Two year follow-up of atypical depression

\ PERGAMON

Journal of Psychiatric Research 22 "0888# 12Ð18

Two year follow!up of atypical depression Jon Kar Zubieta\ Atul C[ Pande\ Mark A[ Demitrack Department of Psychiatry\ The University of Michi`an\ Ann Arbor\ MI 37093!0567\ U[S[A[ Received 15 January 0887^ accepted 05 July 0887

Abstract The symptom cluster of Atypical Depression "AD# has been characterized based on its presentation and selective response to pharmacological treatments\ while relatively little is known about the outcome of these patients after treatment trials[ The present study was undertaken to assess the long term outcome of 39 patients after a controlled treatment trial of ~uoxetine vs phenelzine[ Twenty _ve of these subjects were interviewed approximately two years after completion of the initial trial[ They reported a high frequency of symptom recurrence\ but generally little symptomatic or social impairment between episodes[ Eighteen subjects were taking antidepressants at follow!up[ A higher frequency of depressive episodes was recorded during the times when o} antidepressant medications[ Overall outcome was rated as moderate or good in the majority of subjects[ These results suggest that AD presents from similarities with other subtypes of depression\ with high rates of symptomatic recurrence and lasting response to chronic antidepressant treatment[ Conversely\ social functioning and overall outcome appear more favorable in AD[ Þ 0888 Elsevier Science Ltd[ All rights reserved[ Key words] Atypical depression^ Depressive disorders^ Course^ Outcome^ Recurrence^ Antidepressants

0[ Introduction The symptomatic cluster of atypical depression "AD#\ de_ned as a depressive state with mood reactivity "non! endogenous mood# and reversed vegetative symptoms "hypersomnia\ hyperphagia#\ has received considerable attention from the initial reports of a preferential response to monoamine oxidase inhibitor "MAOI# anti! depressants "Quitkin et al[\ 0873\ 0877\ 0878^ Liebowitz et al[\ 0877#[ MAOI|s also have shown to have a better prophylactic e.cacy than imipramine over six months "Stewart et al[\ 0886#[ However\ there is limited data on the outcome of these patients after their initial treatments\ or whether the symptomatic cluster so de_ned is stable over time[ Patients diagnosed with AD\ many of which present with chronic courses\ have been reported to present low degrees of response to placebo\ and high response rates to active antidepressant medication in short term trials "Quitkin et al[\ 0878^ Stewart et al[\ 0878^ Pande et al[\ 0885#[ It is not clear\ however\ whether the initial improvement is followed by continuous remission and good outcomes once the controlled treatment period was completed[ This is of special importance given the results

 Corresponding author[ Tel[] ¦202!652!5732^ fax] ¦202!825!1589^ e!mail] zubietaÝumich[edu[

of longitudinal studies in major depression\ in which rela! tively poor rates of complete recovery\ frequent relapses and poor social adjustment have been reported "Lee and Murray 0877^ Lehmann et al[\ 0877^ Shea et al[\ 0881^ Wells et al[\ 0881^ Eaton et al[\ 0886#[ For a group of 18 inpatients diagnosed with atypical depression at the index episode\ a one year follow!up study showed also a high degree of symptom chronicity[ A large number of them "39)# also showed changes in symptom pro_le to mel! ancholic\ or bipolar symptoms "Ebert and Barocka\ 0880#[ This report contrasts with a subsequent study showing a high degree of symptom stability "89) of them still showed atypical depressive symptoms# across episodes in 21 outpatients who relapsed in a double!blind ~uoxetine discontinuation protocol "Nierenberg et al[\ 0885#[ Interestingly\ discontinuation of phenelzine\ a MAOI antidepressant\ six months after symptom remission resulted in a 76) recurrence of symptoms "Ste! wart et al[\ 0886#\ suggesting that this is a chronic\ readily recurrent illness if untreated[ In the present study we prospectively evaluated the long!term course of illness\ social functioning\ and out! come of a group of outpatients who met Columbia cri! teria for AD "Quitkin et al[\ 0873#[ These subjects were non!responders to two weeks of placebo administration and completed a randomized\ double!blind trial of phenelzine vs ~uoxetine "Pande et al[\ 0885#[ From the forty patients who completed the initial study\ twenty

