Response patterns of depressed outpatients with and without melancholia: a double-blind, placebo-controlled trial of fluoxetine versus placebo

joumal of AFFECTIVE DISORDERS Journal of Affective Disorders 30 (1994) 163-173

Response patterns of depressed outpatients with and without melancholia: a double-blind, placebo-controlled of fluoxetine versus placebo John H. Heiligenstein Psychopharmtrcology

DilGion,

*, Gary D. Tollefson,

Douglas

Lilly Research Laboratories, Eli Lilly and Company. Indianapolis, IN 4628.5. USA

(Received I July 1993: revision received

10 September

1993; accepted

trial

E. Faries

Lilly Corporate Center 2128.

23 September

1993)

Abstract Fluoxetine (20 mg/day) and placebo were compared in 89 outpatient men and women with major depression with (n = 52) or without (n = 37) DSM-III-R melancholia in an g-week double-blind study to determine predictors of treatment response. Fluoxetine was statistically superior to placebo both within the melancholic subtype and in the total patient group (all measures). Response rate and mean decrease in 17-item Hamilton Depression Rating Scale total score approached statistical significance in favor of fluoxetine-treated melancholic patients compared

with fluoxetinc-treated non-melancholic patients. There were no statistically significant differences between fluoxctine-treated and placebo-treated non-melancholic patients. Results support DSM-III-R melancholia as a predictor of antidepressant response. Kry words: Melancholia;

Depression;

Reduced rapid eye movement latency; Response predictor: Fluoxetinc

1. Introduction In an effort to more effectively select treatment interventions for depressed patients, clinical researchers have sought to distinguish subtypes of depression that would be predictive of a pharmacologic treatment response. To date, this objective has not been fulfilled. While a variety of putative symptom clusters have been proposed, none reliably describes a depressive subtype pref-

* Corresponding 2025.

author.

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erentially responsive to biological treatments (Zimmerman and Spitzer, 1989; Zimmerman et al., 1989). The criteria for melancholia are one such example. If a valid predictor, patients meeting criteria for melancholia should be more likely to respond to biological treatment than patients not meeting such criteria. Operational criteria for subtyping depression became available with the Third Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) (APA, 1985). Although operational definitions for melancholia had previously been published, they seldom had been validated externally (Zimmerman et al., 1986).

B.V. All rights reserved

placebo-controlled

lzcw patients

with

published.

In

ticnts

with

ct

4 patients with

cholia,

Kickcls and

their

rcxponxc

zolarn 44X

ct al.

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with cl

ill.

(If

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inc

or

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whcrca4 patient\ licnfs

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across-group. predict

the

had

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the

melancholic

for

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hasi\

ot

both

two

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1~

Howuvcr,

att

ttot

ot- placcl~o. Spityct-

) of patients

age (50’; c.ritcria

for

tar

to

and

no

\pcctiic

di;i.gnosis

10 1x.

the

with

ticnts

without

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rcsponsc DSM-III-K

tiOWc\CJ’.

ai

it IC;IS hypotttc

0C clepressod incrcac.

p;ttictrt\

%inini~rniari ii higher

that tiith

~‘t

pet-cc’nt.

niclancholia

1twos v,ho met IXM-III criteria ~1.0 date . ;I slud\ ciemot~~traling ticnts

hat.

do inclecd tncc’t DSM-III-K

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along

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4izcc1 Iha!

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to active treatment

In ;I I WC) publication.

with-

did

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~yniptom-hasccii

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rc-

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analysis

on

lcmt

found

non-mclan~hc,li~

the

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of antidcthus.

:lJld

validity

AI’A.

Subscc~~iently.

prcdictivc

nol

r-csponxc.

propos,cd

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ot

amitript~l-

respon5c

patients.

same-trcatnicnt

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with

than

greater

;tt]d

the

DSM-111

employing

wcrc

trcatmcnt

Icngud

with

dept-csxion.

‘I‘hcy

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in DSM-III-K,

;I study

tre~i1mcnt

that

mclancholi~i

prcssant

in

01 alprk

In

rm1jor

rate

patient\ difl’cr

doxcpiti

treated

response

mclan-

not

melancholia.

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2 01

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~~ 30)

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compared


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melancholia

;IX compared

too

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without

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154 outpatients

with

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rlcprexscd hacc

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( IW5)

although

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placclx~.

