98 L.L. Judd et al. / Journal of Affective Disorders 50 (1998)

Transcription

1 Journl of Affective Disorders 50 (1998) Reserch report Mjor depressive disorder: A prospective study of residul subthreshold depressive symptoms s predictor of rpid relpse,b, b,c b Lewis L. Judd *, Hgop S. Akiskl, Jck D. Mser, Pmel J. Zeller, b,c b Jen Endicott, Willim Coryell, Mrtin P. Pulus, Jelen L. Kunovc, Andrew C. Leon, Timothy I. Mueller, John A. Rice, Mrtin B. Keller Ntionl Institute of Mentl Helth Collbortive Progrm on the Psychobiology of Depression, Clinicl Studies, Sn Diego, USA b Deprtment of Psychitry, University of Cliforni Sn Diego, L Joll, CA , USA c The Psychitry Service, Sn Diego VAMC, Sn Diego, USA Abstrct Bckground: The study tested whether level of recovery from mjor depressive episodes (MDEs) predicts durtion of recovery in unipolr mjor depressive disorder (MDD) ptients. Methods: MDD ptients seeking tretment t five cdemic centers were followed nturlisticlly for 10 yers or longer. Ptients were divided on the bsis of intke MDE recovery into residul depressive symptoms (SSD; N 5 8) nd symptomtic (N 5 155) recovery groups. They were compred on time to first episode relpse/ recurrence, ntidepressnt mediction, nd comorbid mentl disorders. Recovery level ws lso compred to prior history of recurrent MDEs (. 4 lifetime episodes) s predictor of relpse/ recurrence. Results: Residul SSD compred to symptomtic recovery ptients relpsed to their next MDE. 3 times fster (medin 5 68 vs. 3 weeks) nd to ny depressive episode. 5 times fster (medin 5 33 vs. 184 weeks). Residul SSD recovery sttus ws significntly ssocited with erly episode relpse (OR ) nd ws stronger thn history of recurrent MDEs (OR ). Rpid relpse in the SSD group could not be ttributed to higher comorbidity or lower ntidepressnt tretment. Limittions: Although inter-rter greement on weekly depressive symptom rtings ws very high (ICC. 0.88), some error my exist in ssigning recovery levels. Antidepressnt tretments were recorded, but were not controlled. Conclusions: MDE recovery is powerful predictor of time to episode relpse/ recurrence. Residul SSD recovery is ssocited with very rpid episode relpse which supports the ide tht SSD is n ctive stte of illness. Asymptomtic recovery is ssocited with prolonged dely in episode recurrence. These findings of this present study hve importnt implictions for the gols of tretment of MDD nd for defining true MDE recovery Elsevier Science B.V. All rights reserved. Keywords: MDE recovery; Residul symptoms; Rpid episode relpse 1. Introduction ence nd incresed psychosocil impirment ssocited with threshold depressive symptoms (SSD) Studies in community smples report high prevl- (Wells et l., 1989; Brodhed et l., 1990; Johnson et l., 199; Judd et l., 1994, 1996, 1997), which * Corresponding uthor. hve been defined s miniml depressive symptoms / 98/ $ see front mtter 1998 Elsevier Science B.V. All rights reserved. PII: S (98)

2 98 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) beneth the dignostic threshold for minor, 1979), who were followed to t lest 10 yers nd dysthymic or mjor depressive disorders (Judd et l., who hd well-defined first well intervl (s defined 1994, 1996, 1997). We hve reported tht SSD re below) during follow-up. Intke dignoses were very commonly observed in ptients with unipolr obtined by Reserch Dignostic Criteri (RDC) mjor depressive disorder nd re n integrl com- (Spitzer et l., 1978) bsed on using Schedule for ponent of the symptomtic course of illness (Judd et Affective Disorders nd Schizophreni (SADS) inl., 1996, 1998). terviews (Spitzer nd Endicott, 1979). Ptients en- In ddition, reltionship hs been described tered the CDS during n MDE in the bsence of between SSD nd mjor depressive episodes ongoing dysthymi; ptients with evidence, t intke (MDEs), since some investigtors hve observed or follow-up, of bipolr disorders (mni, hypo- SSD to be ssocited with significntly incresed mni, cyclothymic personlity), schizoffective disprevlence of future nd pst MDEs (Brodhed et order or schizophreni were excluded from the MDD l., 1990; Howrth et l., 199; Sherbourne et l., cohort of 37 ptients. All CDS ptients were white, 1994; Judd et l., 1997).Other reserchers hve lso English-speking, with no orgnic mentl disorder found residul subthreshold depressive symptoms nor terminl illness nd intelligent quotients. 70. following mjor depressive episode (MDE) recovery Ech site obtined informed consent for study prre ssocited with incresed rtes of episode relpse ticiption. Ninety MDD ptients were excluded in (Frvelli et l., 1988; Simmons nd Thse, 199; dvnce of the nlyses becuse they did not ex- Thse et l., 199; Fv et l., 1994,b; Pykel et l., perience relpse/ recurrence during follow-up (N ). 