9911Ð2845:88:, ! see front matter Þ 0888 Published by Elsevier Science Ltd[ All rights reserved[ PII] S 9 9 1 1 Ð 2 8 4 5 " 8 7 # 9 9 9 2 4 Ð 0

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J[K[ Zubieta et al[ : Journal of Psychiatric Research 22 "0888# 12Ð18

_ve were interviewed approximately two years after com! pletion of the trial[ A naturalistic approach was utilized\ in that no control was placed on the treatment between trial completion and follow!up[ Our initial hypotheses\ based on clinical observations and their favorable response to the treatment "Pande et al[\ 0885# was that these patients would show relatively good outcomes regardless of their presenting symptomatic impairment and length of illness[

1[ Methods The initial sample consisted of 39 "16 women\ 02 men# outpatients with DSM!III!R Major Depressive Disorder meeting the Columbia criteria for atypical depression "Quitkin et al[\ 0873#[ Thirty one met DSM!III!R criteria for recurrent Major Depression^ another six also met the additional temporal criteria for Dysthymia^ and three for Major Depression\ single episode[ Patients with non! depressive DSM!III!R diagnoses "i[e[\ substance abuse or dependence# or de_nite bipolar disorder were excluded[ All patients were drug!free for 3Ð09 days prior to the trial "mean 6 days#\ and underwent a single!blind placebo treatment period of two weeks before being randomized to the active drug[ The subjects included in the study did not signi_cantly improve during the drug!free period and completed a six!week double!blind trial of ~uoxetine vs phenelzine[ Dosing was started with phenelzine 04 mg daily or ~uoxetine 19 mg daily[ The daily dose of phenel! zine could be raised after three days by 04 mg and then weekly by 04 mg:day to a maximum of 89 mg:day[ The dose of ~uoxetine was kept at 19 mg:day for three weeks and then could be raised to a maximum of 59 mg:day[ Double!blind treatment lasted for six weeks after which the treatment could be unblinded in order to allow ongo! ing treatment "Pande et al[\ 0885#[ The rate of response "de_ned either as a HAMD decrease of 49) or more\ or a CGI score of 0 or 1# was 74) for both ~uoxetine and phenelzine[ The rate of remission "_nal HAMD ³ 4 and CGI improvement of 0 or 1# was 79) for ~uoxetine and 69) for phenelzine#[ After completion of the initial treatment period the patients were given the choice of continuing to be followed in the clinic\ treatment dis! continuation\ or treatment in the community[ Treatments after the initial trial were not controlled[ The sample was then contacted 1025 "mean2S[D[# months "range 09Ð29# after completion of the initial trial\ for reevaluation of their status[ Twenty _ve patients "52) of the initial sample# were reached and consented to con! duct the survey[ The small sample recruited during the follow!up contact is likely due to the characteristics of our catchment area] a college town\ with frequently transient residents[ Two additional patients were reached but did not consent to performance of the survey[ The follow!up interview consisted of a direct structured interview by

a psychiatrist "J[K[Z[#\ who did not collaborate in the treatment trial and was blind to its results[ Interviews lasted 0[4Ð2 h and included the Structured Clinical Inter! view for DSM!III!R "SCID# "Spitzer et al[\ 0878# with additional endogenous:melancholic "SADS!RDC and DSM!III!R# and atypical depression criteria\ the Longi! tudinal Interval Follow!up Evaluation II "LIFE II# "Keller et al[\ 0876#\ the Clinical Global Impression Scale "CGI# "McGlashan\ 0862#\ the outcome criteria of the Schedule for A}ective Disorders and Schizophrenia "SADS# "Spitzer and Endicott\ 0864#\ and the outcome criteria of Lee and Murray "0877#[ The study design and objectives were approved by the local Institutional Review Board\ in agreement with the Declaration of Hel! sinki for studies in human subjects[ Informed consent for study participation was obtained for all subjects[ Results were analyzed via descriptive statistics\ or non! parametric tests "Fisher|s exact test for non continuous variables\ Spearman|s rank correlation or MannÐWhit! ney U for continuous data#\ as indicated in the text[ All results are expressed as the mean20 standard deviation "S[D[#[