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DSM-III

tivc conclusions

in

melancholia

a comparison

Stewart

placebo.

studica

DSM-II1

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rnelancholin :I

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pi 1x1.~ pub 11)

placebo, with non-melancholic patients having a higher rate of placebo response, has been reported (Peselow et al., 1992). The authors examined the effects of antidepressant and placebo treatment in outpatients with and without melancholic depression using DSM-III criteria. They concluded that the presence of melancholic symptoms was associated with differential response favoring active medication over placebo. However, there was little difference in response to antidepressant treatment between patients with and without melancholia. In the present S-week, multicenter, doublehl;nA Clllil”

c-+..A., JLuuy,

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tine and placebo in outpatients characterized as having DMS-III-R melancholic or non-melancholic depression using a DSM-III-R melancholia checklist at time of entry into the study. We also evaluated efficacy in such patients stratified by the presence or absence of a reduced rapid eye movement latency (RREML), since patients had been so stratified at the time of random assignment to double-blind therapy (Heiligenstein et al., in review). We hypothesized that depressed patients with melancholia would exhibit a superior response to pharmacotherapy relative to placebo in contrast to depressed patients without melancholia.

2. Patients

and Methods

Patients were recruited at six tertiary care centers. Patients included males and females, 18-65 years of age, who met DSM-III-R (APA, 1987) criteria for major depression with the exception that patients must have satisfied these criteria for a minimum of 1 month. Patients were non-psychotic unipolar depressed (either single or recurrent) or bipolar type II depressed (the latter determined by Research Diagnostic Criteria [Spitzer et al., 19771). Patients were required to have a minimum score of 15 on the first 17 items of the 2%item Hamilton Depression Rating Scale (HAMD,,; Hamilton, 1960). If the patient had a history of recurrent depression, a minimum inter-

val of 10 weeks of euthymia was required between the most recent depressive episodes. Patients were excluded if they were pregnant or lactating, had a serious comorbid medical illness, were considered a serious suicide risk by the screening clinician, or had not responded in the past to three or more antidepressants at a therapeutic dose (200 mg imipramine equivalents) for at least 3 weeks. Additional exclusion criteria were the presence of another axis I disorder within the past year: antisocial personality disorder and/or a history of 3 or more suicide attempts or gestures Aomt ,,f ,.-,,h,hl indepenu~r~l VI an ~~uvavlc conc’urrent K2jjor depressive disorder, melancholic type; fluoxetinc within 12 weeks of screening; conditions or medications that could possibly influence the polysomnographic determination of a RREML with the exception of chloral hydrate: and/or other relative contraindications to fluoxetine.

3. Study design The study was divided into two study periods: a 2-week (14- to IS-day), single-blind, placebo lead-in to eliminate placebo responders and an S-week, double-blind study period. Patients who did not respond to placebo had sleep-staging polysomnography (PSG) for two consecutive nights. Patients were stratified into two groups based upon the mean value of the two PSG ^1,._.:A?.,J rL_.. -,.-&:-.._?I 6,. __: _____ A:-,.” p,luv,uru ,tX”,Ulllg:s, LIIey c”IILIIIlle” L” _^^& ,,,ce:L c,,teria as placebo non-responders at Visit 4 and their Visit 3 urine drug screen was negative. Initially, patients were stratified as having RREML or a non-reduced rapid eye movement latency (N-RREML) based on polysomnographic findings. Within each stratum, patients were randomly assigned to double-blind therapy with fluoxetine 20 mg daily or placebo. An adaptive feature was included in the design which was intended to minimize patient exposure to ineffective or intolerable therapy. This was accomplished by using responses of patients early in the study to increase the probability that patients enrolling later in the study would be randomly assigned to the more effective treatment.

