of
16. Halvorsen JA, Stern RS, Dalgard F, et al. Suicidal ideation, depressive symptoms in acne patients treated with isotret-
mentalhealthproblems,andsocialimpairmentareincreased inoin.JDermatologTreat.2009;20:293-296.
inadolescentswithacne:apopulation-basedstudy.JInvest 36. DiehlDJ,GershonS.Theroleofdopamineinmooddisorders.
Dermatol.2011;131:363-370. ComplPsychiatry.1992;33:115-120.
17. Ergun T, Seckin D, Ozaydin N, et al. Isotretinoin has no 37. O’ReillyKC,TrentS,BaileySJ,etal.13-cis-retinoicacidalters
negativeeffectonattention,executivefunctionandmood.J intracellularserotonin,increases5-HT1Areceptor,andsero-
EurAcadDermatolVenereol.2012;26:431-439. tonin reuptake transporter levels in vitro. Exp Biol Med
18. GnanarajP,KarthikeyanS,NarasimhanM,etal.Decreasein (Maywood).2007;232:1195-1203.
‘‘Hamiltonratingscalefordepression’’followingisotretinoin 38. BremnerJD,McCafferyP.Theneurobiologyofretinoicacidin
therapy in acne: an open-label prospective study. Indian J affectivedisorders.ProgNeuropsychopharmacolBiolPsychia-
Dermatol.2015;60:461-464. try.2008;32:315-331.
19. Hahm BJ, Min SU, Yoon MY, et al. Changes of psychiatric 39. O’Reilly KC, Shumake J, Gonzalez-Lima F, et al. Chronic
parameters and their relationships by oral isotretinoin in administrationof13-cisretinoicacidincreasesdepression-re-
acnepatients.JDermatol.2009;36:255-261. lated behavior in mice. Neuropsychopharmacology. 2006;31:
20. MarronSE,Tomas-AragonesL,BoiraS.Anxiety,depression, 1919-1927.
quality of life and patient satisfaction in acne patients 40. Trent S, DrewCJ, MitchellPJ, etal. Chronictreatmentwith
treatedwithoralisotretinoin.ActaDermVenereol.2013;93: 13-cis-retinoic acid changes aggressive behaviours in the
701-706. resident-intruderparadigminrats.EurNeuropsychopharma-
21. NevoralovaZ,DvorakovaD.Moodchanges,depressionand col.2009;19:876-886.
suicide risk during isotretinoin treatment: a prospective 41. Ferguson S, Cisneros FJ, Gough B, et al. Chronic oral
study.IntJDermatol.2013;52:163-168. treatmentwith13-cis-retinoicacid(isotretinoin)orall-trans-
22. Rehn LM, Meririnne E, Hook-Nikanne J, et al. Depressive retinoicaciddoesnotalterdepression-likebehaviorsinrats.
symptoms and suicidal ideation during isotretinoin ToxicolSci.2005;87:451-459.
1076 Huang and Cheng JAMACADDERMATOL
JUNE2017
42. FergusonS,CisnerosFJ,HanigJP,etal.Oraltreatmentwith 47. McGrathEJ,LovellCR,GillisonF,etal.Aprospectivetrialof
Accutane does not increase measures of anhedonia or the effects of isotretinoin on quality of life and depressive
depressioninrats.NeurotoxicolTeratol.2007;29:642-651. symptoms.BrJDermatol.2010;163:1323-1329.
43. Bigby M. Does isotretinoin increase the risk of depression? 48. FerahbasA,TuranMT,EselE,etal.Apilotstudyevaluating
ArchDermatol.2008;144:1197-1199. anxietyanddepressivescoresinacnepatientstreatedwith
44. Meyskens FL. Short clinical reports. J Am Acad Dermatol. isotretinoin.JDermatologTreat.2004;15:153-157.
1982;6:732. 49. OrmerodAD,ThindCK,RiceSA,etal.Influenceofisotretinoin
45. Goodfield MJ, Cox NH, Bowser A, et al. Advice on the safe onhippocampal-basedlearninginhumansubjects.Psycho-
introductionandcontinueduseofisotretinoininacneinthe pharmacology(Berl).2012;221:667-674.
UK.BrJDermatol.2010;162:1172-1179. 50. FakourY,NoormohammadpourP,AmeriH,etal.Theeffect
46. Simic D, Situm M, Letica E, et al. Psychological impact of of isotretinoin (roaccutane) therapy on depression and
isotretinointreatmentinpatientswithmoderateandsevere qualityoflifeofpatientswithsevereacne.IranJPsychiatry.
acne.CollAntropol.2009;33(Suppl2):15-19. 2014;9:237-240.
SupplementalTable I. Summary ofincluded studies VJ
O A
LU M
Study Studydesign Patientinclusioncriteria Samplesize Isotretinoindose Studyresult Score M A
E C
Population-based studies 7A
6D
Jicketal, 20003 Case controlstudy Between6 monthsand 7195isotretinoin vs N/A Noassociation ,ND
5yearsbefore, and at 13,700antibiotic UM ERM
least12months after, 340isotretinoin vs676 BE A
R T
theirfirstisotretinoin antibiotic 6OL
orantibiotic
prescription.
Hersomet al,20034 Sequence symmetry analysis 12-49years 2821isotretinoinvs7360 N/A Noassociation
Isotretinoinprescriptions antibiotic
betweenJune 1,1999,
andMarch 31,2000
Azoulayetal, 200815 Case crossover study Received$1isotretinoin 30,496(126depression N/A Statistically significant
prescription during patients) associationbetween
1984-2003 isotretinoinand
depression
Nonrandomized controlledtrials
Nget al,20027 Prospective controlled Severecystic acne 174(171) vs41 Startedat40mg/day, Noassociation 1417
study Nocurrent diagnosis of antibiotic/topical increasedto a dosage
depression, of1.0mg/kg/day over
concomitant 1monthand
antidepressants, continuedto total
corticosteroids, cumulativedose of
anabolicsteroids, or 120 mg/kg(over
otherdepression- 5-6 months)
inducing medications
Chiaet al,20055 Prospective controlled 12-19years 59isotretinoinvs 73 1mg/kg/day Bothtreatments 1417
study,intent-to-treat Moderate-to-severe conservative therapy associatedwith a
analysis inflammatory and (49vs52) decreased depression
cystic acne,no history symptoms butno
H
oforcurrent DSM-IV significant difference u
a
AxisI diagnosis n
g
Continued a
n
d
C
h
e
n
g
1
0
7
6
.e
1