2[ Results The characteristics of the 14 subjects included in the survey are described in Table 0[ The subjects lost to follow!up "n  04# did not di}er from the sample con! tacted in their initial HDRS or CGI scores\ demo! graphics\ response to treatment or diagnosis "MannÐ Whitney U or Fisher|s exact test\ P × 9[94#[ Of the pat! ients available at follow!up\ 08 had met criteria for DSM! III!R recurrent MDD at the index episode\ one for MDD single episode\ and _ve were diagnosed with Dysthymia[ During the interval to follow!up\ over half of the sub! jects reported experiencing at least one episode of at least two weeks during which DSM!III!R symptomatic criteria for MDD was met[ At the time of the interview\ however\ only two subjects "7)# reported symptoms su.cient for a diagnosis of MDD[ Ten subjects "39)# did not experi! ence episodes of MDD during the follow!up period\ while 01 "37)# met DSM!III!R criteria for one episode\ two "7)# for two episodes\ and one subject "3)# experienced three\ totaling 08 episodes for the entire sample\ or 9[34 episodes per patient!year of follow!up[ In all cases\ the episodes described presented atypical features "possible or probable atypical depression^ Quitkin et al[\ 0873#\ with none of the subjects meeting DSM!III!R Mel! ancholic or RDC Endogenous criteria at any time during the follow!up period[ Four subjects "05)# described epi! sodes of hypomania^ these all occurred while taking anti! depressant medications "three on phenelzine 29Ð59 mg per day\ one while taking ~uoxetine 59 mg per day#[ No episodes of psychosis or frank mania were reported[ Eighteen of the subjects "61)# were taking anti!

J[K[ Zubieta et al[ : Journal of Psychiatric Research 22 "0888# 12Ð18 Table 0 Sample group and index episode characteristics Age "years# Follow!up period "months# Sex] Female Male Marital status] Single Married Divorced Widowed Other Duration of index episode] 0Ð2 months 2Ð5 months 5Ð01 months ×0 year Study drug] Fluoxetine Phenelzine Initial rating scores] Hamilton\ 06 item Hamilton\ 10 item CGI End of 7!week trial rating scores] Hamilton\ 06 item Hamilton\ 10 item CGI

2428 1925 10 3

"range 11Ð40# "range 09Ð29# ")# "73# "05#

8 7 4 1 0

"25# "21# "19# "7# "3#

3 5 3 00

"05# "13# "05# "33#

03 00

"45# "33#

02[821[9 03[521[1 2[329[4 2[422[7 2[523[9 0[329[7

Values are expressed as the mean2standard deviation or as the number of subjects in each category[ In parenthesis appear the range of values or the percentage of subjects in each category\ as indicated[

depressant medications at the time of the interview[ Over! all\ the group averaged 0428 months of antidepressant medication treatment during the follow!up period[ Inter! estingly\ all the patients who initiated treatment with phenelzine had discontinued the drug or switched to ano! ther antidepressant\ while 03 were still being prescribed ~uoxetine "average dose at follow!up\ 35215 mg#[ Two patients had also required inpatient hospitalization\ which lasted 3 and 01 days\ respectively[ Since treatment utilization was high\ and a majority of the patients were untreated for relatively short periods of time\ rarely for as long as one year\ the periods of time medicated or unmedicated were pooled for the entire sample\ to obtain a rough estimate of the number of depressive episodes experienced under those two conditions[ The number of months treated with anti! depressants "no antipsychotics were utilized# totaled 262[4 for the sample\ during which nine of the episodes of MDD occurred[ The number of episodes per patient! year while on medication were then 9[2\ while 9[8 MDD episodes per patient!year o}!medication "023 months\ 09 episodes# were reported[ The time during which diag! nostic MDD was experienced was retrospectively esti! mated as 35[4 months for the entire sample\ averaging 0[821 months per subject^ range 9Ð6 months[