Efficacy was assessed by the HfiMD ,, (Hamilton. lYhO), the Montgomery-Azberg Rating Scale (MADRSI (Montgomery and Asberg. lY7YI. Clinical Global Impressions (CGI )-severity and improvement (Guy, 1976). and Patient Global Impressions (PGI) (Guy, 1976). The HAMD,-, MADRS, and CGI-severity were collected at each visit during the study. CGI-improvement and PGI were collected beginning at Visit 2. ‘The investigator-rated HAMD,, served as the primary efficacy instrument. Open-ended questions by the interviewer at each visit, rather than a standardized form, were used to elicit adverse events. Adverse events analyzed were those that first occurred or worsened following randomization (treatment-emergent adverse events). The US Food and Drug Administration’s COSTART thesaurus ( 1985) was used to ensure uniformity of language in this trial. Four variables, response rates, remission rates. change from baseline in HAMD,? total scores. and weekly change in HAMD ,, total scores, wcrc included in the efficacy analyses. The protocol specified that the primary analysis would bc based upon response rates. A patient whose endpoint HAMD,, total (score) decreased by an amount 2 50% from baseline was defined as a responder to therapy. A patient whose endpoint HAMD,7 total (score) was I 6 at endpoint was defined as a remitter. Response and remission rate analysts included all patients who completed at least .q weeks after randomization. The HAMD,, change analyses included all patients with at least one postbaseline measurement and used a last-visitcarried-forward approach. The weekly HAMD ,: change analysis at each visit included all patients with scores at the visit. In order to assess the efficacy of tluoxetinc compared with placebo, treatment differcnccs in and mean rates, remission rates, response change were analyzed within each HAMD,, group. To test the hypothesis that the presence of DSM-III-R melancholia predicted antidepressant treatment response, data were assessed to detcrmine whether fluoxetine(placebo-) treated patients with melancholia responded in the same manner as fluoxetine(placebo-) treated patients without melancholia. Response rates. remission

rates. and mean HAMD,, change were compared across groups for each treatment. To check the robustness of the results. these analyses (cxcept the weekly analysis) were repeated using the CGI and PGI. The weekly analysis of HAMD,. change was performed to assess the timing of any differences in response between tluoxetine and placebo. Similar analyses have been completed with the MADRS (Heiligenstein et al., in press). Because of the adaptive randomization scheme (Wci and Durham, 1978) Bayesian statistical methodology was used to analyze the data (Press, IYXY). Pl was defined as the true probability 01. response (remission) on placebo and P2 as the true probability of response (remission) on fluoxetine. Bayesian posterior probabilities (Bayes-/‘I. the probability that Pl is greater than P3 given the observed data, were calculated. Bayes-P val< 0.05 or > 0.Y5 were considered statisticalLlCS ly significant. For example, a Bayes-P value ot < 0.05 is strong evidence that fluoxetine has a highct- true response (remission) rate than placebo. while a Bayes-P > 0.95 is strong cvidence that placebo has a higher true response (remission) rate than fluoxetine. A similar analysis was used for change in HAMD,? total scores. Noninformative prior distributions (Press, IYXY) were used in all calculations in order to avoid influencing the posterior distribution for OI against either trcatmcnt.

4. Results One hundred sixty-four outpatients with major depression wcrc enrolled in the single-blind placebo lead-in. A total of 8Y patients were randomly assigned to double-blind therapy. Seventyfive patients were excluded for the following rcasons prior to randomization: 9, placebo response: Y. organic sleep disturbance; 33, entry criteria not met; 3, positive urine drug screen; 13, patient 2, lost to follow-up; decision: 2. noncompliance; ) adverse events; 1, lack of efficacy; and I, enI. tered after the cut-off date. Fifty-two (58.4% 1 patients met DSM-III-R criteria for melancholia and 37 (41.6%) did not. Of the 51 melancholic patients with at least one follow-up visit, 7.1 (45.1%) were assigned to tluoxetine and 2X

J. H. Heiligenstein et al. /Journal Table 2 Demographic

and baseline

of Affectbe

167

Lhsorders 30 (1994) 163-I 73

characteristics

Group/Treatment

n

Age, years mean + SD

% female

% RREML

HAMD ,, total score mean + SD

Depression with melancholia Fluoxetine Placebo

24 28

44.4 * 10.1 39.2? 9.2

54.2 75.0

50.0 53.6

21.6 k 3.2 22.6 f 3.0

Depression without melancholia Fluoxetine 22 Placebo 15

38.4 * 11.2 39.2 f 11.1

12.1 86.7

50.0 46.7

20.3 f 3.5 19.7 * 3.1

Total group Fluoxetine Placebo

41.6 k 10.9 39.2 k 9.8

63.0 79.1

50.0 51.2

21.1 i 3.4 21.6 ? 3.3

HAMD,,

46 43

= 17-item Hamilton

Depression

Rating

Scale. SD = standard

rates and reasons

Reason discontinued

Completed Completed

protocol 3 weeks

Discontinued for: Adverse event Lack of efficacy Other ’

for early discontinuation

Depression

with melancholia

Fluoxetine (n = 24)