44), hd missing or unrelible dt (N 5 10) or did To determine more definitively the clinicl signifi- not meet the criteri for residul SSD or symptocnce of residul SSD, we investigted the course of mtic recovery defined below (N 5 36). illness of lrge cohort of ptients with unipolr MDD, followed prospectively for 10 yers by the.. Follow-up procedures NIMH Collbortive Depression Study (CDS) (Ktz nd Klermn, 1979; Ktz et l., 1979). Ptients who Trined rters interviewed ptients every 6 months recovered from intke MDEs with residul SSD vs. for the first 5 yers, nd yerly therefter, using symptomtic recovery were compred on wide vritions of the Longitudinl Follow-up Evlution spectrum of clinicl nd course vribles. More (LIFE) (Keller et l., 1987). Ptients re the primry specificlly, the study ws designed to determine if source of informtion for the LIFE; chronologicl completeness or level of MDE recovery (residul memory prompts re used to obtin ccurte in- SSD vs. symptomtic recovery) predicted durtion formtion on weekly symptom severity for ll mood of recovery. Further, since erlier CDS studies hve or other mentl disorders. Interviews through 5 yers reported history of ntecedent MDEs (1 3 vs.. 4) were supplemented by detiled review of clinicl, to be the strongest predictor of erly relpse (Keller medicl nd reserch records. Weekly depressive et l., 198, 1983), this relpse risk fctor ws lso symptomtology ws rted using the LIFE Psychitcompred to residul SSD recovery of MDEs. ric Sttus Rting (PSR) Scles (Keller et l., 1987) shown in Tble 1. CDS interviewers undergo rigorous trining, resulting in very high intr-clss corre-. Methods ltion coefficients (ICC) for rting weekly symptom chnge points (ICC 5 0.9) episode recovery (ICC 5.1. The NIMH Collbortive Depression Study 0.95) nd point of subsequent depressive symptom (CDS) clinicl studies progrm ppernce (ICC ) Subjects.3. First well intervl vribles Subjects were nonbipolr MDD ptients seeking tretment t one of five cdemic centers during As described in Tble 1, RDC defines MDE 1978 to 1981 (Ktz nd Klermn, 1979; Ktz et l., recovery s. 8 consecutive weeks t PSR-MDD 1

3 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) Tble 1 Psychitric sttus rting scles e Six-point weekly psychitric sttus rting scle for RDC mjor depressive disorder (PSR-MDD) Code Sttus Definition 1. Asymptomtic/ returned to usul self Subject is returned to usul self without ny residul symptoms of the MDD disorder, lthough significnt symptomtology from underlying conditions my continue.. Residul/ mild depressive symptoms Subject clims not to be completely bck to usul self or rther notes presence of one or more symptoms of the MDD disorder in no more thn mild degree. 3. Prtil remission (moderte symptoms Considerble less psychopthology thn full criteri, or impirment) with no more thn moderte impirment in functioning, but still with obvious evidence of the disorder. 4. Mrked/ mjor symptoms or impirment Hs mjor symptoms or impirment but does not meet definite RDC criteri for MDD. 5. Definite criteri without prominent Meets RDC criteri for definite MDD episode, but hs psychotic symptoms or extreme no prominent psychotic symptoms nd no extreme b impirment impirment in functioning. 6. Definite criteri with prominent Meets RDC criteri for definite MDD episode, nd hs psychotic symptoms or extreme either prominent psychotic symptoms or extreme b impirment impirment in functioning (incpcittion). Three-point weekly psychitric sttus rting scle for RDC minor depressive or dysthymic disorders (PSR-MinD) (short-term or long-term) e nd for DSM-III typicl depression (96.8) or DSM-III djustment disorder with depressed mood (309.00) t intke Code Sttus Definition 1. c Asymptomtic Previously met RDC criteri for the disorder, but currently shows no evidence of it.. Probble criteri/ mild symptoms Previously met RDC criteri nd now hs some minor mnifesttions of the disorder but does not meet full RDC criteri. For the two DSM-III disorders, the subject does not hve to meet definite criteri first. 