Response

of Patients

to Treatment

With

With Severe or Moderate Nonpsychotic and of Patients With Psychotic Depression

Martin

M.

James Katz, Charles

Hospitalized patients chotic severely depressed erately depressed (N=54), (N=25) groups and treated amitriptyline, up to 250 response occurred in 39% 67% of the 49 moderately

H. Kocsis, M.D., Jack L. Croughan, M.D., Ph.D., Thomas P. Butler, M.D., Steven Secunda, L. Bowden, M.D., and John M. Davis, M.D.

were divided into non psy(N=53), nonpsychotic modand psychotic depressed with either imipramine or mg/day, for 4 weeks. Good ofthe 38 severely depressed, depressed, and 32 % of the

1 9 psychotic depressed patients who completed treatment. The response of the patients with nonpsychotic severe depression did not differ significantly from the response of those with psychotic depression, and both groups fared worse than the group with nonpsychotic moderate depression. (Am J Psychiatry 1990; 147:621-624)

R

Depression

M.D.,

ment response data from the National Institute of Mental Health (NIMH) Clinical Research Branch Collaborative Program on the Psychobiology of Depression. The depressed sample contained a large number of patients who had major depression without psychotic features. Thus, we were able to divide this group into severely depressed and moderately depressed subgroups. Response to tnicyclic antidepressants could then be examined on the basis of severity of illness unconfounded by presence on absence of psychosis and could be compared to response in a separate psychotic depressed group. The hypothesis was that patients with nonpsychotic severe depression would respond to tnicyclics

as poorly

and

both

that

vorably

than

as those

of these the

groups

nonpsychotic

with

psychotic

would

depression

respond

moderately

less

fa-

depressed

group.

eports of relatively poor with tnicyclic antidepnessants the widespread clinical practice settings

of

treating

psychotic

response to treatment (1, 2) have led to in psychiatric inpatient unipolan

major

Received Nov. 29, 1988; revisions received July 20 and Sept. 19, 1989; accepted Oct. 30, 1989. From the NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression-Biological Studies. Address reprint requests to Dr. Kocsis, Dcpartment of Psychiatry, New York Hospital-Cornell Medical Center, 525 East 68th St., New York, NY 10021. Supported by NIMH grants MH-38084, MH-2697S, MH-26977, MH-26979, MH-26978, MH-31921, and MH-36232.

J

Psychiatry

1 47:5,

May

1990

METHOD

depres-

sion with ECT or with a combination of tnicyclics and antipsychotic drugs. It is not entirely clean whether the poor response to tnicyclics of patients with psychotic major depression is a function of some qualitative difference associated with the psychotic state or of a more general refractoriness to treatment associated with more severe symptoms of depression (1, 3). Resolution of this issue has important implications for treatment selection. If severity alone accounts for poor response to treatment with tnicyclics, then nonpsychotic severe major depression, which is operationally defined in the mood disorders section of DSM-III-R, might also nequire alternatives to treatment with tnicyclics alone. This report is based on results of reanalysis of treat-

Am

Antidepressants

The search

design Branch

biology

of

and rationale Collaborative Depression-Biological

of the NIMH Clinical ReProgram on the PsychoStudies

have

been

described in detail (4-6). For the present study, hospitalized patients with diagnoses of depression were interviewed with the Schedule for Affective Disorders and Schizophrenia (SADS) (7) and were included if they met the Research Diagnostic Criteria (8) for majon depressive disorder. Patients with unipolar depression, if they were under the age of 35, had to have had at least one prior depressive episode; if they were oven age 35, no prior episodes were required. Patients who fulfilled criteria for schizoaffective disorders were excluded. This study was conducted in six U.S. hospital centers (see Acknowledgment). A total of 85 unipolar patients (39 male, 46 female) and 47 bipolar patients (31 male, 16 female) were studied. Diagnosis of the psychotic subtype was derived from the SADS interview plus two SADS-C (9) interviews done by research psychiatrists during the first 2 weeks of the patients’ hospitalizations but before initiation of antidepressant medication. Thus, any depressed pa-