Placebo (n = 28)

RREML

= reduced

rapid eye

movement latency.

completed study. In the nonmelancholic group, 14 of 22 (63.6%) fluoxetine-treated and 11 of 15 (73.3%) placebo-treated patients completed the study. Seven of 46 (15.2%) fluoxetine-treated patients and 7 of 43 (16.3%) placebo-treated patients discontinued the study because of an adverse event or lack of efficacy. None of the treatment differences in completion or discontinuation rates were statistically significant. Twenty-one (91.3%) of 24 fluoxetine-treated and 27 of 28 (96.4%) placebo-treated patients in the group with melancholia and 20 of 22 (90.9%) fluoxetine-treated and 15 of 15 (100%) placebotreated patients in the group without melancholia completed at least 3 weeks of treatment and were

(54.9%) to placebo. Of the 37 patients who did not meet criteria for melancholia, 22 (59.5%) were assigned to fluoxetine and 15 (40.5%) were assigned to placebo. Demographic and baseline clinical characteristics of each group of patients are shown in Table 2. Fluoxetine-treated patients had a statistically significantly (Bayes-P = 0.028) higher mean age than their placebo counterparts in the melancholic group. However, this difference (44.4 years to 39.2 years) was not considered clinically significant. Completion rates and reasons for early discontinuation are presented in Table 3. In the melancholic group, 18 of 24 (75%) fluoxetine-treated and 22 of 28 (78.6%) placebo-treated patients

Table 3 Completion

deviation;

‘I Depression Bayes-P

’

Fluoxetine (n = 22) n (%‘)

without

melancholia Placebo (n = 15)

Bayes-P

n (%)

n (%c)

18 (75.0) 21 (91.3)

22 (78.6) 27 (96.4)

0.622 0.867

14 (63.6) 20 (90.9)

11 (73.3) 15 (100)

0.715 0.806

0 (0.0) 2 (8.3) 4 (16.7)

0 (0.0) 5 (17.9) 1 (3.6)

_ 0.821 0.066

2 (9.1) 3 (13.6) 3 (13.6)

0 (0.0) 2 (13.3) 2 (13.3)

0.194 0.522 0.522

’

n (%)

“ All randomly assigned patients included. ’ Bayes-P = Bayesian posterior probabilities. A value > 0.950 or < 0.050 is considered statistically significant. ’ Other category includes lost to follow-up (depression without melancholia: fluoxetine, 2; placebo, l), patient decision (depression with melancholia: fluoxetine, 2; placebo, 0; depression without melancholia: fluoxetine, 1; placebo, l), and protocol requirement (depression with melancholia: fluoxetine, 2; placebo, 1)

eligible for response and remission rate analysts. Table 4 summarizes those rates for fluoxetinc and placebo across subgroups and in the groups combined. Fluoxetine produced a statistically significantly higher response rate in patients with melancholia than placebo (Bayes-P -==0.002): however, there was no significant difference among the patients without melancholia. Ten 01 21 (47.6?) fluoxetinc-treated melancholic patients achieved remission, in contrast to only 3 01. 27 ( 1 I. IV) placebo-treated melancholic patients (Bayes-P = 0.003). When the melancholic and non-melancholic groups wcrc combined, fluoxctine again proved statistically significantly more effective than placebo in achieving a I-esponse (Baycs-P = 0.032) and was also statistically superior to placebo (39.0% vs. 2 1.4c/; ) in achieving a remission (Bayes-P = 0.042). Fig. I shows the baseline-to-endpoint mean change in HAMD ,? scores for patients by group

Tabltl -1 HAMD,-.

responw

and remission rate analysts

Groupjtrcatment

II 2 -3

Response ”

Week3

Depression

II

Kcmiwon

(Y )

”

II (‘;)

with melancholia

Fluoxrtine

71

Placebo

17

I5 (71.4)

’

Bayes-f’

Depression

IO (37.(l)

x (2c).6)

i(l1.l)

0.00’

