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Yo U Are P Ro H Ib Ited from M Aking Th Is P D F P U B Licly Availab Le. It Is

You are prohibited from making this PDF publicly available. isIt illegal to post this copyrighted PDF on any website. J ClinPsychiatry 78:5,May 2017 For [email protected]. reprints orpermissions, contact ♦ the end of the article. the the endof relationships. Faculty financialdisclosure appearsat any staffreported Institute relevant personalfinancial CME newsletter.in Psychiatry the Nomemberof Biological Therapiesthe has beenowner andeditor of shareholder ofHealthcare Technology Systems, and been aconsultant for Zynx Health,hasbeenastock past year, Alan J. Gelenberg, MD, Editor inChief, has any ofinterest conflicts that were identified. the In commercial interest. The hasresolved CME Institute andanybetween themselves ortheir spouse/partner regarding allrelevant personalfinancialrelationships were askedto activity complete astatementthis of All individualsinapositionto influence thecontent Financial Disclosure material was March 2017. this review of 1 Credit™ throughCategory May 31, 2019. The latest iseligible forThis educational AMAPRA activity Date ofOriginal Release/Review for completing thisprogram. may receive Icredit amaximumof1hourCategory recognized state medicalsociety. Physician assistants Credit™ from organizations accredited by ACCME ora 1 for Category AMAPRA certified educational activities (AAPA) for accepts ofparticipation certificates Note: The Academy American ofPhysician Assistants intheactivity. participation their extent of should claimonlythecredit commensurate withthe 1Credit™. Physicians Category maximum of1AMAPRA forInc., designates a CMEactivity thisjournal-based The ofPhysicians CMEInstitute Postgraduate Press, Credit Designation medical education for physicians. Education to provide continuing Council for Continuing Medical accredited by theAccreditation Postgraduate Press, Inc.,is The ofPhysicians CMEInstitute Accreditation Statement youAfter shouldbeableto: studyingthisarticle, CME Objective Evaluation. A$5processing fee willapply. the questionsinPosttest, andcomplete the To obtaincredit, answer correctly read thearticle, with desired results. planned usingaprocess that linksidentified needs throughout eachvolume.topics are Activities of onavariety ofCMEarticles with acurriculum ofproviding withthepurpose participants, readers educational needsofCME the on anassessment of are for selected creditArticles designation based CME Background • symptoms for bipolarity depressiveScreen patients withpostpartum Focus on Women’s Mental Health ([email protected]) 8210 4, V, Allé Denmark Aarhus Fuglesangs University, Aarhus Research, based Denmark Denmark J Clin Psychiatry 2017;78(5):e469–e476 J ClinPsychiatry disorder.bipolar spectrum and concerning symptoms, healthprofessionals shouldconsider apossible monotherapy isineffective ortheindividualwoman experiences persistent manic symptoms andmonitored longterm. Clinically, whenantidepressant prescription shouldbeaskedabouthypomanic following or childbirth bipolarity. ofunderlying be amarker Women whofillanantidepressant Conclusions: affective First-onset disorder nonpsychotic can postpartum period. monotherapy outsidethepostpartum prescription for anxiolyticswhenthesetherapies were compared to antidepressant7.13–14.46) for therapy postpartum plusasubsequent antidepressant1.12–2.48) for monotherapy postpartum and10.15(95%CI, disorder was 1.66(95%CI, period.bipolar outside thepostpartum The of risk affective episodewas higherthanthat inwomen withanaffective episode disorder amongwomenResults: withapostpartum bipolar The of risk we estimated hazard ratios usingCox regressions. psychiatric for follow-up, contact during criteria) bipolardisorder (ICD-10 and period.antidepressant outcome Our was prescription outsidethepostpartum onset affective disorder, to women within1year withafirst-time postpartum a first-time antidepressant prescription, whichwas ourindicator ofafirst- antidepressant prescription 1997–2012. during We compared women with 122,622 parous women whoreceived withoutpsychiatric history afirst-time Aregister-based of Methods: studywas inDenmark conducted cohort disorder.bipolar an increased of risk affective episodetreatednonpsychotic postpartum withantidepressants have bipolarity.of underlying Therefore, we aimedto studywhetherwomen witha affective episodesare alsoindicators whethermilderpostpartum unknown disorder,bipolar butitis of canbeamarker period in thepostpartum Objective: affectiveThe episoderequiring first-onset inpatient treatment Xiaoqin Liu, PhD Register-Based Study Cohort A Danish Nationwide ofand Risk : in thePostpartum Period Depression and Anxiety f e d c b a © Copyright 2017Physicians Postgraduate Press, Inc. https://doi.org/10.4088/JCP.16m10970 Medicine, Chapel Hill Chapel Medicine, Veerle Bergink, PhD * ‡ Jiong Li, PhD ABSTRACT The Department of Psychiatry, Erasmus Centre, Department Netherlands The The Medical Rotterdam, The National Center for Register-based Research, Aarhus University, Aarhus, Denmark Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Aarhus, iPSYCH, Research, Psychiatric Integrative for Initiative Foundation Lundbeck Department of Psychiatry, University of North Carolina at Chapel Hill School of of School Hill Chapel at Carolina North of University Psychiatry, of Department Department ofDepartment Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark CIRRAU-Centre for Integrated Register-based Research, Aarhus University, Aarhus, Aarhus, University, Aarhus Research, Register-based Integrated for CIRRAU-Centre Drs Bergink and Munk-Olsen are shared last Bergink and authors. Drs Munk-Olsen Corresponding author: . d ; Samantha Meltzer-Brody, MPH © 2017Copyright Physicians Postgraduate Press, Inc. a, Xiaoqin Liu, PhD, The National Center for Register- for Center National PhD, The Liu, Xiaoqin * ; EsbenAgerbo, DrMedSc a,f,‡ ; and Trine Munk-Olsen, PhD a,b,c e ; ;