621

TREATMENT

OF NONPSYCHOTIC

DEPRESSION

tient rated as having definite delusions and/or hallucinations at the time of the initial interview or as having possible delusions and/or hallucinations on the SADS, which were confirmed as definite by the subsequent SADS-C interviews, was included in the psychotic depressed group. Training procedures for clinicians in the collaborating centers were held to establish and maintain interrater reliability. A method based on videotape recordings of brief interviews with a sample of representative patients was developed, and a cross-center reliability study was conducted. The kappa coefficients of the paired average ratings on the SADS of presence or absence of critical symptoms of depression such as delusions ranged from 0.63 to 0.92. Severity of depressive illness was measured before and after treatment with tnicyclics by means of the Hamilton Rating Scale for Depression (10) total score and the SADS-C global assessment scale. Assignment to the nonpsychotic severely depressed group or the nonpsychotic moderately depressed group was done according to a median split of the patients’ day 10 Hamilton total scores (median score=26 for the nonpsychotic patients). Ratings were made by research psychiatrists at the end of 4 weeks of treatment to determine treatment outcome. Hamilton depression scale and global assessment scale ratings were based on live interviews, while clinical global improvement and clinical global severity ratings were based on videotaped interviews (11). Patients were categorized as good responders, poor responders, or indeterminate responders on the basis of an algorithm derived from the four scales. The specific details have been published (4). Days 1-14 of hospitalization constituted a drug-free placebo baseline period. Active treatment with amitniptyline

on imipnamine

was

double-blind;

it was

nan-

domly assigned and began on day 15 according to the following schedule: days 15 and 16, 100 mg; days 17 and 18, 150 mg; days 19 and 20, 200 mg; days 21-41, 250 mg. Every effort was made to achieve the maximum dose. Twelve patients (eight taking amitniptyline and four taking imipramine) required treatment at lower doses because of side effects. Analysis of variance was used to compare ages and scale scores across the three groups, and Duncan’s multiple range test was used for pairwise comparisons. Chi-square analysis was used to test for differences in distribution of the sexes and outcome categories.

13

One cluded chotic chotic median scores patients

psychotic

622

unipolar)

and

32

unipolar)

bipolar,

severely

pressed

groups;

moderately

depressed

subgroups.

The

dis-

depressed it was

and

less

for

the

the

psychotic

de-

nonpsychotic

mod-

erately depressed group. One hundred six patients completed 4 weeks of treatment with either amitniptyline or imipramine and could be classified as good, poor, or indeterminate responders. Higher, but not significantly different, dropout rates occurred in the nonpsychotic severely depressed and the psychotic depressed groups than in the nonpsychotic moderately depressed group. Response classifications did not differ significantly

between

groups

or

between

the the

unipolan

and

imipnamine-

bipolar

and

sub-

amitniptyline-

treated subjects. The results are summarized in table 1. Response to treatment with tnicyclic antidepressants was significantly better for the nonpsychotic modenately depressed group. Sixty-seven percent of the 49 moderately depressed patients who completed 4 weeks of treatment were found to have a good outcome, compared to 39% of the 38 severely depressed and 32% of the 19 psychotic patients who completed treatment. Posttreatment scores on the Hamilton depression scale and the global assessment scale indicated less pathology in the nonpsychotic moderately depressed group than in the other two groups. Painwise group comparisons

revealed

significant

all

on

among psychotic

groups group

posttreatment

the

differences

Hamilton

compared

to the

scale other

two

and

for

groups

the on

the global assessment scale (see table 1). The final scores for the nonpsychotic severely depressed group were in between those of the psychotic depressed and nonpsychotic moderately depressed groups on both scales.

DISCUSSION

There were outcome

tnicyclic

hundred thirty-two depressed patients were inin the study. Twenty-five were classified as psy(12 bipolar, 13 unipolar), and 107 as nonpsy(35 bipolar, 72 unipolar). On the basis of a split of pretreatment Hamilton depression (N= 107; median scone=26), the nonpsychotic were divided into severely depressed (N53;

40 22

tnibutions of the sexes and of the unipolar and bipolar subtypes were not significantly different among the three groups (severe, moderate, psychotic), although there was a trend toward a higher proportion of unipolar patients in the severely depressed group and a higher proportion of bipolar patients in the moderately depressed group. The nonpsychotic severely depressed patients were found to be older than the other two groups. Severity of illness at baseline was about the same for the non-

the RESULTS

bipolar,

(N54;

two primary of 4 weeks

findings in this study. First, of treatment with standard

antidepressants

was

better

in a moderately

de-

pressed group of nonpsychotic hospitalized patients than in a severely depressed group. Second, the outcome for the nonpsychotic severely depressed group was intermediate between that of the patients with psychotic depression and that of the nonpsychotic moderately depressed group. Good outcome, defined as recovery

of the

or

moderately

marked

improvement,

depressed,

Am

]

39%

Psychiatry

occurred

of the

1 47:5,

in 67%

severely

May

de-

1990

KOCSIS,

TARt F 1 -

Response

ment

Tricyctic

With

of Nonpsychotic

Severely

or Moderately

Depressed

Patients

and Psychotic

CROUGHAN,

Depressed

Patients

KATZ,

to 4 Weeks of Treat-

Antidepressants Nonpsychotic Severeiy Depresseci litients (S) (N=S3)

Nonpsychotic Moderateiy Depressea Patients (M) (NS4)

.