3. d Definite criteri/ severe symptoms Meet definite RDC criteri for the disorder. Eight consecutive weeks of PSR-MDD 1 or defines the end of RDC MDD episode. b Two consecutive weeks of PSR-MDD 5 or 6 defines the strt of n RDC MDD episode. c Eight consecutive weeks t PSR-MDD 1 or defines the end of n RDC episode of Minor Depressive or Dysthymic Disorder. d Two consecutive weeks t PSR-MinD 3 defines onset of n RDC episodes of Minor Depressive or Dysthymic Disorder. e Fluctutions in PSR rtings my be recorded without limittion during the time ptients re in n RDC depressive episode; once recovered there re coding prohibitions ginst incresing PSR scores until criteri for n episode of MDD or MinD re met. Increses in symptomtology tht do not meet criteri for n MDD episode my be recorded on the PSR-MinD scle if the ptients meets definite RDC criteri for MinD. Miniml increses in depressive symptomtology not meeting MinD or MDD criteri cn be recorded s n Other Psychitric Condition under one of two DSM-III codes: Atypicl Depression (DSM-III code 96.8) or Adjustment Disorder with Depressed Mood (DSM-III code ) using the three-point PSR-MinD scle. or ; RDC definition of episode relpse/ recurrence.4. Definition of the two recovery groups is defined by. consecutive weeks t PSR-MDD 5 or 6 MDE or. weeks t PSR-MinD 3, All weeks of the first well intervl, during 10 which is where ll new episodes of minor depressive yers of follow-up were clssified into two or dysthymic disorder (MinD) re coded. Strt of the ctegories: weeks when ptients were rted symptofirst well intervl ws identified s the first week of mtic s PSR-MDD 1 nd/or PSR-MinD 1 ; nd intke MDE recovery; end of the first well intervl weeks ptients were rted with residul subws defined s the lst week before onset of the first sthreshold depressive symptoms (SSD) or PSRprospective episode relpse/ recurrence. (see bove) MDD nd PSR-MinD. Following these two

4 100 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) recovery groups were creted: (1) the residul SSD (two-tiled lph level of P ). The nonrecovery group 8 ptients with ll of their well prmetric Wilcoxon Rnk Sum Test ws used to test intervl weeks rted PSR-MDD or PSR-MinD ; the reltionship between recovery sttus nd ordinl nd () the symptomtic recovery group 155 vribles. ptients with t lest 80% of well intervl weeks Comprison of the recovery period were mde rted PSR-MDD nd PSR-MinD 1. The 36 ptients using life-tble methods to model the cumultive eliminted from the nlysis smple did not meet probbility of depressive episode relpse s funcpriori definitions of residul SSD or symptomtic tion of successive numbers of weeks remining MDE recovery nd were extremely vried in per- well (Cox nd Okes, 1984). The Kpln Meier centge of weeks symptomtic (medin weeks t product limit estimte (Kpln nd Meier, 1958) ws PSR %; rnge 79%). It ws felt tht this used to ccommodte dt censored prior to end of group ws too heterogeneous in their recovery sttus the first well intervl. The reltive importnce of to be included in the nlysis smple for this first history of recurrent MDEs nd the recovery sttus investigtion of the recovery sttus risk fctor. risk fctors were evluted three wys. First, the predictive vlue of ech risk fctor ws tested seprtely using the generlized Wilcoxon test to.5. Antidepressnt mediction tretment during compre relpse curves for number of lifetime the first well intervl depressive episodes or for recovery sttus in the first well intervl (Klbfleisch nd Prentice, 1980). Sec- Antidepressnt mediction dosge ws combined ond, survivl nlysis ws repeted for four groups into five-point weekly composite ntidepressnt defined by combintions of these two dichotomous (CAD) score: 0 5 none; mg/qd of vribles to explore the possible interctive effects imiprmine or equivlent; mg/ qd between the two predictors of depressive episode imiprmine or equivlent; mg/ qd of relpse. Third, the Cox Proportionl Hzrds model imiprmine or equivlent; mg/ qd nd ws used to exmine the strength of ech vrible bove of imiprmine or equivlent (Keller et l., while controlling for the other (Cox nd Okes, 199). Recovery groups were compred on men 1984). weekly CAD scores for the intke MDE nd the first Previous CDS reports on UD hve focused priwell intervl. Percentge of weeks during the well mrily on relpse to MDEs (Keller et l., 198, intervl with ny (CAD. 1 ) nd dequte 1983, 199). For this pper, the survivl nlyses (CAD. 3 ) ntidepressnt mediction tretment were performed two wys-predicting time to first were lso compred. episode of ny depressive condition (mjor, minor depressive or dysthymic disorders) nd predicting.6. Reltionship of comorbid mentl or substnce time to first MDE relpse. use disorders to intke MDD episode recovery sttus Prevlence of comorbid mentl or substnce use disorders during the intke MDE nd first well intervl were compred for the two recovery groups. 3. Results 3.1. Demogrphic nd clinicl chrcteristics Significntly more symptomtic recovery ptients.7. Sttistics hd intke MDEs of, 6 months. Almost twice the percentge of residul SSD recovery ptients hd Sttisticl comprisons of the two recovery groups intke MDEs. yers, nd there were non-signifiwere mde for continuous vribles using t-tests; cnt trends for residul SSD ptients to hve higher comprisons cross ctegories of nominl vribles GAS scores nd higher rtes of in-ptient tretment were mde with Chi-squre or Fisher s Exct tests (Tble ).