a,‡

e469 Clinical Points C episodes notepisodes related to childbirth. conversion rate to bipolar disorder compared to psychiatric facilities during have postpartum the period ahigher various psychiatric treated episodes at inpatient psychiatric requiring inpatient treatment. to what documented in postpartumhas been episodes associated with later developmentbipolar disorder similar of nonpsychotic postpartum affective may episodes be also that childbirth abipolar can trigger course, disease and fromevidence observations, clinical we hypothesized anddisorder empiricalthis later inlife. basis of Onthe for postpartum depression were with rediagnosed bipolar now, asingle study [TCAs]). reuptake inhibitors [SNRIs], andantidepressants reuptake inhibitors [SSRIs], - options are antidepressant serotonin (selective important risk factor for postpartum . bipolar disorder, and bipolar infamily history members is an correlated postpartum psychosis with later conversion to from Danish national registers. We first women identified Definition ofStudy Population bipolar disorder at of later stages. treatedepisode with had an increased risk investigate women whether with apostpartum affective bipolar disorder. presentof the study The aim was to of and postpartum studiedin the period subsequent risk first-onset affective statuschildbirth as indicatorthe the of by general practitioners for an antidepressant following cohort study using information on first-time prescription the e470 For [email protected]. reprints orpermissions, contact ♦ practitioners in Denmark. arepostpartum treated period care inprimary by general or health care seek who both during both and outside the mothers and anxiety disorders, approximately 13%. depressive disorders around affecting 5%–13%of new common morbidities with during postpartum the period, Liu etal around mothers 1/1,000 new psychiatric hospitalization. Consistent evidence METHODS It isIt illegal to post this copyrighted PDF on any website. ■ ■ The population-based cohort study on data was based Most women with symptoms of anxiety, depression, Nonpsychotic affective disorders are among most the ■ ■ hypomania ormaniaandmonitoredhypomania longterm. be askedaboutcurrent andprevious symptoms of antidepressant prescription should following childbirth disorder.bipolar increased of risks Women whofillan Postpartum affective episodes are associated with are indicators bipolarity. ofunderlying affectivewhether mildto moderate episodes postpartum isunknown period. It thepostpartum during morbidities Nonpsychotic affective disorders are themostcommon hildbirth mayhildbirth asevere psychiatric trigger episode, often as postpartum labeled psychosis,

11 Consequently, we conducted apopulation-based 9 has reported that 54%of women referred 10 Frequently treatment used 7 1 and usually requires acute 7 4 which affects affects which 6 Moreover, 8 3,5 Up to has 1–3

postpartum period and tookpostpartum into period account ifantidepressants first-onset affectiveour during episode indicatorthe the of for an antidepressant within 1 year after any as delivery symptomatology. We prescription first-time the identified depressive disorders and anxiety disorders as well as mixed of affective symptomatology spectrum a wide including acknowledge that SSRIs, SNRIs, and TCAs are to treat used We term antidepressants the use first-onset affective interchangeably episode study. inthis prescriptiontime for an antidepressant the and date of first-onset affective episode. Wethe first- the date used of antidepressant recorded DNPRin the as indicator the of First-Onset Postpartum Affective Episode Definition ofExposure Variables: end of 2012,whichever came first. first-time psychiatricthe contact for bipolar disorder, or the an antidepressant during 1997–2012 until emigration, death, was followed up from day the of afirst-time prescription for for bipolar disorder at later stages (Figure woman 1).Each analysis,the of whom 843women had apsychiatric contact exclusion criteria, we included 122,622 parous women in before prescription this (n birthday (n or received an antidepressant prescription before 15th their were F**.We excluded also women died, emigrated, who for psychiatric disorders were 290–351 and ICD-10 codes Tenth Revision Diseases of treatments since 1995.The International Classification general hospitals from 1969onward and includes outpatient treatments at psychiatric hospitals and psychiatric wards in The register diagnoses. with all holds information on all contains information on date the of psychiatric contact along the Danishthe National Prescription (DNPR). Registry prescriptionthe for an antidepressant from was extracted within nationaland all between registers. Information on identificationpersonal number that for used can be linkage residents inDenmark. It includes aunique 10-digit individual contains information on live-born all children and new Civil RegistrationCivil System (CRS)(N 2012 and were who during born 1955–1997from Danish the with aprescription for an antidepressant 1997and between for an antidepressant during 1997–2012 (n any other psychotropic prescription prior to prescription the excluded women had who apsychiatric or history received as awashout inpharmacoepidemiology. period Further, we during 1995–1996 (n excluded women were who any dispensed psychotropic first-onset affective episode,was anwethe indicator of available. To ensure that dispensation the of an antidepressant 1995, and information on prescriptions prior to 1995is not covers prescriptions dispensed all Registry inDenmark since the Danishthe Psychiatric Research Central Register, or outpatient visit for psychiatric disorders registered in Psychiatric as any was defined history previous inpatient We first prescription the used ever redeemed for an © 2017Copyright Physicians Postgraduate Press, Inc. , Eighth Revision Eighth , = ( 2,029) and women didnot who give birth ICD-10), from 1994onward. The ICD-8 codes ) was used until (ICD-8) was 1993and used = 57,121). After applying these J ClinPsychiatry 78:5,May 2017 throughout article but this = 57,120), which 57,120), iswhich known = 370,816).