.

Psycnotic Patients

Depressea (P) (N25)

Overall

Significant . Pairwise Differences (pM,

0.003

S>P

-

-

-

-

-

65.8

2, 127

0.0001

S>M,

-

21.9

2, 127

0.0001

SM

icess-

35

score

ment

I)rp(v1r Plasnia tratioi

14

-

Bipol

N

SD

c

VeIN

Fern

ET AL.

7

-

49

-

-

15

28

-

13

-

35 S

-

9

-

-

6

24

PM,

10.2

2, 105

0.0001

P>S,

P>M -

S>M,

P>M Posttreatment global assessment score Response to drug” Good Por Indeterminate aD1ncans multiple hSignifiant

-

groups

Pior

(1,

depression.

dressel

the

severity

of

this

8

16

(2=13.1,

df=4,

in response

patients

and

c’ggt-t\ respond depressed arti(le

originally responses p nients.

I Psychiatry

demonstrated

study

poor

25

19

-

-

-

-947

-

-

p’O.Ol).

8.8

-

6

32

4

21

Nonsignificant

between

severe

considering

a less

psychotic

unipolar

tnicyclic

had

a recovery

that

has

directly

3, 105

difference

0.0003

in response

and

psychotic

groups

and

rather

the

depressed

M>P,

the

results.

Prior

between

combined

and

the

to

the

nonpsychotic

more

poorly than

tnicyclics

sample

and

depressed

bipolar

did

not

S>P

severe

moderate

Twelve

difference

treatment

and

poor

and group

of

ill-

response

designed

method

that

Our

cyclics

of data

to address

Several

caveats

147:5,

May

the and must

1990

from

a study

respective

treat-

nonpsychotic

be mentioned

lasted

that

occurred longer

de-

in

the

subjects

unipolar

and

rates

of

in these

two

nonpsychotic

good

sub-

severely

depressed

responded

sign

of

systematic

dividing

the

resulted in small important issue

indeterminate ing scores group than

to 4 weeks of treatment do nonpsychotic moder-

and of

of the

psychotic

depression

but

treatment Another

depressed

unipolan unipolan

psychotic

equivalent that

and

with

patients

unfavorably

to

treatment with tnicyclics alone. It should also be noted that for reasons unrelated to the current analysis, two different antidepressant drugs were used for treatment. Good, indeterminate, and poor responses were similar with imipramine and am-

was

Glassman

results.

severely

analysis

psychotic

patients

itniptyline,

sample

were

psychotic

both

However,

it appeared

bipolar

those

number

analysis

response

with

in the

separately.

response

on

small

meaningful

Thus,

suggests an

permit

The

of poor

patients included

patients

groups. subgroups

with

patients. reportc of

mostly

current

depressed

severity

led to different

it

focused

The

of Hamil-

recovered.

nonpsychotic

same

analysis

have

groups. 27,

by

depression.

above

56%.

of these than

poor

is the

reports

antidepressants

depression

bipolar

group.

study the th

75%

ad-

a nonpsy-

nonsignificant

psychosis for

of

tnicyclic

nonpsychotic

versus

tnicyclics

scored

rate

this

nonpsy-

state

to

patients

27,

antide-

with

psychotic

response

Nine

according

ately

Am

33 67 816

difference

with

scores.

current

standard

pressed

-

study (1), which divided the basis of a median split

below

psychotic

with

ment

-

groups

patients

of

accounted

et al. used,

This

three

with

only

to

al. on

that

In the

clearly

to

interpreted

alone

patients

-

depressed

treatment

The

scored

evidence

study

-

-

46

-

to

2) have

illness

authors

divided

-

Significant

psychotic

contribution

group

pati11tc

the

to

depression

in the

the

n.s.).

compared

Glassman et chotic sample

ness

34

among

of patients

when

chotic

not

of

depression

The

13

-

2.6, dt=2,

response

pressants

and

39

49

treatment.

studies

favrahle

ton

15

17

test.