5 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) Tble Demogrphic nd clinicl chrcteristics: A comprison of ptients with unipolr mjor depressive disorder who recover from the intke MDD episode to subsyndroml residul depressive symptoms vs. the symptomtic sttus Residul symptom Asymptomtic Significnce recovery group (N 5 8) group (N 5 155) Age: Men (S.D.) 39.7 (15.4) 40.0 (15.5) 0.15; df 5 35; P (NS) Age group: 17 to 30 N (%) 3(8.0) 64 (41.3) X ; 31 to 50 N (%) 36 (43.9) 49(31.6) df 5 ; Over 50 N (%) 3 (8.0) 4 (7.1) P (NS) Femle: N (%) 55(67.1) 93 (60.0) X ; df 5 1; P (NS) Eduction: High school or less N (%) 46 (56.1) 67 (43.) X ; College or more N (%) 36 (43.9) 88 (56.8) df 5 1; P (NS) Mritl sttus: Mrried/ living together N (%) 40 (48.8) 91(58.7) X ; Seprted, divorced, or N (%) 1(5.6) 4 (15.5) df 5 widowed P (NS) Never mrried N (%) 1(5.6) 40 (5.8) Age t onset of first Men (S.D.) 9.6 (14.1) 33.0 (14.7) t 5 1.0; df 5 35; ffective episode P (NS) Age t onset of first MDD Men (S.D.) 30.3 (14.0) 33.0 (14.7) t ; df 5 35; episode P (NS) Number of lifetime ffective episodes (including intke) X 5.10; 1 to 3 N (%) 57 (69.5) 11 (78.1) df 5 1; 4 or more N (%) 5 (30.5) 34 (1.9) P (NS) In-ptient sttus t intke N (%) 65 (79.3) 107 (69.0) X 5.8; df 5 1 P 5 0.O93 (NS) Globl ssessment scle (GAS) score: Men (S.D.) 37.6 (10.0) 40.0 (10.9) t ; Worst week of df 5 35; intke episode P (NS) Totl durtion of intke,b MOD episode (weeks) 0 to 6 months N (%) 5 (6.1) 44 (8.4) 5 4.5; 6 months to 1 yer N (%) 15 (18.3) 34 (1.9) c P to yers N (%) 6 (31.7) 41(6.4) Over yers N (%) 36 (43.9) 36 (3.) Men weekly composite Men (S.D.) 1.68 (1.07) 1.70(1.11) t ; ntidepressnt (CAD) df 5 33;,d,e score P (NS) Significnt differences cross study sites occurred for this vrible. b From onset to recovery. c Wilcoxon Smple Rnk Sum Test, by SAS NPAR1 WAY procedure on originl vlues (not recorded). d Dosge equivlents of five ntidepressnt drug clsses nd ECT re summed nd combined into five-point score for ech week s follows: (0) none; (1) 1 99 mg/qd of imiprmine or equivlent; () mg/qd imiprmine or equivlent; (3) mg/qd of imiprmine or equivlent; (4) 300 mg/ qd nd bove imiprmine or equivlent. e Two cses missing dt.

6 10 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) Tble 3 Comprison of ptients with unipolr mjor depressive disorder who recover from the intke MDD episode to subsyndroml residul depressive symptoms vs. the symptomtic sttus: nture of first prospective episode relpse during 10 yers of follow-up Residul symptoms Asymptomtic Significnce recovery group recovery group (N 5 8) (N 5 55) Overll three ctegory comprison: Remined well (no relpse) N (%) 11(13.4) 53(34.) Relpsed first to minor/ intermittent N (%) 45 (54.9) 43 (7.7) X ; depressive episode df 5 Relpsed first to MDD episode N (%) 6(31.7) 59(38.1) P, Remined well vs. relpsed: Remined well N (%) 11(13.4) 53 (34.) X ; Relpsed (ny depressive Dx) N (%) 71(86.6) 10 (65.8) df 5 1; P, Within relpse groups only: Relpsed first to minor/ intermittent N (%) 45(63.4) 43(4.1) X ; depressive episode df 5 1; Relpsed first to MDD episode N (%) 6 (36.6) 59 (57.9) P, 0.01 Within relpse groups only First to minor/ intermittent depression: Minor/ intermittent only (no MDD) N (%) 17 (37.8) 16 (37.) X Minor/ intermittent episode merges with N (%) 13 (8.9) 15 (34.9) df 5 ; MDD episode P (NS) Minor/ intermittent episode followed by N (%) 15 (33.3) 1 (7.9) seprte MDD episode lter 3.. Dignosis of first prospective relpse episode relpse re combined: recovery sttus (SSD vs. symptomtic); nd history of recurrent depressive As shown in Tble 3, significntly more sympto- episodes (1 3 vs.. 4 prior episodes, including the mtic recovery ptients hd no episode recurrence intke episode) (Keller et l., 198, 1987). The throughout 10 yers of follow-up thn residul SSD history of. 4 depressive episodes ws significntly recovery ptients (34. vs. 13.4%, respectively). ssocited with erly relpse only within sympto- Nerly two-thirds (63.4%) of SSD recoverers who mtic recovery ptients (medin 5 79 vs. 4 weeks, relpsed, did so first to episodes of MinD; the respectively; P, ). The recurrent MDEs risk mjority of symptomtic recovers (57.9%) relpsed fctor hd little effect on weeks to relpse mong to MDEs. residul SSD recovery ptients; in fct, the two survivl curves re virtully superimposed 3.3. Survivl nlysis of the first well intervl (medin 5 8 vs. 34 weeks, respectively; P ; compring residul SSD nd symptomtic NS). The two vribles were compred in Cox recovery ptients Proportionl Hzrds models. After controlling for the effect of recurrent MDEs history, unipolr MDD In Fig. 1 it is shown tht MDE relpse ws more ptients with residul SSD recovery were 368% thn three times fster for residul SSD thn symp- more likely to relpse during ny given intervl tomtic recovery (medin 5 68 vs. 31 weeks; P, following recovery thn symptomtic recovery p ). The second survivl nlysis (Fig. ), tients (OR ; 95% CI ). In contrst, shows tht SSD recovery ptients relpsed to ny the. 4 recurrent ntecedent MDE history risk depressive episode (MinD or MDD) 5.5 times fster fctor, fter controlling for MDE recovery, incresed thn symptomtic recoverers (medin 5 33 vs. 184 the likelihood of relpse by only 64% over the weeks; P, ). probbility for ptients with one to three prior In Fig. 3 two risk fctors ssocited with erly episodes (OR ; 95% CI ).