12 =

The CRS 131,924). 14 which 13 The The

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. onset postpartum affective into episode 2groups: within 0–180days and of postpartum initial first- affective episode, wethe categorized timing the of to illustratecurves cumulative the bipolar disorder. incidence rates of running-line least-squares smoothing technique to Kaplan-Meier smooth the outsideepisode (reference postpartum the period group). We employed a in comparison postpartumthe period to women with a first-onset affective bipolar disorder inwomen(HRs) of with afirst-onset affective during episode using Cox proportional hazards regression model. We estimated hazard ratios Statistical Analysis bipolar disorder were F30and F31. from Danish the Psychiatric Research Central Register. The for ICD-10 codes prescriptiontime for an antidepressant, and information this was extracted (main diagnosis only) during maximum the 16-year follow-up after first- the Outcome Variable: BipolarDisorder Definition of listdetailed of ATC and names codes generic drug inSupplementary eTable 1. typical and atypical (N05Aexcluding a N05AN01).See N03AF02, N03AG01, N03AX09,N03AX11,N03AX12,N05AN01),and and zolpidem and zopiclone stabilizers [N05CF]), mood (N03AF01, derivatives( [N03AE01and N05BA], [N05BE01], (ATC) classification were codes for used antidepressants (N06A),anxiolytics antipsychotics was obtained from DNPR. the Anatomic therapeutical chemical practitioner and subsequent prescriptions for anxiolytics, stabilizers, mood or anxiolytics, stabilizers, mood or antipsychotics were added. were administered as monotherapy or subsequent whether prescriptions for J ClinPsychiatry 78:5,May 2017 For [email protected]. reprints orpermissions, contact ♦ Study PopulationFigurethe 1.Flowchart Illustrating theIdentification of It isIt illegal to post this copyrighted PDF on any website. 122,6 370,816 Tobipolar disorder on depended timing the examine risk of the whether dataAll were analyzed inStata 13.1(Statacorp, Station, College Texas) outcomeOur was first-time psychiatric the contact for bipolar disorder Information on antidepressant monotherapy prescribed by ageneral

t 97 w pe r dur a Pa Wom e he  c r e r e ous post i i c od. 843Wm n i om v t e g i e ve n w 195–97 d a w Excluded: e pa e om n r • • • • • i pi t r h a t 57, 2, 82, 49, 57 e r sode um e st-t c n 029 e , pr 12 325 59 120 i w pe ve i m , b e e e pr Wom d a n ha sc r e a r Wom be Wom Wom m Wom e e i od. e l r t e i sc w nt e f pt di or f d a r e t e r i st-t i c de i i e e e e e e on f n w pt a n t t n w n w n w n w n 197a sube t pr h i i i on be m on dur he ho di e or e ho di ho r ho a ho w pr e sa a

pr a que na e n a nt pr e f s e e o nd 201a e c d not c i d, e l sc d a ng nt y r r r e n e i e si i pt r ve t a i pr i 195–6 s, de ps e bi m pt i ge sc on f d a g a e i i p pol g y on f nd am r sc i 1 r c i r ve pt n e a hi r 5 or a a sa nd w t y i bi be i or ed, orr a r y ot on d di t e r r nt, an n a d a on a i t he c sor h be r h hi s ur an i g nt n o w r ps de t nt y ps st e i i ng he de f c or or ndi i r, a e y e de c r t m i pr y y e e ve hot he c nd pr c t bo 7,8w e hot a hi d a sa e post t r o a s s r o n m r n r pr pi nt of opi a a ong nt c pr e pa dur nt a sc c dur om n

