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Placebo response rates in psychotic and nonpsychotic depression
Journal ofAf/ective Elsevier
21
Disorders, 14 (1988) 21-23
JAD 00504
Placebo response rates in psychotic and nonpsychotic depression Duane G. Spiker and David J. Kupfer University of Pittsburgh School
of Medium and the Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, U.S.A. (Received 16 July 1987) (Accepted 4 August 1987)
The authors reanalyzed data from two earlier studies that used double-blind placebo-controlled formats to study the efficacy of amitriptyline. Using a 16day drug-free ‘wash-out’ period, they found that the placebo response rates were 0% for psychotic depressives and 13.3% for nonpsychotic depressives. Amitriptyline was significantly superior to placebo for both psychotic (P I 0.05) and nonpsychotic (P I 0.05) depressed patients.
Key worcis: Depression,
psychotic;
Amitriptyline;
Placebo
Introduction Some depressed patients who are delusional clearly respond to tricyclic antidepressants (Spiker et al., 1986). However, in a double-blind study in which patients were randomly assigned to perphenazine alone, amitriptyline alone, or the combination of amitriptyline and perphenazine, the combination was clearly superior with a response rate of 78% versus 40% for amitriptyline alone and 19% for perphenazine alone (Spiker et al., 1985). Given the variation of drug responsiveness to different types of medication, we were interested in
Address for correspondence: Dr. D.G. Spiker, Western Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213, U.S.A. Supported in part by National Institute of Mental Health Grants MH-25642 and MH-30915. 0165-0327/88/$03.50
0 1988 Elsevier Science Publishers
response
the placebo response rate of delusionally depressed patients. Although such patients were undoubtedly included in early efficacy studies of tricyclic antidepressants, not enough information about the samples is given to separate delusional from nondelusional depressives (Rogers and Clay, 1975; Kantor and Glassman, 1977). Between 1974 and 1977 two such studies which included delusional depressives were conducted at Western Psychiatric Institute and Clinic. Enough information was systematically collected to allow us to retrospectively rediagnose the patients. The principal goals of the projects were to examine the sleep of depressed patients and to determine what changes occurred in their sleep when they were treated with either amitriptyline or placebo (Kupfer et al., 1976, 1980; Coble et al., 1979, 1981). The primary purpose of this article is to report the response rate of depressed psychotic and nonpsychotic patients treated with placebo.
B.V. (Biomedical
Division)
22 Methods
TABLE
1
RESPONSE
BY DIAGNOSIS
All of the records from the two studies, which were conducted between 1974 and 1977, were
Treatment
reviewed and the patients were rediagnosed using the DSM-III criteria. Patients who met the criteria for Major Depressive Disorder were included.
Psychotic on& Placebo Amitriptyline
Psychotic psychosis
patients had to meet the criteria for based on the presence of a delusion,
which was defined as a fixed false belief not shared by the patient’s family or cultural group. Patients
with
schizophrenia,
previous
or present
organic brain syndrome,
diagnoses
of
or anorexia
nervosa were excluded. Patients with a diagnosis of drug abuse or alcoholism were excluded unless they had been abstinent for 2 years prior to entering the study. Patients
who had a medical
illness
or were on a medication that affected the central nervous system were also excluded. The basic design of the two studies included a 2-week drug-free ‘wash-out’ period. During that time, approximately 20% of the potential patients had a spontaneous remission of their symptoms. Accurate records on these patients were not kept so no comment can be made on the presence or absence of psychotic features in this group. To enter the study, patients had to have a Hamilton Rating Scale (HRS) score of 30 or more based on the sum of two raters’ scores using the 17-item HRS (Hamilton, 1960). Patients were subsequently rated twice weekly. All patients received one placebo capsule 4 times a day for 7 days on a single-blind basis. They were then assigned on a random double-blind basis to either amitriptyline or to continuance of placebo for 4 additional weeks. Patients were not given any other psychoactive medications during the 5-week study. All patients gave informed consent to participate in the trial. Thirty-six patients (13 male, 23 female) with a mean (+ SD) age of 45.5 & 13.9 years and an HRS score of 43.0 + 10.4 were assigned to amitriptyline. Thirty-one patients (11 male, 20 female) with
Nonpsychotic Placebo Amitriptyline
AND TREATMENT
Responder
Nonresponder
0 4
10 6
2 11
13 9
only
Ps.ychotlc and nonpsychotlc Placebo 2 Amitriptyline 15
23 15
score 2 20 or who were still psychotic at the end of the protocol were considered nonresponders. If the patient’s HRS score was 13-19 and he or she was not psychotic, the patient was considered to be a responder if the final HRS score was one third or less than the entering
score.