7 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) Fig. 1. Survivl nlysis of weeks to mjor depressive episode relpse (MDE): compring ptients with unipolr mjor depressive disorder who recovered from intke MDE with residul subsyndroml depressive symptoms vs. symptomtic sttus. Wilcoxon Chi Squre Test of Difference ; P, Reltionship of ntidepressnt mediction equivlent qd) for SSD recovery ws.4% (sd 5 tretment to recovery sttus nd durtion of the 38.4%) nerly double the 1.6% (sd 5 6.5%) for first well intervl symptomtic recovery ptients (t 5.09; df 5 35; P ). Men weekly CAD scores during the intke MDE were not significntly different between residul SSD 3.5. Comorbid mentl or substnce use disorders nd symptomtic recovery ptients (Tble ). Men weekly CAD scores during the first well intervl The overll prevlence of comorbid mentl or were significntly higher for SSD recovery t 1.3 substnce use disorders t intke ws significntly (sd 5 1.3), compred to 0.9 (sd 5 1.1) for sympto- higher for the SSD thn the symptomtic recovery mtic recovery (CAD of mg of imi- group (39.0 vs. 6.4%; Chi-squre ; df 5 1; prmine or equivlent qd) (t 5.48; df 5 35; P 5 P ). The only specific dignosis on which the 0.014). SSD recovery ptients received ny ntide- groups differed ws the Other Psychitric Disorders pressnt mediction for n verge of 50.9% (sd 5 ctegory (4.4 vs. 1.3% Chi-squre , df 5 1; 44.9%) of weeks during the well intervl, compred P ), ctch-ll RDC ctegory tht includes to 38.4% (sd 5 4.8%) of weeks for the symptomt- personlity disorders nd miscellneous other digic recoverers (t 5.10; df 5 35; P ). Percent noses. However, during the first well intervl, the of first well intervl weeks t therpeuticlly two recovery groups did not differ significntly in dequte doses of ntidepressnt mediction (defined their rtes of overll or individul comorbid mentl s CAD. 3, or t lest 00 mg of imiprmine or or substnce use disorders.

8 104 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) Fig.. Survivl nlysis of weeks to ny depressive episode relpse: compring ptients with unipolr mjor depressive disorder who recovered from the intke MDD episode with residul subsyndroml depressive symptoms vs. symptomtic sttus. Wilcoxon Chi Squre Test of Difference ; P, Discussion nlyses of the prospectively studied MDD-CDS cohort showed it to be predictor of very rpid The min finding is tht ptients with symptomt- episode relpse, the results of these two studies were ic recovery remined well for medin of 31 weeks not explined by lower ntidepressnt mediction (4.4 yers) before MDE recurrence, which indictes tretment. In the ggregte there is strong contrue or full MDE recovery, compred to 68 weeks fluence of scientific evidence tht residul SSD for residul SSD recovery, indicting the MDE ws recovery is n importnt predictor of very rpid nd incompletely or only prtilly remitted (DMS-IV, frequent episode relpse (Frvelli et l., 1988; APA, 1994). We conclude tht residul SSD recovery Simmons nd Thse, 199; Thse et l., 199; Fv from depressive episodes is robust nd importnt et l., 1994,b; Pykel et l., 1995). clinicl mrker, strongly ssocited with very rpid Keller et l. (198), (1987) reported tht history of episode relpse in unipolr MDD. recurrent MDEs (. 4) ws the strongest predictor of Our findings re similr to the observtions of erly MDE relpse in MDD ptients in the 5 yer Pykel et l. (1995) who reported on smller MDD CDS follow-up dt (Keller et l., 198, 1983). smple (N 5 60) followed-up more briefly (15 These nlyses of the CDS 10 yer dt confirms months). Both studies found tht bout one-third (34 their prior observtions. However, residul SSD nd 3%, respectively) of UD ptients recover from recovery hs significntly stronger ssocition with MDEs with residul SSD. Pykel et l. (1995) found erly depressive episode relpse thn the recurrent residul SSD recovery to be ssocited with sig- MDE risk fctor (OR ) vs. 1.64, respectively). nificntly elevted rtes of relpse, while our present In fct, the effect on relpse time of ntecedent