O.O(l3

without melancholia

Fluoxetinc

20

PlacetX,

Ii

(1 lilJ.il)

IO (50.0) 0 (60.1))

Baye\-f’

(1.711

(> I-IO (1) II :III

Ih (31).(1)

l’ota1group Fluoxetinc

41

2s (hl.ll)

Placebo

32

I7 (50.5)

Uuye\-f’

‘) (21.4

0.037

I I.1142

Across groups Fluoxetine

l&yes-f

j’

0.0?3

O.l.%l

PlGXll~~

BaycG

”

0.(1.30

(1.(117

I’ ~50’; week\

decrease

in HAMD,,

total

with ;i minimum

01 1

of therapy.

” FiAMD,:

total

1 h at endpoint

with ;I minimum

ot 7 \seekr

of therap’. ’ &yes-P

=

Bayesian posterior

or < 0.050is considered ” Bayes-P =

Bayesian posterior

across gwup within treatment. conaidel-cd \tatktically

prohabilitie\.

statistically

probabilities A value

significant.

(l.Wl

A \;ilue

significant. comparing

:, 0.‘)50 or

rates

,: 0.050 IS

I II -14

’

Patients With Melancholia

LJ Placebo

Patients Without Melancholia

** Total Patient Sample

and for the groups combined. Fluoxctine was statistically significantly superior to placebo in the group with melancholia (Bayes-P = 0.001) and in the total group (Bayes-P = 0.008). There was no difference between fluoxetinc and placebo in the group without melancholia. Although not necessarily appropriate when using adaptive randomination. an analysis of variance on HAMD,-, changes was pcrformcd as a secondary analysis and a statistically significant interaction betwcan treatment and melancholia status was obscn/ed. Fig. 2 illustrates the mean HAMD,, change by week for the melancholic group, the nonmelancholic group, and the total group, rcspcctively. Separation between fluoxetine-treated and placebo-treated patients with melancholia began as early as Week I (Bayes-P = 0.063). reached statistical significance as early as Week 2 (BayesI’ = O.OSO), and was statistically significant with adjustment for multiplicity at Weeks 5. 7. and 8 (Hommell, lY88). In the total sample with adjustmcnt for multiplicity, fluoxetinc demonstrated statistically significant differences from placch~j beginning at Week I and continuing throughout the study. ‘l‘herc were no statistically significant differences between fluoxetinc and placebo in the group of patients without melancholia. In comparing results in fluoxetinc-treated patients (with and without melancholia) across groups (Table 41, fluoxetine-treated patients with

J. H. HcGligensiein et al. / Jourrral of Affktil,e

melancholia had numerically greater response and remission rates as well as a greater mean decrease in HAMD,, scores than fluoxetine-treated patients without melancholia. These differences approached statistical significance for response rates (Bayes-P = 0.085) and mean decrease in HAMD,, scores (Bayes-P = 0.051). For placebotreated patients, response and remission rates as well as decrease in HAMD,, scores were statistically significantly greater (Bayes-P = 0.030, 0.017, and 0.042, respectively) in the group without melancholia than in the group with melancholia. CGI-severity change, CGI-improvement response rates, and PGI-improvement response rates are summarized in Table 5. Statistically significant differences for fluoxetine-treated compared with placebo-treated patients in the group with melancholia were seen for CGI-improvement response rates (Bayes-P = 0.0021, CGIseverity baseline-to-endpoint change (Bayes-1’ = 0.007), and PGI-improvement response rates (Bayes-P = 0.003). There was no statistically significant difference between fluoxetine and placebo on any of these efficacy measures in patients without melancholia. When comparing fluoxetine-treated patients across groups (with and without melancholia), fluoxetine was statistically significantly more effective in patients with melancholia than in patients without melancholia based on change in