i r r de t t e i i um pt he n sc e i pr g n n i r m on 197–20 g i

e pt sa

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© 2017Copyright Physicians Postgraduate Press, Inc. Postpartum Affective Disorders andBipolarDisorder prescription for an antidepressant). or ≥ single, divorced, or widowed), and parity (first years, or ≥ 1984, or 1985–1997),age (< (1955–1969,1970– birth for calendar year of antidepressant. later discontinuedthey their even if group. Women were groups placed in these stabilizer ormood therapy therapy group or antidepressant anxiolytic antidepressant +subsequent subsequent to antidepressant therapy, ie, anxiolytic or antipsychotic/mood stabilizer and included be group in the receiving an women would change then treatment group bipolar disorder,prior to diagnosis the of antipsychotic prescription was dispensed for an anxiolytic, stabilizer, mood or treatment.initial If asubsequent prescription antidepressantthe monotherapy group at the time-dependent variable. women All were in we treated antidepressant treatment as a different of antidepressant types treatment, 0–5 years, 6–10years, and 11–16years. first-onsetthe affective into episode 3 periods: over time, we elapsed the divided since time bipolar disorder changed risk of the whether 181–365 days after delivery. To determine at baseline quartile, third quartile, or highest quartile) school) and income (lowest quartile, second school,(elementary or above elementary adjustmentsincluded further for education stratifying on age groups. Sensitivity analyses wepostpartum analyzed data the period, by with afirst-onset affective outside episode the postpartum affective episode and women difference inwomen with afirst-onset associations were by influenced age variable. psychiatric as atime-dependent history) psychiatric disorder ineither parent, or no (bipolar disorder ineither parent, other We adjusted for parental psychiatric history index prescription or during 1995–1999. prescription either dispensed before the to 2012with no previous psychotropic antidepressant prescriptions from 2000 women during born filled 1955–1997who to 5years and included 109,108 parous we expanded our washout defined period index antidepressant prescription. Further, pregnant again at of time the receiving the In multivariate the analyses, we adjusted Tobipolar disorder explore in risk the of To investigate observed whether 2) at baseline (ie, time of the first-time the 2) at (ie, baseline of time 16 35 years), status civil or (married; and excluded women were who 25 years, 25–34 + subsequent

12,14,15 e471

Parity Civil status Age, y Age, Income Calendar year of birth Calendar year of Education Characteristic age distribution and parity, but groups both were comparable affective outside episode regarding postpartum the period affective differed episode from women with afirst-onset study population. Women with afirst-onset postpartum Tableperiod. 1presentsthe characteristics baseline the of had afirst-onset affective during episode postpartum the e472 For [email protected]. reprints orpermissions, contact ♦ 35.2 mean parous women had afirst-onset affective episode. The according to legislation the inDenmark. study with public interest health on anonymized based data Agency. No informed consent for is needed aregister-based Ethical Considerations c b a the Postpartum Period and Women With aFirst-Onset Affective EpisodeOutside First-Onset Affective thePostpartum Period EpisodeDuring Table Characteristics 1.Baseline of Women With a Liu etal Parental psychiatric history RESULTS It isIt illegal to post this copyrighted PDF on any website. Income statusIncome of21women 1ofwhichhadbipolardisorder. was unknown, Outside the postpartum period referred period thepostpartum toOutside any timeoutside0−12months In the entire cohort, 5,384women theentire (4.4%)hadmissinginformationIn cohort, All 21women group. were includedinthehighestquartile antidepressant. to prior thefirst-time prescription ofan childbirth the of on parity postpartum. Unknown ≥ 1 Unknown Single, divorced, orwidow Married Married ≥ 25–34 < 1985–1997 Highest quartile Highest 1970–1984 Unknown Third quartile 1955–1969 Unknown Above elementary school Above elementary Second quartile No psychiatric history Elementary school Elementary Lowest quartile Other psychiatric disorderOther in Bipolar disorder ineitherparent During ourDuring 1997–2012,atotal study of 122,622 period The study was approved by Danish the Data Protection 2 35 25 either parent ± c ± 8.7 years (range, 15.0–57.9).Altogether, 7,877women

SD age at the time of the affective was episode SDthe age at of time the b the Postpartum Episode During 4,547 3,241 3,443 4,353 1,224 5,035 1,618 1,748 5,493 2,249 1,472 1,065 5,166 2,394 5,405 2,402 1,486 1,338 912 309 n (n Affective 81 89 69 Period = 7,877) 57.7 41.2 43.7 55.3 15.5 63.9 11.6 20.6 22.2 69.7 28.5 18.7 13.5 65.6 30.4 68.6 30.5 18.9 17.0 % 1.0 3.9 1.1 0.9 Episode Outside the Postpartum 75,292 34,158 50,681 62,212 61,663 37,325 15,757 25,838 50,207 30,261 59,030 16,956 76,058 33,050 78,537 35,606 25,596 18,231 1,852 5,508 3,081 5,295 1,021 (n n Affective = Period 114,745) a 65.6 29.8 44.2 54.2 53.8 32.5 13.7 22.5 43.8 26.4 51.4 14.8 66.3 28.8 68.4 31.0 22.3 15.9 % 1.6 4.8