9 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) Fig. 3. Survivl nlysis of weeks to ny depressive episode relpse, combining two relpse risk fctors in ptients with unipolr mjor depressive disorder: History of recurrent mjor depressive episodes (1 3 vs.. 4 episodes) nd recovery sttus (SSD vs. symptomtic recovery). Wilcoxon Chi Squre Test of Difference: A (4.0 weeks) vs. B (79.0 weeks) Chi Squre ; P, ; A (4.0 weeks) vs. C (34.0 weeks) Chi Squre ; P, ; A (4.0 weeks) vs. D (5.0 weeks) Chi Squre ; P, ; B (79.0 weeks) vs. C (34.0 weeks) Chi Squre ; P ; B (79.0 weeks) vs. D (8.0 weeks) Chi Squre ; P ; C (34.0 weeks) vs. D (8.0 weeks) Chi Squre ; P (NS). recurrent MDEs is significnt only mong sympto- ntidepressnt mediction, or ugmenttion with mtic recovery ptients. Thus, risk for erly relpse mood stbilizers. Other investigtors hve reported ssocited with residul SSD recovery is so strong tht subsyndroml nd minor depressive symptht it ppers to override the effect of the history of tomtology respond to depression-specific brief psyrecurrent MDEs. chotherpies (Mirnd nd Munoz, 1994; Fv et l., We found no evidence tht rpid episode relpse is 1994,b) or hve delyed episode relpse (Frnk et ttributble to less intense ntidepressnt tretment l., 1991,b; Fv et l., 1994,b). It will be imduring the intke MDE or the first well intervl. In portnt to determine in lrge prospective controlled fct, SSD recovery ptients received significntly tretment studies, whether ll MDD ptients cn be more ntidepressnt mediction nd dequte medi- treted to the symptomtic sttus nd which therction for more well intervl weeks thn sympto- peutic strtegies re most successful in chieving this mtic recoverers. Our findings lso support other importnt nd necessry therpeutic gol. studies which hve correlted residul depressive Full symptom free recovery from MDEs is strongsymptoms with poor tretment response rther thn ly ssocited with significntly prolonged delys in indequte ntidepressnt tretment (Mindhm et l., episode recurrence or no episode recurrence l- 1973; Prien nd Kupfer, 1986; Georgots nd together. Resolution of MDEs to residul SSD, McCue, 1989; Mj et l., 199). lthough defined by RDC (PSR 1 or ) s This suggests tht residul SSD my require recovery is, in fct, not recovery. It is prtil or higher doses, different clsses or combintions of incomplete MDE remission (DSM-IV, APA, 1994),

10 106 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) indicting the MDE is still ctive nd the tretment Only few clues emerge from this study bout response is incomplete. These dt combined with clinicl differences between residul SSD nd other reports tht SSD is ssocited with psycho- symptomtic recoverers. Residul SSD recoverers socil impirment nd incresed helth service use hd non-significnt trends towrd greter illness (Wells et l., 1989; Brodhed et l., 1990; Johnson severity t intke (GAS scores nd inptient sttus) et l., 199 Judd et l., 1994, 1996, 1997) dd further nd their intke MDE episodes lsted significntly confirmtion tht SSD is cliniclly relevnt stte of longer thn those of the symptomtic recovery illness ctivity in unipolr MDD. group. During the intke MDE but not the first well Some methodologicl limittions re inherent in intervl, residul SSD recovery group hd sigthis study. The CDS is five site prospective nificntly higher overll rte of comorbid mentl nturlistic study of mood disorder ptients initited disorder dignoses, prticulrly the ctegory tht during 1978 to 1981 continuing to the present. Site includes personlity disorders nd miscellneous differences were present in some demogrphic nd psychopthology. Whether certin tempermentl clinicl chrcteristics s result of the CDS sm- trits or personlity disorder predispose MDD ppling strtegy to obtin diverse MDD cohort, but tients to incomplete MDE recovery is the subject of the impct of recovery sttus on time to relpse ws current study. consistent cross ll five sites. Although inter-rter In 1991, respected mood disorder reserchers greement is high (ICC. 0.88) there my be some reviewed the scientific literture nd proposed terms degree of error in ssigning PSR levels. One would for the course of unipolr MDD, inviting the field to expect ny such error to ttenute systemtic group test empiriclly their preliminry definitions (Frnk differences, which proved to be quite robust, pro- et l., 1991,b). Our dt do not support the proposed viding further evidence of symptom rting relibility. definition, tht MDE full remission or recovery is Reltively few (13.4%) of SSD recoverers hd the chieved when the ptient no longer meets... end of their first well intervl extending beyond 10 syndroml criteri for the disorder nd hs no more yers of follow-up (i.e., censored relpse dt). The thn miniml symptoms or tht symptomtic rte ws higher (34.