Disordm

164

30 (I YY4/ It% 17-3

CGI-severity (Bayes-P = 0.045). A trend toward greater efficacy for fluoxetine in the patients with melancholia compared with the patients without melancholia was found based on CGI-improvement response (Bayes-P = 0.085 ). In contrast to fluoxetine, placebo was statistically significantly more effective in the group without melancholia than in the group with melancholia based on change in CGI-severity and endpoint CGI-improvement rates (Bayes-I’ = 0.021 and 0.030, respectively). A trend toward significance was found in PGI-improvement rcsponse rates (Bayes-P = 0.05 1). In addition to the above analyses, an analysis of the HAMD,, was completed for patients in each of the following subgroups: patients with melancholia with a reduced rapid eye movement latency (RREML), patients with melancholia without a RREML (N-RREML), patients without melancholia with RREML, and patients without melancholia without a RREML. The results of these analyses are presented in Table 6. As can be seen, fluoxetine-treated patients with melancholia and RREML had statistically significantly greater response and remission rates than placebo-treated patients (Bayes-P = 0.008 and 0.032, respectively) and had a statistically significant greater baseline-to-endpoint reduction in the HAMD,, (Bayes-P = 0.002). Fluoxetine-treated patients with melancholia but without RREML

Table 5

Clinical global improvement (CGI) and patient global improvement Group/treatment

Depression Fluoxetine Placebo Bayes-P

,1

II 1 3 Weeks

CGI-severity

(PGI) analyses mean + SD

Baseline

Change

CGI-improvement response h

PGI-improvement response ‘

”

with melancholia 23 28

21 27

4.04 * 0.37 4.18 + 0.48

-1.70+ 1.36 -0.75 * 1.27 0.007

IS (71.4) 8 (29.6) 0.002

1s (71.4) 9 (33.3) 0.00s

22 1s

20 15

3.82 + 0.66 4.00 + 0.65

- 1.09 k 0.92 -1.67k 1.54 0.918

10 (50.0) 9 (60.0) 0.714

IO (50.0) 9 (60.0) 0.714

’

Depression without melancholia Fluoxetine Placebo Bayes-P “ h ’ ’

’

Change in CGI-severity score from baseline to endpoint. CGI-improvement endpoint score I 2 with at least 3 weeks of treatment. PGI-improvement endpoint score 5 2 with at least 3 weeks of treatment. Bayes-P = Bayesian posterior probabilities. A value > 0.950 or < 0.050 is considered

statistically

significant.

had ;I statistically significantly greater remission rate (Bayes-f-’ = 0.025) and a trend toward ;t significantly grater rcsponsc rate (Baycs-I’ = 0.060) and greater baseline-to-endpoint change (Baycs-f’ = 0.093) compared with placebo. There were no statistically significant differences in fluoxetinetreated and placebo-treated patients in either the categorical or the continuous efficacy mcasurcs in the RREML and N-RREML. groups without melancholia. Treatment-emergent adverse events were XI;Ilyzed by group. In the group of patients with melancholia. significantly

somnolence more

often

occurred

statistically

in the fluoxetine-tre;ltect (20.85) than in the placebo-treated patients (3.6“;) whereas headache (lh.7r)i vs. Y9.35 ). clyspepsia (4.2”; vs. 21.4c: ). nausea (0.0% vs. 14.3’~; ). and palpitation (O.O’/i vs. 14.3% ) occurred statistically significantly more often in the placrbotreated than in the fluoxetine-treated patients. In

N-RREMI. Depression with melancholia Fluoxctirw

PlacL!tx) Hay<\-/’ ’ Depression Fluoxctint,

Placeh~~ Bayed’

without melancholia

the patients without melancholia, only diarrhea showed it statistically significant differcncc (22.7%. tluoxetine-treateclit~d patients: O.Wi. placcbo-treated paticnta). None 01’ the patients in this study attempted suicide. The suicidality item l’rom the HAM11 (Item 3) ~calc was analyzed to compare the treatments with respect to their ef’fcct on suicidality. The ~IIC;III change in HAMD Item 3 for tluoxctine and placebo is shown in Table 7. Fluoxctinetreated patients demonstrated ;I statistically bignil’icant grater reduction in HAMD Item 3 scorch than placebo-treated patients in the melancholic group and in the total group. Two patients cxpc rienccd cmcrgcnt suicidal ideation (an increase in baseline HAMD Item 3 from 0 or I to a KOI‘C ot 3 or 4 at any time during double-blind therapy). Both of thcsc patients had been randomly ahsignal to placebo (one with melancholia and one without melancholia).