14

A summary of clinician ratings is presented in Table 1[ Approximately 89) of the subjects were considered by the clinician rater to have none or relatively little symp! tomatic or social impairment during the follow!up period\ and a benign course and outcome[ While this appeared to be a uniform _nding for all the outcome criteria utilized\ residual symptomatology "between epi! sodes# not meeting full diagnostic criteria was described by approximately 39) of the subjects\ although this did not re~ect on clinician or patient ratings of social adjust! ment or work performance\ which were generally good or very good[ Patients| ratings of outcome measures extracted from LIFE II and SCID interviews are presented in Table 2[ A majority of patients were employed full time\ and reported minimal di.culty in work activities\ or inter! personal relationships[ Interpersonal relationships with family or friends\ and overall satisfaction with life were rated as good by two thirds or more of the patients[ CGI scores at follow!up were signi_cantly lower than those prior to the initial treatment "MannÐWhitney U\ P ³ 9[90#\ but not di}erent from those at the end of the 5!week trial "P ³ 9[94#[ CGI scores recorded at the end of the initial treatment trial were positively correlated with those at follow!up "r  9[42\ P ³ 9[90#\ and with the SADS outcome criteria score "r  9[45\ P ³ 9[90# and negatively with Global Assessment of Symptoms "GAS# scores at follow!up "r  −9[31\ P ³ 9[94#[ Conversely\ the pre!trial CGI or HRSD scores were not signi_cantly associated with any of the outcome measures employed[ No signi_cant correlations were noted between the dur! ation of the index episode\ the reported age of onset of mood symptoms or the number of episodes of mood disturbance prior to the trial\ and any of the outcome measures "Spearman|s rank correlation and MannÐWhit! ney U\ P × 9[94#[ The small group of males included "n  3# seem to have more di.culties in social adjustment that the larger group of females\ with worse scores in self! reported interpersonal relationships with family "2[420 vs 0[429[5\ MannÐWhitney U\ P ³ 9[90#\ or friends "2[420 vs 0[829[8\ P ³ 9[90#\ recreational levels "120[3 vs 9[529[8\ P ³ 9[94#\ overall satisfaction with life "2[420 vs 0[729[8\ P ³ 9[90# and rater|s Global Social Adjustment scores "2[220[4 vs 0[729[6\ P ³ 9[90#[

3[ Discussion The present report describes the outcome of a small cohort of outpatients diagnosed with atypical depression as de_ned by Quitkin et al[ "0873#[ This work addresses the long!term outcome of this depressive subtype\ since most prior studies have not di}erentiated between di}er! ent forms of depressive syndromes[ The results obtained suggest that AD is associated with a relatively good over! all outcome\ contrasting with a number of published stud!

15

J[K[ Zubieta et al[ : Journal of Psychiatric Research 22 "0888# 12Ð18 Table 1 Outcome measures^ clinician ratings Dysthymia and interepisodic function after trial] Asymptomatic Residual symptoms\ mild Partial remission Marked symptoms Meets Major Depression criteria Course] Episodic with return to baseline Episodic with residual symptoms Episodic with social impairment Episodic with progressive deterioration Steady\ continuous impairment Initial deterioration\ later improved Global social adjustment "LIFE II#] No impairment\ very good No impairment\ good Slight impairment\ fair Moderate impairment\ poor Marked impairment\ very poor Outcome] Complete return to baseline Some residual impairment Considerable residual impairment Marked deterioration\ never recovered Very good Moderate\ not hospitalized Moderate\ hospitalized Very poor Clinical global impression scale scoresa Global assessment of functioning scoresb