2.7 4.6 0.9 bipolar disorder did not change substantially after further of afirst-onset postpartum affective and episode subsequent age ≥ 2.73); for age 25–34years, 1.57(95%CI,1.19–2.07); and for age groups: HRfor the age < wepostpartum analyzed data period, the by stratifying on and women with afirst-onset affective outside episode the women with afirst-onset postpartum affective episode AnalysesSensitivity 95% CI,15.30–33.03)(Table 2). addition stabilizer of or amood antipsychotic (HR inpostpartum womenwas observed subsequent with the disorder (HR bipolaranxiolytic was associated with risk of a higher postpartumuse with asubsequent prescription for an postpartum was 1.66(95% CI,1.12–2.48).Antidepressant HRfor the postpartum period, antidepressant monotherapy Compared to antidepressant monotherapy outside the by of type the first-time antidepressant (SSRIs vs non-SSRIs). stabilizerof mood or antipsychotic, was which not affected and 1.9years (interquartile range, 0.5–4.8)to date of addition antidepressant to date of addition of subsequent anxiolytic first-time prescriptionthe 0.5–4.9) from for date an of (Supplementary eTable 2). remained increased during entire the follow-up period days after delivery. Additionally,bipolar disorder risk of the had a first-onset affective 0–180days episode and 181–365 for anxiolytics, stabilizers, mood or antipsychotics. did not into take account any of subsequent effects prescription (HR postpartum period compared to women with an affective outside episode the women with apostpartum affective as was episode higher bipolar disorder among The risk of postpartumthe period. 1.28%–2.44%) of women with an affective outside episode developed bipolar disorder incomparison to 1.77%(95%CI, 2.06%–3.39%) of women with a postpartum affective episode after treatment initial with antidepressants, 2.64%(95%CI, bipolar disorder by using Kaplan-Meier Sixteen years curves. 1.8–7.7). Figure 3displays cumulative the incidence rate of for bipolar disorder was 4.5years (interquartile range, first-time psychiatric contactthe affective to episode date of affective episode. having lower first-onset educationthe level at of time the younger, single, divorced or widowed, and nulliparous and other psychiatric disorder. risk factors Other included being disorder and 1.49 (95% CI, 1.26–1.76) for parental of history of 4.68 (95% CI, 3.28–6.69) forbipolar parental history of included records of parental psychiatric history, with HRs entirein the cohort. Identified risk factors for bipolar disorder and income. in terms of parental psychiatric history, civil status, education, To account for influence by the age difference between The median duration was 2.1 years (interquartile range, Similar associations among were observed women who first-onset postpartumThe medianthe from time date of Figure 2shows possible the risk factors for bipolar disorder 35 years, 1.99 (95% CI,1.05–3.76).The associations © 2017Copyright Physicians Postgraduate Press, Inc. = 10.15; 95% CI, 7.13–14.46). The highest risk = 1.67; 95% CI, 1.35–2.08). Note, this 25 years was 1.79(95%CI, 1.17– J ClinPsychiatry 78:5,May 2017 = 22.48;

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. J ClinPsychiatry 78:5,May 2017 For [email protected]. reprints orpermissions, contact ♦ adjustment for income and education at (HR baseline b a ofBipolarDisorder Risk Figure Curves Illustrating 3.SmoothedKaplan-Meier Absolute change significantly. we extended our washout to 5years, results the period did not associations were In sensitivitythe observed. analyses, when pregnant first-onset affective episode, similar the at of time the 95% CI,1.35–2.08).After excluding 1,131women were who It isIt illegal to post this copyrighted PDF on any website. Cumulative incidence rate ofbipolardisorder amongwomen withafirst-onset Time since thefirstonsetofaffective episode episode outside the postpartum period. episode outsidethepostpartum affective episodeversus affective womenpostpartum withafirst-onset prescription for anantidepressant. umulative ncidence ate Affective episode outside te postpartum period Affective episodeoutsidetepostpartum Postpartum affective episode Baseline CharacteristicsBaseline intheEntire (n Cohort Figure 2.Crude Hazard for Ratios BipolarDisorder theFollow-Up During Period According to a Income statusIncome of21women 1ofwhichhadbipolardisorder. was unknown, All 21women were includedinthe Income Education Parity Civil status birth Calendar year of Parental psychiatric history Characteristic Age, y Age, ime ince irstnset Affective pisode highest quartile group.highest quartile Above elementary school Above elementary Unknown school Elementary ≥ Unknown First parity Married Unknown Single, divorced, orwidow ≥ 25–34 1985–1997 1970–1984 1955–1969 No psychiatric history Unknown psychiatric disorderOther ineitherparent Bipolar disorder ineitherparent < Highest quartile Highest Third quartile Second quartile Lowest quartile 2 35 25 a a = time since thefirst-time = aard atio 1.68; = 122,622)