J.H. Hriligenstrin et al. /Journal

of Affectire

,

1

0’ Baseline Placebo Fluoxetine

20 24

1

I 2

I 3

28 23

27 22

27 21

I 4 Week 27 20

I

I 5

6

I 7

I 6

23 20

22 20

22 19

22 19

(b) Patients Without Melancholia 25

171

5. Comment

(a) Patients With Melancholia 25

Disorders 30 (1994) 163-l 73

,

I

“:I , , , , , , , ,I Baseline

1

2

3

4

5

6

7

6

15 17

10 14

11 14

11 14

In this study, 58.4% of depressed outpatients met DSM-III-R criteria for melancholia. This compares favorably with the rate reported by Zimmerman et al. (1989). In patients with melancholia, treatment with fluoxetine 20 mg per day statistically significantly outperformed placebo. Fluoxetine-treated patients with melancholia had statistically significantly greater reduction in HAMD,, scores than patients with melancholia treated with placebo. Among patients with melancholia completing 3 or more weeks after random assignment, fluoxetine-treated patients had statistically significant greater response rates (71.4% vs. 29.6%) and remission rates (47.6% vs. 11.1%) than placebo-treated patients. These findings support the hypothesis that patients with melancholia are more likely to derive substantial benefit from pharmacologic treatment than from placebo. As expected, placebo treatment in patients with melancholia met with minimal success. Separation between fluoxetine-treated and placebo-treated patients with melancholia began as early as Week 1 and achieved statistical significance at Weeks 2, 4, 5, 7 and 8 (see Fig. 2a). In

Week Placebo Fluoxetine

15 22

15 22

15 22

15 20

14 19

Table 7 Suicidality

(c) Total Patient Sample 25

, 0

Placebo

n

Flumetine

analysis

Group/treatment

Depression

n

HAMD

Item 3

Baseline

Change

- 0.65 *0.x3

with melancholia

Fluoxetine

23

0.78 + 0.80

Placebo

28

0.75 * 0.65

Bayes-P ” 5-

E i

Ui

Baseline Placebo Fluoxetine

43 46

,

,

1

2

3

43 45

42 44

42 41

I

I

4 Week 41 39

I

I

I’

5

6

7

6

30 37

32 34

33 33

33 32

I

Fig. 2. Mean HAMD,, change by week for depressed patients with melancholia (A) and without melancholia (B) and for the total patient sample (0. Asterisks denote a statistically significant treatment difference (* = Bayes-P < 0.05; * * = Bayes-P < 0.01).

0.00 + 0.94 O.OOh

Depression without melancholia Fluoxetine 22 1.14_to.77 Placebo 15 0.73_+0.70 Bayes-P ”

- 0.64 * 0.79 - 0.40 i 0.74 0.182

Total group Fluoxetine Placebo Bayes-P ”

- 0.64 +0.x0 -0.14~0.8Y 0.003

45 43

0.96 f 0.80 0.74 + 0.66

HAMD Item 3 = suicide item of the Hamilton Depression Rating Scale. a Bayes-P = Bayesian posterior probabilities. A value > 0.950 or < 0.050 is considered statistically significant.

the total

patient

;I atalistically bcginninp mcnt.

group.

significant the

first

In contrast,

cholia.

there

fcrcncc4

fluoxctinr

clcmonstrated

separation

I‘r-om placcb~~

week

after

were

or mean

in HAMD,,

change

lack of difference

without

In comparing ticnth

with

rates

of

the

This

in

that

the

tients

with

melancholia

of biologic

depression

to sclcctivc

serotonin

paticnta

I-ia for

;I RREML

melancholia.

htantial

overlap

ratorq

markers.

t’ound

that

RREMI, fluoxctine with

based

a purer

form

response

inhibitors.

only

3)

01 5

I (3 l.tYi ) also had ;I 76 of 44 t5CI. 1’; 1 pa-

only

met DSM-III-R

also

‘This

suggests

with

both

followctl

without

crite-

;t lack of sub-

and

these clinical

were those most likely

melancholia

sugoutpa-

a robust

Nonetheless.

response.

outpatients depressed

labo-

subgroup

analysts mclancholin and ;I to have :I positive next

1~)’ patients

a RREML..