") of sample# 01 "37# 8 "25# 1 "7# 0 "3# 0 "3# 02 "41# 09 "39# 9 9 0 "3# 0 "3# 6 "17# 02 "41# 2 "01# 0 "3# 0 "3# SADS Criteria 08 "65# 4 "19# 0 "3# 9 Lee and Murray Criteria 04 "59# 7 "21# 0 "3# 0 "3# 0[729[8 "range 0Ð3# 65200 "range 40Ð89#

a

Scores at the time of the follow!up interview[ Re~ecting the worst week during the six months prior to the follow!up interview[

b

ies of patients diagnosed with Major Depression[ The patients surveyed generally showed good response to treatment regardless of prior history\ although symptom recurrences were common[ When recurrent\ we observed stability of the symptomatic cluster\ which in the majority of subjects did not seem to cause serious impact on their overall social functioning[ High incidences of symptom recurrence and residual symptomatology were observed in the sample\ similar to those encountered in other longitudinal studies of major depression[ Sixty percent of subjects experienced at least one major depressive episode during the follow!up period[ In most cases this appeared to represent recur! rences and not a chronic course\ which was noted for only two of the subjects "7) of the sample#[ The incidence of episodic recurrence noted was similar or even some! what higher than that reported in longitudinal studies of adult outpatients with major depression while in the community "Sargeant et al[\ 0889^ Shea et al[\ 0881^ Wells et al[\ 0881^ Solomon et al[\ 0886^ Eaton\ 0886#[ A recent trial of imipramine or phenelzine discontinuation in AD patients who initially responded to these medications

showed recurrence rates of 36) and 76)\ respectively\ after switch to placebo\ con_rming a readily relapsing illness "Stewart et al[\ 0886#[ Mild to moderate degrees of interepisodic depressive symptomatology were reported by nearly half of the sample\ in spite of frequent utilization of antidepressant medications[ This _nding also resembles those of prior longitudinal studies reporting high rates of symptom per! sistence in major depression "Ceroni et al[\ 0873^ Bronisch et al[\ 0874^ Lee and Murray\ 0877^ Sargeant et al[\ 0889^ Wells et al[\ 0881#\ and in atypically depressed patients "Ebert and Barocka\ 0880#[ Overall\ it appears that a larger proportion of episodes occurred during the periods of discontinuation "9[2 vs 9[8 episodes per patient!year on! and o}!medications\ respectively#[ In most cases\ psy! chotropics were reinitiated shortly after reemergence of symptoms\ probably accounting for the relatively short periods of time during which fully diagnostic MDD was present "two months in average#[ Fluoxetine was the most widely prescribed agent\ probably because most responders to ~uoxetine during the double!blind study were maintained on it[ All subjects who were tried on

J[K[ Zubieta et al[ : Journal of Psychiatric Research 22 "0888# 12Ð18 Table 2 Outcome measures^ patient ratingsa Living arrangements] ") of Sample# Alone 02 "41# With nuclear family 8 "25# With parents 1 "7# With relatives or friends 0 "3# Hospital\ nursing home\ adult foster care 9 Employment status] Full time Part time Student Unemployed\ retired\ on leave\ other

19 "79# 2 "01# 1 "7# 9

Impairment in work activities] No impairment "high level# No impairment "satisfactory level# Mild impairment Moderate impairment Severe impairment

03 "45# 7 "21# 0 "3# 1 "7# 9

Interpersonal relationships with family] Very good Good Fair Poor Very poor

00 "33# 09 "39# 0 "3# 2 "01# 9

Interpersonal relationships with friends] Very good Good Fair Poor Very poor

7 "21# 8 "25# 4 "19# 1 "7# 0 "3#

Recreational level] Very good Good Fair Poor Very poor Sexual Activity] None\ satis_ed None\ unsatis_ed Sexually active\ good Sexually active\ fair Sexually active\ poor

02 "41# 5 "13# 2 "01# 2 "01# 9 4 "19# 6 "17# 7 "21# 2 "01# 1 "7#

Percent time with depressed mood during follow!up periodb] None "9) of the time# 1 "7# Rarely "4Ð09)# 6 "17# A minority "19Ð29)# 4 "19# Half the time 6 "17# A majority "69Ð79)# 2 "01# Almost all "89Ð099)# 0 "3# All the time 9 Subjective satisfaction with own life] Very good Good Fair Poor Very poor