%) in symptomtic recoverers, sttus is defined by, depressive symptoms but nerly hlf the censored cses in this group (SADS) or Hmilton Depression Rting Scle (49%) still hd. 5 yers of well intervl dt. We (HDRS) (Hmilton, 1967) scores of, 7. These felt this ws mple informtion for vlid nd stble definitions of full remission or recovery re in error ssignment of recovery sttus. Thirty-six of 73 since they llow for residul SSD to be present nd MDD ptients (13.%) not meeting one of the two do not require the complete bsence of depressive priori recovery definitions were omitted from the symptoms. In ggregte, our nd other investigtions nlyses; these ptients were very heterogeneous in (Frvelli et l., 1988; Simmons nd Thse, 199; their recovery sttus (medin weeks PSR 1 5 Thse et l., 199; Fv et l., 1994,b; Pykel et l., 41.4%; rnge 79%). In this initil investigtion of 1995; Fv, 1996) indicte tht n essentil requirethe SSD recovery risk fctor, we chose to develop ment for defining of full MDE remission or MDE two reltively homogeneous recovery groups for recovery is the chievement of completely deprescontrst, nd define recovery sttus bsed upon ll sive symptom free sttus. Indeed, previous reserch weeks of the first well intervl, rther thn on hs shown tht in MDD ptients with residul specific period of recovery (e.g., first 8 weeks well symptomtic chronicity the illness continues to be intervl, etc.) to highlight the effect of recovery cliniclly nd neurophysiologiclly ctive (Akiskl, sttus on durtion of the first well intervl. In 198). Widespred cceptnce of tretment gols ddition, the CDS recorded, but did not control primrily emphsizing resolution of symptomtology tretment, which limits conclusions from tretment below syndroml criteri for the episode (e.g., HDRS dt. Also, becuse of censored dt, men CAD of 7 ), but not requiring complete resolution of tretment scores my hve been clculted from residul SSD, could indvertently contribute to furdifferent time intervls cross subjects; tretment ther chronicity of MDD ptients. Filure to tret dt should be interpreted with this in mind. MDE s to the symptomtic sttus my hve resulted

11 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) in MDD ptients being treted only to residul SSD, Frnk, E., Kupfer, D.A., Wgner, E.E., Efficicy of inter- resulting in heightened risk for erly relpse in person psychotherpy s mintennce tretment of recurrent depression. Arch. Gen. Psychitry 48, cycle repeting itself throughout the course of ill- Georgots, A., McCue, R.E., Relpse of depressed ptients ness. fter effective continution therpy. J. Affect. Disord. 17, In conclusion, further prospective controlled study is needed to determine if chieving the gol of Hmilton, M., Development of rting scle for primry depressive illness. Br. J. Soc. Clin. Psychology 6, symptomtic recovery for MDEs cn consistently Howrth, E., Johnson, J., Klermn, G.L., et l., 199. Depressive prevent or dely episode relpse or recurrence nd symptoms s reltive nd ttributble risk fctors for first-onset improve socil nd voctionl functioning through- mjor depression. Arch. Gen. Psychitry 49, out the unipolr MDD ptient s lifetime. Johnson, J., Weissmn, M.M., Klermn, G.L., 199. Service utiliztion nd socil morbidity ssocited with depressive symptoms in the community. J. Am. Med. Assoc. 67, 1478 Acknowledgements Judd, L.L., Rpport, M.H., Pulus, M.P., Brown, J.L., Subsyndroml symptomtic depression (SSD): new mood This mnuscript hs been reviewed by the Publi- disorder?. J. Clin. Psychitry 55 (4), 18S 8S. ctions Committee of the Collbortive Depression Judd, L.L., Akiskl, H.S., Pulus, M.P., The role nd clinicl significnce of subsyndroml depressive symptoms (SSD) in Study nd hs its endorsement. Funds for the conunipolr mjor depression. J. Affect. Disord. 167, duct of this study were provided in prt by the Judd, L.L., Pulus, M.P., Wells, K.B., Rpport, M.H., NIMH Mentl Helth Clinicl Reserch Grnt Socio-economic burden of subsyndroml depressive symptoms PHSMH30914 PHSMH49671, nd the Roehr Fund nd mjor depression in smple of the generl popultion. of the University of Cliforni, Sn Diego. Am. J. Psychitry 153 (11), Judd, L.L., Akiskl, H.S., Mser, J.D., Zeller, P.J., Endicot, J., Coryell, W., Pulus, M.P., Kunovc, J.L., Leon, A.C., Mueller, References T.I., Rice, J.A., Keller, M.B., A prospective 1 yer study of subsyndroml nd syndroml depressive symptomtology in unipolr mjor depressive disorders. Arch. Gen. Akiskl, H.S., 198. Fctors ssocited with incomplete recovery Psychitry, submitted. in depressive illness. J. Clin. Psychitry 43, Klbfleisch, J.D., Prentice, R.L., The sttisticl nlysis of Brodhed, W.E., Blzer, D.G., George, L.K., Tse, L.K., filure time dt. John Wiley nd Sons, New York. Depression, disbility dys nd dys lost from work in Kpln, E.L., Meier, P., Nonprmetric estimtion from prospective epidemiologic survey. J. Am. Med. Assoc. 