Results Of the 67 patients who entered protocol, six patients on amitriptyline
the 35-day and six on
placebo were dropped. Four of the six amitriptyline noncompleters were psychotic compared to three of the six placebo noncompleters. Two of the amitriptyline patients were dropped because they became manic. The responses of the 55 completers are shown in Table 1. The overall placebo response rate was 8%. The placebo response rate for the psychotic
patients
was 0% and for the nonpsy-
chotic patients 13.3%. There is no significant difference between these response rates. Patients treated with amitriptyline responded at a significantly higher rate than those treated with placebo regardless of whether one looks at psychotic patients (Fisher’s exact test, P I 0.05, l-tailed), nonpsychotic patients (x2 = 6.37, P I 0.05) or the combined group (x2 = 11.26, P 5 0.001).
a mean ( f SD) age of 41.3 f 15.0 years and an HRS score of 43.5 + 10.7 were assigned to placebo.
Discussion
To be considered a reseponder, the patient had to have an HRS score I 12 and, if they were in the
The 55% response rate for the nonpsychotic patients treated with amitriptyline is similar to the
psychotic group, no longer be psychotic at the end of the 35-day protocol. Patients with an HRS
response rate reported over the last 15 years for studies using inpatient populations (Potter and
23 Goodwin,
1978). More importantly,
this reanalysis
of data from two older studies clearly demonstrates that patients with a psychotic depression do not respond to placebo. We were unable to find any other articles that present their results in a similar manner. As noted by Kantor and Glassman (1977) this is primarily because earlier studies did not differentiate between delusional and nondelusional depressives. The only report that attempts to do so is by Quitkin and associates (1978) who considered any patient with a positive rating on the F factor of the LORR Multidimensional
Scale for Rating
Psychiatric
Patients
to be
psychotic. psychotic
Four psychotic patients and nine nonpatients were assigned to placebo; nine
psychotic
patients
and 12 nonpsychotic
patients
were assigned to imipramine. They reported patients treated with imipramine responded significantly higher rate than those treated
that at a with
placebo regardless of the presence or absence of psychosis. However, their patient population is probably not the same as in this report as a positive rating on the F factor of the LORR Multidimensional Scale is not necessarily equivalent to the presence of a delusion (Minter, 1979). We hypothesized that our design using a 14-day drug-free period before beginning the protocol would yield a low placebo response rate. This was indeed the case. Of the 25 patients assigned to placebo only two (8%) were responders. Even if one excludes
the psychotic
patients,
the response
rate is still only 13.3%. This is substantially
below
the placebo response rate reported in other inpatient double-blind placebo controlled studies (Rogers and Clay, 1975, Kantor and Glassman,
1977).