8 "25# 5 "13# 2 "01# 2 "01# 9

a Items extracted from the Longitudinal Interval Follow!up Evalu! ation "LIFE II# Interview[ b Adapted from SCID[

16

phenelzine during the initial drug study had discontinued the medication on their own or initiated other medi! cations and none were still taking it at the follow!up interview[ The reasons for the discontinuation are unknown\ albeit a higher incidence of side!e}ects with phenelzine during the initial trial is likely to have been the main factor[ The decision to change treatments after the initial double!blind trial was based purely on clinical criteria\ but the generally good results "similar improve! ment rates with both medications\ but a lower incidence of side!e}ects with ~uoxetine# obtained in the trial may have biased the clinicians towards supporting medication change[ The symptomatic cluster of AD was stable during sub! sequent episodes[ None of the subjects reported experi! encing other subtypes of depressive clusters "mel! ancholic:endogenous or psychotic#[ One possible exception is that a small number of patients "three subjects\ 05)# described short!lived hypomanic symp! tomatology while being treated with phenelzine or high dose ~uoxetine\ which may or may not represent a dis! tinct subgroup "Akiskal\ 0872#[ In a prior report by Ebert and Barocka "0880#\ 06) of patients diagnosed with AD during an index episode developed manic symptoms during a one year follow!up[ These data suggest that a proportion of subjects who initially present with a depressive episode and atypical features may develop bipolar illness later during their course[ With that excep! tion\ the symptom stability noted in the present study is in direct contrast with data obtained from other authors "Angst and Merikangas\ 0886#\ who observed\ over a 16!year follow!up period\ little diagnostic stability with frequent switches of depressive symptoms into di}erent diagnostic subtypes[ Also\ with that of Ebert and Barocka "0880#\ who showed that 39) of patients diagnosed with atypical depression changed their presentation to other symptom pro_les "melancholic depression or bipolar ill! ness#[ On the other hand\ Nierenberg et al[ "0886# noted\ similarly to the present report\ that symptom recurrences in AD patients most frequently "89) of cases# were also atypical in pro_le during a ~uoxetine discontinuation study\ supporting the view that AD is a distinct subtype of depression[ Interestingly\ a documented history of chronicity for the index episode\ an earlier onset of depressive symp! tomatology\ or the number of depressive episodes prior to the initial treatment did not predict a worse outcome in this patient population\ for any of the measures employed[ This _nding seems to be in agreement with the observation that AD responds to short!term and long! term treatment trials regardless of past illness history "Quitkin et al[\ 0877\ 0878^ Stewart et al[\ 0878\ 0886^ Pande et al[\ 0885#[ In contrast\ in the Epidemiologic Catchment Area\ Medical Outcomes\ and the National Institute of Mental Health Collaborative studies\ the dur! ation of index episode and the number of prior episodes