the postpartum period (HR postpartumthe period women with afirst-time antidepressant therapy outside with bipolar diagnosed being disorder compared to 1 year after childbirth are at risk of ahigher subsequently with prescription afirst-time for an antidepressant within diagnosis. In present the study, we showed that women hypomanic or manic symptomsof or bipolar disorder antidepressant therapy and asubsequent occurrence as elevation of episodes mood misconstrued as can be therefore apossible explanation results, for observed the bipolar symptoms during is postpartum the period Misdiagnosis of postpartum inthe period. especially and Subsequent BipolarDisorder Postpartum Affective Episode treatment with an anxiolytic. among postpartum women received who subsequent for subsequent bipolar disorder was more pronounced during a maximumperiod 16-year follow-up. The risk a first-onset outside affective episode postpartum the bipolar disorder in comparisonrisk of to women with first-onset postpartum had affective an episode increased DISCUSSION © 2017Copyright Physicians Postgraduate Press, Inc. Diagnosing bipolar symptomatology is complex, In our cohort study, we found that women with a Previous work Postpartum Affective Disorders andBipolarDisorder 17,18 has suggested an association between Hazard (95%CI) Ratio 1.37 (0.94–2.00) 1.25 (1.09–1.44) 1.18 (0.86–1.60) 1.32 (1.15–1.52) 1.21 (0.73–1.99) 1.37 (1.20–1.57) 1.83 (1.56–2.15) 2.32 (1.93–2.78) 2.91 (2.14–3.96) 1.94 (1.68–2.24) 0.63 (0.49–0.81) 1.49 (1.26–1.76) 4.68 (3.28–6.69) 1.12 (0.92–1.37) 1.10 (0.91–1.33) 1.11 (0.90–1.36) = 1 (reference) 1 (reference) 1 (reference) 1 (reference) 1 (reference) 1 (reference) 1 (reference) 1.67; 95%CI,1.35–2.08).

e473 19

stabilizers or antipsychotics. distress exposure to with long-term unnecessary mood postpartum might episode to significant lead maternal A formal diagnosis of “bipolar disorder” after a single groupin this of women have also will severe consequences. during follow-up. However, overdiagnosing bipolar disorder only 2.64%of women were with bipolar diagnosed disorder is amajorperiod concern, inabsolute because numbers, overdiagnosisbipolar disorder during of postpartum the are present equally practice. inclinical We that donot expect disorder, concerns regarding overdiagnosing disordersthe unfavorable course for disease women. these subsequent pregnancies. undoubtedly This will result in an psychiatric care, and underestimation of relapse risks after treatmentineffective strategies, delayed referral to specialized bipolar disorder might have severe consequences, including bipolar vulnerability andof possible underdiagnosis of e474 For [email protected]. reprints orpermissions, contact ♦ prior hypomanic or manic symptoms. a bipolar depressive absence inthe of episode current or to distinguishis difficult amajor depressive from episode disorder present initially with depressive symptoms, and it bipolar disorderdate diagnosis. Many bipolarof of episodes first-onset postpartum affective to episode the the date of supported by our finding of amedian of 4.5years from the butacute postpartum period emerge at a later stage. This is hypomanic or manic symptoms are not present during the joyof motherhood. normal the Liu etal disorder. Moreover, among postpartum psychiatric episodes of recurrence following inwomen childbirth with bipolar various studies. Previous studies andBipolarDisorder The Link Between Childbirth symptoms over toward time abipolar course. disease bipolar disorder achange could reflect increased risk of in It isIt illegal to post this copyrighted PDF on any website. In contrast to concerns of underdiagnosing bipolar Another explanation results for is that observed the Childbirth andChildbirth bipolar disorder have across linked been

b a Postpartum period Diagnosis ofBipolarDisorder Treatment Prior to the an Antidepressant as Well as Treatment Strategy Table 2.Hazard for Ratios BipolarDisorder According First-Time to the Timing of Prescription for Outside the postpartum period thepostpartum Outside Treatment variable. All women was treated were asatime-dependent intheantidepressant monotherapy group at Adjusted for calendar year of birth, age, civil status, parity at the date of the first-time prescription for anantidepressant,the age, civilstatus, at thedate parity of birth, Adjusted for calendaryear of and parental psychiatric history. antidepressant in thegroup receiving ananxiolyticorantipsychotic/mood stabilizer subsequent to antidepressant therapy, ie, disorder,bipolar towomendispensed prior thediagnosis would of thenchangetreatment group andbeincluded the initialtreatment. asubsequent prescription If for ananxiolytic, moodstabilizer, orantipsychotic prescription was therapy group. Antidepressant monotherapy Antidepressant Antidepressant Antidepressant Antidepressant Antidepressant monotherapy stabilizer orantipsychotic stabilizer orantipsychotic + 21 + + + + subsequent anxiolytictherapy group orantidepressant subsequent anxiolytic subsequent mood subsequent mood subsequent anxiolytic 22,23