In this study, tluoxetinc overall was both saf’e rffcctivc. There wcrc few patient discontinuations lxx~use of’ lack of efficacy or an adverse event. ‘l‘hc study corroborated that tluoxetine was associated with ;I statistically significantly greater reduction in suicidality (based on HAM11 Item 3) than placebo. Only two patients, both assigned to and

placebr) by random allocation. cxpcrienced 8 trcatliient-associated emergence ol’ substantial \uicid;tl idcation. There were no suicide attempts

placeho-

pharmacother~tpy. While requiring further \alidation, this observation should bc helpful to both health care providers and health care utilization i-c\icMs agcncics to cnsurc that melancholic dcprcssion is aggressively diagnosed and succce l’ully treated. The data by no means counter \omatic

treatments

for

non-melancholic

paticrits.

Rather. f’~)r both practicing clinicians and IXhcarchers alike. they suggest that ;I greater hetcrogcneity of factors may bc invol\~cd. The data t’urthcr suggest that placebo rcsponsc can bc I~Cduccd when targeting ;I clinical subtype of nl:tjo~dcprcssion characterized with melancholia. I:uturn studies in response prediction and placcbtrrcsponsc profiling iiru awaited.

tluoxctinc-truate~l

melancholia

between

patients

on

or the

In summar>. the most important finding in lhis study was that the presence of melancholia prcdictcd a more favorable treatment response to

Furthermore.

may exhibit and/or

with

C‘onverscly,

with

depression

of

that

subtyped

RREML..

tients

in am-

study

DSM-III-R

in

bs

first the

uptake

i\ 01’ interest

rcsultk antide-

response.

population

ap-

scores

as ;I mean4

of

efficacy

in pa-

a superior

placebo-treated

gests

It

in

rcsponsc

[Thcsc

is the

supportive

treatment

with

of fluox~tinc

in HAMD,-

melancholic

diffcrencc

compared

to t’luoxetine

melancholia

patients

This

placebo

melancholia.

can predict

response].

antidepressant

ba~elinc.

significance.

DSM-III-R

bulatory

remission.

by ;I greater

response

dccreasc

practitioners

subtyping

from

without

pressant

diiand

melancholia.

statistical

support which

significant

response.

the efficacy

and

and mean

proached

in

was driven

a laser

and/or

melan-

fluoxctine-trcatcd

patients

the patients

assipn-

without

no statistically

bctwccn

placeho-lrentcd

effect

random

among patients

in cithcr the fluoxctine-treated treated patients.

6. References

Reimherr. F.W.. Chouinard. G., Cohn, C.K., Cole, J.O., Itil, T.M.. Lapierre, Y.D.. Masco. H.L. and Mendels, J. (19YO) Antidepressant efficacy of sertraline: a double-blind, placebo- and amitriptyline-controlled. multicenter comparison study in outpatients with major depression. .I. Clin. Psychiatry 51 (Suppl. B). 1X-27. Rickels. K., Feighner, J.D. and Smith. W.T. (1985) Alprazolam, amitriptylinc. doxepin and placebo in the treatment of depression. Arch. Gen. Psychiatry 41. 134-141. Spitzer, R.L.. Endicott. J. and Robins, E. (1977) Research Diagnostic Criteria (RDC) for a Selected Group of Functional Disorders, 3rd Edn. Biometrics Research. New York, NY. Stewart, J.W., McGrath. P.J., Liebowitz, M.R., Harrison. W.M.. Quitkin, F.M. and Rabkin. J.G. (10x5) Treatment outcome validation of DSM-III depressive subtypes. Arch. Gen. Psychiatry 42, 113X-l 153.

US Food and Drug Administration (IYXS). COSTART Coding Symbols for Thesaurus of Adverse Reaction Terms. 2nd Edn. Rockville. Md, Food and Drug Administration. Wei, L.J. and Durham. S. (1978) The randomized play-thrwinner rule in medical trials. J. Am. Stat. .As\oc. 73. 840-X43. Zimmerman, M.. C‘oryell. W.. Pfohl. B. and Stangl. D. (IOH6) The validity of four definitions of endogenous depression. II. Clinical. demographic, familial, and psychosocial corrclates. Arch. Gen. Psychiatry 43, 234-244. Zimmerman. M. and Spitrer. R.L. (1YXY) Mclanchtrlia: from DSM-III to DSM-III-R. Am. J. Psychiatry 1%. X-78. Zimmerman, M.. Black. D.W. and Coryell, W. (IYXY) Diagnostic criteria for melancholia: the comparative validity of DSM-III and DSM-III-R. Arch. Gcn. Psychiatry 4(x X)136X.