17

J[K[ Zubieta et al[ : Journal of Psychiatric Research 22 "0888# 12Ð18

were found to be signi_cant predictors of outcome "Keller and Shapiro\ 0870^ Keller et al[\ 0871a\b\ 0873^ Sargeant et al[\ 0889^ Wells et al[\ 0881#[ Bearing in mind the limitations of the present study\ speci_cally the small number of subjects included\ which limits the statistical power of the analysis\ the results may suggest some di}erences between AD and other subtypes of depression[ On the other hand\ the degree of response from the initial treatment trial was positively correlated with better out! come ratings\ while the opposite was the case for GAS scores at follow!up[ This suggests that initial response to treatment predicts a better long!term outcome in these patients\ as has been suggested in studies examining young and older adults "Greenhouse et al[\ 0876^ Dew et al[\ 0886#[ Social adjustment and overall outcome was regarded as good or very good in a majority of the patients[ Most of the subjects were fully employed\ described none or little impairment at work\ recreational level\ and sub! jective ratings of overall satisfaction with life were high[ Interpersonal relations received poorer ratings\ specially with non!family members\ with approximately one third of the patients describing fair to poor relationships with friends^ this may not be surprising considering that life! long interpersonal sensitivity is one of the symptoms included in the cluster of AD[ It is possible that the presence of life!long interpersonal sensitivity in the pat! ients causes changes in their lifestyles and occupations which reduce the impact of the illness\ and its recurrences\ on their overall social function[ Interestingly\ the small group of men included in the sample reported poorer social adjustment and interpersonal relationships that the women studied[ The generally good outcome observed in the patients of this sample tends to support the hypothesis that AD is a syndrome with less biological impairment than non! atypical ddepressive episodes[ In this regard\ the cortisol response to desipramine was found less blunted in AD than in non!atypical depressive patients "Asnis et al[\ 0884#\ and both sleep disturbances and event!related potentials were noted to be less severely impaired in AD than in subjects diagnosed with non!atypical depression "Quitkin et al[\ 0874^ Bruder et al[\ 0880#[ The present study\ although limited in its conclusions by the small number of subjects surveyed\ points out both similarities and di}erences between the course of illness and outcome of patients diagnosed with AD and those reported for other subtypes of depressive symptom clus! ters[ Further studies\ with larger patient cohorts\ would be necessary for the validation and expansion of our results and further de_nition of the syndrome of AD[ Speci_cally\ a de_nite lack of association between prior symptomatic chronicity and outcome can only be _rmly ascertained in larger studies[ These studies would also be of importance in the exploration of subtypes of AD\ such as variants of bipolar disorder "e[g[\ subjects who

responded to clinically used doses of antidepressants with episodes of hypomania#[ That data would also strengthen the validity of AD as a distinct diagnosis[

References Akiskal HS[ The bipolar spectrum] New concepts in classi_cation and diagnosis[ In] Grinspoon L\ editor[ Psychiatry Update[ Washington D[C[] American Psychiatric Press 0872[ p[ 160Ð81[ Angst J\ Merikangas K[ The depressive spectrum] diagnostic classi! _cation and course[ Journal of A}ective Disorders 0886^34]20Ð39[ Asnis GM\ McGinn LK\ Sanderson WC[ Atypical depression] clinical aspects and noradrendergic function[ American Journal of Psy! chiatry 0884^041]20Ð5[ Bronisch T\ Wittchen HU\ Krieg C\ Rupp HU\ von Zerssen D[ Depress! ive neurosis[ A long!term prospective and retrospective follow!up study of former inpatients[ Acta Psychiatrica Scandinavica 0874^60]126Ð37[ Bruder GE\ Towey JP\ Stewart JW\ Friedman D\ Tenke C\ Quitkin FM[ Event!related potentials in depression] in~uence of task\ stimulus hemi_eld and clinical features on P2 latency[ Biological Psychiatry 0880^29]122Ð35[ Ceroni GB\ Nevi C\ Pezzoli A[ Chronicity in major depression[ Journal of A}ective Disorders 0873^6]012Ð21[ Dew MA\ Reynolds CF\ Houck PR\ Hall M\ Buysse DJ\ Frank E\ Kupfer DJ[ Temporal pro_les of the course of depression during treatment[ Predictors of outcome toward recovery in the elderly[ Archives of General Psychiatry 0886^43]0905Ð13[ Eaton WW\ Anthony JC\ Gallo J\ Cai G\ Tien A\ Romanoski A\ Lyketsos C\ Chen L!S[ Natural history of diagnostic interview schedule:DSM!IV major depression[ Archives of General Psy! chiatry 0886^43]882Ð8[ Ebert D\ Barocka A[ The early course of atypical depression[ European Archives of Psychiatry and Clinical Neurosciences 0880^130]020Ð1[ Greenhouse JB\ Kupfer DJ\ Frank E\ Jarrett DB\ Rejman KA[ Analysis of time to stabilization in the treatment of depression[ Journal of A}ective Disorders 0876^02]148Ð55[ Keller MB\ Klerman GL\ Lavori PW\ Coryell W\ Endicott J\ Taylor J[ Long term outcomes in major depression[ JAMA 0873^141]677Ð8[ Keller MB\ Lavori PW\ Friedman BL\ Nielson E\ McDonald!Scott P\ Andreasen NC\ Endicott J[ The LIFE II] a comprehensive method for assessing outcome in prospective longitudinal studies[ Archives of General Psychiatry 0876^33]439Ð8[ Keller MB\ Shapiro RW[ Major depressive disorder] initial results from a one year prospective naturalistic follow!up[ Journal of Nervous and Mental Disorders 0870^058]650Ð7[ Keller MB\ Shapiro RW\ Lavori PW\ Wolfe N[ Recovery in major depressive disorder] analysis with the life table[ Archives of General Psychiatry 0871a^28]894Ð09[ Keller MB\ Shapiro RW\ Lavori PW\ Wolfe N[ Relapse in major depression] analysis with the life table[ Archives of General Psy! chiatry 0871b^28]800Ð4[ Lee AS\ Murray RM[ The long!term outcome of Maudsley depressives[ British Journal of Psychiatry 0877^042]630Ð40[ Lehmann HE\ Fenton FR\ Deutsch M\ Feldman S\ Engelsmann F[ An 00!year follow!up study of 009 depressed patients[ Acta Psychiatrica Scandinavica 0877^67]46Ð54[ Liebowitz MR\ Quitkin FM\ Stewart JW\ McGrath PJ\ Harrison WM\ Markowitz JS\ Rabkin JG\ Tricamo E\ Goetz DM\ Klein DF[ Antidepressant speci_city in atypical depression[ Archives of Gen! eral Psychiatry 0877^34]018Ð26[ McGlashan T[ The Documentation of Clinical Psychotropic Drug Trials[ National Institute of Mental Health\ Rockville\ MD 0862[ Nierenberg AA\ Pava JA\ Clancy K\ Rosenbaum JF\ Fava M[ Are