20 have rates reported high An underestimation a 17 In scenario, this the Cases 329 202 215 28 38 31 3.9 1.7 5.5 1.2 4.0 6.1 Person- Years × × × × × × 10 10 10 10 10 10 4 5 5 3 4 4 particular bipolarparticular disorder, regarding parental of history psychiatric disorders, in be a useful assessment auseful be instrument. Mood Disordersthe Questionnaireadministration of could to antidepressants may provide aclue about an underlying response apoor Overall, or failure to maintain response current and prior hypomanic or manic symptoms, for depressive or episodes anxiety are asked questions about is recommended that postpartum women all help seeking haveepisodes potential implications for practice. clinical It with a range of antidepressant-treated postpartum affective in Women With Postpartum Affective Episodes Detailed Assessment for BipolarDisorder Clinical Relevance: episode. disease milder initial abipolarcan trigger inwomen course also disease with an Jointly, results these reconfirm that childbirth inparticular markers can be childbirth also of underlying bipolar disorder. that less severe, nonpsychotic following affective episodes add to existing the knowledge as we base, now demonstrate 15-year follow-up period. womenthe converted of to bipolar disorder during the treated at inpatient psychiatric facilities, approximately 15% a relapse of bipolar disorder.a relapse of mood-stabilizing medications are inpreventing effective bipolar disorder, risk of given that shows evidence that that additional pharmacologic treatments increase the Importantly, we donot interpret finding as this indicating addition of an anxiolytic, stabilizer, mood or antipsychotic. amongobserved women required who a subsequent adequate bipolar risk profile. or emergence of comorbid psychiatric conditions. due of to severity the symptoms, treatment refractoriness, is that additional pharmacologic treatment is prescribed Incidence Rate Incidence person-years) Our findings of a higher risk of bipolar disorder inwomen findings ofOur risk of ahigher In our study,bipolar disorder was risk of ahigher (per 1,000 © 2017Copyright Physicians Postgraduate Press, Inc. 3.67 1.96 0.35 7.67 3.26 0.72 + subsequent moodstabilizer orantipsychotic

Hazard Ratio Crude 12.91 27.17 11.63

7.07 1 2.01

7 Results from presentthe study 6 will further help further to assess will an 12.77 (10.44–15.62) 22.48 (15.30–33.03) 10.15 (7.13–14.46) J ClinPsychiatry 78:5,May 2017 26 Adjusted Hazard 7.27 (6.05–8.73) 1.66 (1.12–2.48) Ratio (95%CI) Ratio Amore likely explanation 1 (reference) 25 Last, clinical questions clinical Last, b

24 and and 27

You are prohibited from making this PDF publicly available. You are prohibited from making this PDF publicly available. 1. and Munk-Olsen and Financial disclosure: knowledge, their of best the to that, determined Disclosure of off-labelusage: 2016. Submitted: presented in this article. this in presented has labeling been Administration–approved Drug and USFood outside is that agents investigational pharmaceutical about information Supplementary material: interpretation, or publicationthis study. of analysis, collection, data design, study the in sponsor:the Role of incentive). VENI and fellow (clinical Netherlands Organization for ScientificResearch The from funding received has 129830). Bergink Dr (2013- Union Cancer Nordic the and PROGEURO) European Research Council (ERC-2010-StG-260242- the by supported is Li Dr Research. Psychiatric Integrative for Initiative Foundation Lundbeck the iPSYCH, by supported are Agerbo and Munk-Olsen (R01MH104468). Drs Health Mental of Institute National the by supported are Meltzer-Brody Ms Funding/support: article. the to relative disclose to interest commercial any affiliations relationships withfinancial or personal REFERENCES J ClinPsychiatry 78:5,May 2017 might to lead an exacerbation of current episodes antidepressant monotherapy, may not and effective be bipolar disorder with spectrum antidepressants, especially in the treatmentbipolarin the disorder. of For [email protected]. reprints orpermissions, contact ♦ antidepressant prescription may not necessarily indicate first treated by antidepressants are not included. Moreover, first affective episode. Women with an affective disorder not prescription for an antidepressant as aproxy for first-onset important confounders. nationalseveral registers enables us to adjust for several rangea wide of of severity affective disorders. Linkage of an antidepressant as indicator the of affective status includes prescriptionthe for and Theof long use periods. observation impact of bias. study selection Our has alarge sample size with almost complete follow-up, minimizesthe which ConsiderationsMethodological bipolarity, postpartum, majority of women with depressive and anxiety disorders thePostpartum PeriodDuring Monitoring ofAntidepressant Use disorder.bipolar spectrum symptoms, professionals health should consider apossible ineffective or individual the woman changes experiences in increase of risk the suicide. symptom response to treatment course. and disease the It isIt illegal to post this copyrighted PDF on any website.

Our studyOur limitations. has several First, we first used The Danish registers cover entire the Danish population Antidepressants are afirst-line treatment option for the population-based register study. register JAMA population-based a disorders: mental and parents New al. et CB, Pedersen TM, T, Laursen Munk-Olsen May 24, 2016; accepted September 8, 8, 24, May 2016; September accepted 27,28 11 and Ms Meltzer-Brody and Drs Liu and Munk-Olsen and and Munk-Olsen and Liu Drs but antidepressants have shown little efficacy and antidepressant when monotherapy is The supporters had no role role no had supporters The Drs Liu Drs See accompanying pages. , Agerbo The authors have have authors The 31 It to carefully monitor is crucial , Li, Bergink have no no have . 29 no no To treat patients with , 10 9. 8. 7. 6. 5. 4. 3. 2. .