32%

nmpletcd

major

66

-1026

in response -

-

-

-

range

(

and

presced,

as

-

38

df= .2, p:-OOO7)

9.8

who

6

-

difference

psychotic

(x2

58

only

4 weeks.

diagnostic

numbers is that There

groups

in each treatment were

drug

trends

for

more

outcomes and better posttreatment ratin the nonpsychotic severely depressed in the psychotic depressed group, which a higher

rate

of good

response

could

in the duration the

by

subgroup. with tn-

severely ill group if there of treatment. Unfortunately, current study did not include

treatments

or

follow-up.

We

have

had

been a the desubsequent

do

not

know

623

TREATMENT

OF NONPSYCHOTIC

DEPRESSION

what treatments were added on substituted after the unsuccessful 4 weeks of treatment with tnicyclics. It is likely that many of these patients required ECT. Other possible treatments may have included longer trials of a tnicyclic alone, addition of antipsychotic drugs on lithium, or other so-called “enhancing” techniques. Despite these methodologic concerns, the results of the current data analysis are presented to alert clinicians to the possibility that patients with nonpsychotic severe major depression may respond less favorably than patients with nonpsychotic moderate depression to treatment with tnicyclic antidepressants alone. Thus, alternative interventions may be needed in the treatment of the former group of patients. These results will require replication in a prospective study that uses a longer duration of treatment before implications become firmly accepted.

REFERENCES 1 . Glassman and 2.

drug

Brown chotic Ment

ACKNOWLEDGMENT Institute Program

logical

was

Studies

carried

out

with

the

cooperation

and

participa-

tion of the collaborative program investigators and institutions: S.H. Koslow (project director), S. Secunda (deputy project director), M.M. Katz (senior investigator), I. Hanin (consultant), J.W. Maas (chairman),

Redmond, Jr., A. Swann, Yale University School of Medicine; J.M. Davis, R. Casper, S. Chang, D. Garver, J. Javaid, Illinois State Psychiatric Institute; J. Mendels, D. Brunswick, A.

Frazer, Stokes,

D.E.

A. Ramsey,

J.

S. Stern,

Kocsis, Cornell Croughan, Washington R. Shulman, University Antonio.

624

Philadelphia

University University of Texas

VA Medical

Medical College; School of Medicine; Health Sciences

Center;

P.E.

E. Robins, J. C. Bowden, Center at San

SJ,

S.

Shostak

M:

J Psychiatry

Am

A, Kocsis comparison

a

1479-1489 Katz MM,

critical

review.

Koslow

SH,

JH, of

671 Maas

JW,

Koslow

of

Davis

tricyclic

Gen N,

JM,

and Psychol

Secunda 5, Koslow nent of the NIMH on the analysis.

Spitzer

RL,

SH, Redmond Clinical Research

affect Rep

et at: Biological

Psychobiology Psychol Med Endicott

8. Spirzer (RDC) New Research,

9. Spitzer

RL,

J, Robins a Selected Group New York State

1977 Endicott

Affective

E: Research of Functional Psychiatric

J: Schedule

Schizophrenia-Change

for din55:619-

component

for

on

compoProand

Disorders York

Diagnostic Disorders, Institute,

Affective

of

Program and theoretical

et al: Biological Branch Collaborative

ed. New York, New Research, 1977

RL, Endicott for York,

for

33: ap-

states 1984;

of Depression, II: methodology 1980; 10:777-793

J: Schedule

Schizophrenia (SADS), 3rd chiatric Institute, Biometrics

DE,

1976;

A multi-vantaged

the NIMH Clinical Research Branch Collaborative the Psychobiology of Depression, I: background considerations. Psychol Med 1980; 10:759-776 6.

nonpsyJ Nerv

antidepressant

Psychiatry

et at:

of behavioral research. SH,

delusions,

132:716-719

et at: Psychotic vs treatment response.

Arch

Berman

Depression,

1975;

Dis 1982; 170:635-637 RJ, Friedet RO: Prediction

proach to measurement ical and psychobiological

7.

of Mental Health Clinical Research Branch on the Psychobiology of Depression-Bio-

response.

response: 4.

Kantor

RP, Frances depression:

3. Bielski

gram data

The National Collaborative

AH,

State

and Psy-

Criteria 3rd ed. Biometrics

Disorders

and

(SADS-C). New York, New York State Psychiatric Institute, Biometrics Research, 1978 10. Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23:56-62 1 1. Katz MM, Itil TM: Video methodology for research in psycho-

pathology 1974;

and

Version

psychopharmacology.

Arch

Gen

Psychiatry

3 1:204-210

Am

]

Psychiatry

147:5,

May

1990