J[K[ Zubieta et al[ : Journal of Psychiatric Research 22 "0888# 12Ð18 neurovegetative symptoms stable in relaing or recurrent atypical depressive episodes< Biological Psychiatry 0885^39]580Ð5[ Pande AC\ Birkett M\ Fechner!Bates S\ Haskett RF\ Greden JF[ Fluox! etine versus phenelzine in atypical depression[ Biological Psychiatry 0885^39]0906Ð19[ Quitkin FM\ Harrison W\ Liebowitz M\ McGrath P\ Rabkin JG\ Ste! wart J\ Markowitz J[ De_ning the boundaries of atypical depression[ Journal of Clinical Psychiatry 0873^34]08Ð10[ Quitkin FM\ McGrath PJ\ Stewart JW\ Harrison W\ Wager SG\ Nunes E\ Rabkin JG\ Tricamo E\ Markowitz J\ Klein DF[ Phenelzine and imipramine in mood reactive depressives[ Further delineation of the syndrome of atypical depression[ Archives of General Psychiatry 0878^35]676Ð82[ Quitkin FM\ Rabkin JG\ Stewart JW\ McGrath PJ\ Harrison W\ Davies M\ Goetz R\ Puig!Antich J[ Sleep of atypical depressives[ Journal of A}ective Disorders 0874^7]50Ð6[ Quitkin FM\ Stewart JW\ McGrath PJ\ Liebowitz MR\ Harrison WM\ Tricamo E\ Klein DF\ Rabkin JG\ Markowitz JS\ Wager SG[ Phenelzine versus imipramine in the treatment of probable atypical depression] de_ning syndrome boundaries of selective MAOI responders[ American Journal of Psychiatry 0877^034]295Ð00[ Sargeant JK\ Bruce ML\ Florio LP\ Weissman MM[ Factors associated with 0!year outcome of major depression in the community[ Archives of General Psychiatry 0889^36]408Ð15[ Shea MT\ Elkin I\ Imber SD\ Sotsky SM\ Watkins JT\ Collins JF\ Pilkonis PA\ Beckham E\ Glass DR\ Dolan R[ Course of depressive

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