64, incomplete observtions. J. Am. Stt. Assoc. 53, Ktz, M.M., Klermn, G.L., Overview of the clinicl studies Cox, D.R., Okes, D., Anlysis of Survivl Dt. Chpmn progrm of the ntionl institute of mentl helth-clinicl nd Hll, London nd New York. reserch brnch collbortive progrm on the psychobiology of Dignostic Sttisticl Mnul of Mentl Disorders (DSM-IV)., depression. Am. J. Psychitry 136, , 4th ed. Americn Psychitric Assocition, Wshington, Ktz, M.M., Secund, S.K., Hirschfeld, R.M., Koslow, S.H., D.C. NIMH clinicl reserch brnch collbortive progrm on the Frvelli, C., Amboneti, A., Plente, S., Pzzgli, A., psychobiology of depression. Arch. Gen. Psychitry 36, 765 Depressive relpse nd incomplete recovery from index epi sode. Am. J. Psychitry 143, Keller, M.B., Shpiro, R.W., Lvori, P.W., et l., 198. Relpse in Fv, G.A., Grndi, S., Zielezny, M., Cnestrti, R., Four mjor depressive disorder: nlysis with the life tble. Arch. Yer Outcome for Cognitive Behviorl Tretment of Residul Gen. Psychitry 39, Symptoms in Mjor Depression. Am. J. Psychitry 153, 945 Keller, M.B., Lvori, P.W., Lewis, C.E., Klermn, G.L., Predictors of relpse in mjor depressive disorder. J. Am. Med. Fv, G.A., Grndi, S., Zielezny, M., Cnestrti, R., Assoc. 50, Cognitive Behviorl Tretment of Residul Symptoms in Keller, M.B., Lvori, P.W., Friedmn, M.A., Nielsen, E., Endicott, Primry Depressive disorder MA.. Am. J. Psychitry 151, J., McDonld-Scott, P., Andresen, N.C., The longi tudinl intervl follow-up evlution: A comprehensive method Fv, G.A., The concept of recovery in ffective disorders. for ssessing outcome in prospective longitudinl studies. Psychother. Psychosom. 65, 13. Arch. Gen. Psychitry 44, Frnk, E., Prien, R.F., Jrrett, R.B., Keller, M.B., Kupfer, D.J., Keller, M.B., Lvori, P.W., Mueller, T.I., Endicott, J., Coryell, W., Lvori, P.W., Rush, A.J., Weissmn, M.M., Conceptuli- Hirschfeld, R.M.A., Shy, T., 199. Time to recovery, ztion nd rtionle for consensus definitions of terms in mjor chronicity nd levels of psychopthology in mjor depression. depressive disorder. Arch. Gen. Psychitry 48, Arch. Gen. Psychitry 49,

12 108 L.L. Judd et l. / Journl of Affective Disorders 50 (1998) Mj, M., Veltro, F., Pirozzi, R., Lobrce, S., Mglino, L., 199. Criteri for Selected Group of Functionl Disorders, 3rd ed. Pttern of recurrence of illness fter recovery from n episode New York Biometrics Reserch Division, New York Stte of mjor depression. Am. J. Psychitry 149, Psychitric Institute. Mindhm, R.H., Howlnd, C., Shephrd, M., An evlution Spitzer, R.L., Endicott, J., Schedule for Affective Disorders of continution therpy with tricyclic ntidepressnts in depres- nd Schizophreni (SADS), 3rd ed. New York Biometrics sive illness. Psychol. Med. 3, Reserch Division, New York Stte Psychitric Institute. Mirnd, J., Munoz, R., Intervention for minor depression in Simmons, A.D., Thse, M.E., 199. Biologicl mrkers, tretment primry cre ptients. Psychosom. Med. 56, outcome, nd 1-yer follow-up in Endogeneous Depression: Pykel, E.S., Rmn, R., Cooper, Z., Hyhurst, H., Kerr, J., Electroencephlogrphic sleep studies nd response to cogni- Brock, A., Residul symptoms fter prtil remission: tive therpy. J. Consult. Clin. Psychol. 60, n importnt outcome in depression. Psychol. Med. 5, 1171 Thse, M.E., Simmons, A.P., McGery, J., Clhne, J.F., Hughes, C., Hrden, B., Friedmn, E., 199. Relpse fter cognitive Prien, R.F., Kupfer, D.J., Continution drug therpy for behvior therpy of depression: potentil implictions for mjor depressive episodes. Am. J. Psychitry 1743, longer courses of tretment. Am. J. Psychitry 197, 1046 Sherbourne, C.D., Wells, K.B., Hys, R.D., Rogers, W., Burnm, 105. M.A., Judd, L.L., Subthreshold depression nd depres- Wells, K., Stewrd, A., Hys, R., Burnm, A., Rogers, W., sive disorder: clinicl chrcteristics of generl medicl nd Dniels, M., Berry, S., Greenfield, S., Wre, J., The mentl helth specilty outptients. Am. J. Psychitry 151, functioning nd well-being of depressed ptients: results from the Medicl Outcomes Study. JAMA 6, Spitzer, R.L., Endicott, J., Robins, E., Reserch Dignostic