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Article Title: Depression and Anxiety in the Postpartum Period and Risk of Bipolar Disorder: A Danish Nationwide Register-Based Cohort Study

Authors: Xiaoqin Liu, PhD; Esben Agerbo, DrMedSc; Jiong Li, PhD; Samantha Meltzer-Brody, MPH; Veerle Bergink, PhD; and Trine Munk-Olsen, PhD

DOI Number: https://doi.org/10.4088/JCP.16m10970

List of Supplementary Material for the article

1. eTable 1 Anatomical Therapeutical Chemical (ATC) Classification Codes for Antidepressants, Anxiolytics, Mood Stabilizers, and Antipsychotics

2. eTable 2 Hazard Ratios for Bipolar Disorder According to Elapsed Time Since the Date of the First- Onset Affective Episode

Disclaimer This Supplementary Material has been provided by the author(s) as an enhancement to the published article. It has been approved by peer review; however, it has undergone neither editing nor formatting by in-house editorial staff. The material is presented in the manner supplied by the author.

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Supplementary Table 1 Anatomical therapeutical chemical (ATC) classification codes for antidepressants, anxiolytics, mood stabilizers, and antipsychotics ATC codes Generic drug names Antidepressants N06A Selective serotonin reuptake inhibitors N06AB zimeldine, , citalopram, paroxetine, , alaproclate, fluvoxamine, , escitalopram Serotonin-norepinephrine reuptake N06AX16, -17, - venlafaxine, milnacipran, duloxetine, inhibitors 21, -23 desvenlafaxine Tricyclic antidepressive agents N06AA , , imipramine oxide, , , , , , , , , , , , , , , , , , Anxiolytics Benzodiazepine derivatives N03AE01, N05BA clonazepam, diazepam, chlordiazepoxide, medazepam, oxazepam, potassium clorazepate, lorazepam, adinazolam, bromazepam,clobazam, ketazolam, prazepam, alprazolam, halazepam, pinazepam, camazepam, nordazepam, fludiazepam, ethyl loflazepate, etizolam, clotiazepam, cloxazolam, tofisopam, lorazepam (combinations) Azaspirodecanedione derivatives N05BE01 buspirone Benzodiazepine related drugs N05CF zopiclone, zolpidem, zaleplon, eszopiclone Mood stabilizers, including lithium N03AF01, , , valproic acid, N03AF02, lamotrigine, topiramate, gabapentin, lithium N03AG01, N03AX09, N03AX11, N03AX12, N05AN01 Antipsychotics with aliphatic side-chain N05AA , , , , , , Phenothiazines with structure N05AB , , , , , , , , , Phenothiazines with piperidine structure N05AC , , , derivatives N05AD , , , , , , , , Indole derivatives N05AE , , , , derivatives N05AF , , , , derivatives N05AG , , Diazepines, oxazepines, thiazepines and N05AH , , , , oxepines , N05AL , , , , , , Other antipsychotics N05AX , , , , , , , ,

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Supplementary Table 2 Hazard ratios for bipolar disorder according to elapsed time since the date of the first-onset affective episode*

Elapsed time since the date of Cases Person- Incidence rate Crude Adjusted hazard

the first-onset affective episode years (per 1000 hazard ratio (95% CI)

person-years) ratio

Whole follow-up period

0-180 days after delivery 39 2.1×104 1.84 2.06 1.70 (1.23 - 2.36)

181-365 days after delivery 58 3.3×104 1.74 1.94 1.64 (1.25 - 2.16)

Outside the postpartum period 746 8.3×105 0.90 1 1 (ref)

0-5 years

0-180 days after delivery 23 1.3×104 1.82 2.26 1.85 (1.21 - 2.83)

181-365 days after delivery 30 1.9×104 1.56 1.93 1.63 (1.12 - 2.37)

Outside the postpartum period 386 4.8×105 0.80 1 1 (ref)

6-10 years

0-180 days after delivery 11 6.5×103 1.70 1.63 1.30 (0.71 - 2.39)

181-365 days after delivery 20 1.1×104 1.89 1.81 1.48 (0.93 - 2.34)

Outside the postpartum period 280 2.7×105 1.04 1 1 (ref)

11-16 years

0-180 days after delivery 5 2.0×103 2.45 2.55 2.46 (0.98 - 6.16)

181-365 days after delivery 8 3.5×103 2.27 2.37 2.36 (1.12 - 4.97)

Outside the postpartum period 80 8.4×104 0.95 1 1 (ref)

Adjusted for calendar year of birth, age, civil status, parity at the date of the first-time prescription for an antidepressant, and parental psychiatric history; * Date of the first-onset affective episode=date of the first-time prescription for an antidepressant

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