We
believe
that
this
1Cday
drug-free
‘wash-out’ period should be given serious consideration when researchers are designing inpatient treatment studies for depressed patients that do not use a placebo control. References Coble, P.A., Kupfer, D.J., Spiker, D.G., Neil, J.F. and McPartland, R.J. (1979) EEG sleep in primary depression. A longitudinal placebo study. J. Affect. Disord. 1, 131-138. Coble, P.A., Kupfer, D.J. and Shaw, D.H. (1981) Distribution of REM latency in depression. Biol. Psychiatry 16,453-466. Hamilton, M. (1960) A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56-62. Kantor, S.J. and Classman, A.H. (1977) Delusional depressions: natural history and response to treatment. Br. J. Psychiatry 131, 351-360. Kupfer, D.J., Foster, F.G., Reich, L., Thompson, K.S. and Weiss, B. (1976) EEG sleep changes as predictors in depression. Am. J. Psychiatry 133, 622-626. Kupfer, D.J., Spiker, D.G., Cable, P.A., Neil, J.F., Ulrich, R. and Shaw, D.H. (1980) Depression, EEG sleep, and clinical response, Compr. Psychiatry 21, 212-220. Minter, R.E. (1979) Predicting imipramine response. Am. J. Psychiatry 136, 731. Potter, W.Z. and Goodwin, F.K. (1978) Antidepressant drug levels and clinical response, Lancet i, 1049-1050. Quitkin, F., Rifkin, A. and Klein, D.F. (1978) Imipramine response in deluded depressive patients. Am. J. Psychiatry 135, 806-811. Rogers, S.C. and Clay, P.M. (1975) A statistical review of controlled trials of imipramine and placebo in the treatment of depressive illnesses. Br. J. Psychiatry 127, 599-603. Spiker, D.G., Weiss, J.C., Dealy, R.S. et al. (1985) The pharmacological treatment of delusional depression. Am. J. Psychiatry 142, 430-436. Spiker, D.G., Dealy, R.S., Hanin, I., Weiss, J.C. and Kupfer, D.J. (1986) Treating delusional depressives with amitriptyline. J. Clin. Psychiatry 47, 243-246.
21
Disorders, 14 (1988) 21-23
JAD 00504
Placebo response rates in psychotic and nonpsychotic depression Duane G. Spiker and David J. Kupfer University of Pittsburgh School
of Medium and the Western Psychiatric Institute and Clinic, Pittsburgh, PA 15213, U.S.A. (Received 16 July 1987) (Accepted 4 August 1987)
The authors reanalyzed data from two earlier studies that used double-blind placebo-controlled formats to study the efficacy of amitriptyline. Using a 16day drug-free ‘wash-out’ period, they found that the placebo response rates were 0% for psychotic depressives and 13.3% for nonpsychotic depressives. Amitriptyline was significantly superior to placebo for both psychotic (P I 0.05) and nonpsychotic (P I 0.05) depressed patients.
Key worcis: Depression,
psychotic;
Amitriptyline;
Placebo
Introduction Some depressed patients who are delusional clearly respond to tricyclic antidepressants (Spiker et al., 1986). However, in a double-blind study in which patients were randomly assigned to perphenazine alone, amitriptyline alone, or the combination of amitriptyline and perphenazine, the combination was clearly superior with a response rate of 78% versus 40% for amitriptyline alone and 19% for perphenazine alone (Spiker et al., 1985). Given the variation of drug responsiveness to different types of medication, we were interested in
Address for correspondence: Dr. D.G. Spiker, Western Psychiatric Institute and Clinic, 3811 O’Hara St., Pittsburgh, PA 15213, U.S.A. Supported in part by National Institute of Mental Health Grants MH-25642 and MH-30915. 0165-0327/88/$03.50
0 1988 Elsevier Science Publishers
response
the placebo response rate of delusionally depressed patients. Although such patients were undoubtedly included in early efficacy studies of tricyclic antidepressants, not enough information about the samples is given to separate delusional from nondelusional depressives (Rogers and Clay, 1975; Kantor and Glassman, 1977). Between 1974 and 1977 two such studies which included delusional depressives were conducted at Western Psychiatric Institute and Clinic. Enough information was systematically collected to allow us to retrospectively rediagnose the patients. The principal goals of the projects were to examine the sleep of depressed patients and to determine what changes occurred in their sleep when they were treated with either amitriptyline or placebo (Kupfer et al., 1976, 1980; Coble et al., 1979, 1981). The primary purpose of this article is to report the response rate of depressed psychotic and nonpsychotic patients treated with placebo.
B.V. (Biomedical
Division)
22 Methods
TABLE
1
RESPONSE
BY DIAGNOSIS
All of the records from the two studies, which were conducted between 1974 and 1977, were
Treatment
reviewed and the patients were rediagnosed using the DSM-III criteria. Patients who met the criteria for Major Depressive Disorder were included.
Psychotic on& Placebo Amitriptyline
Psychotic psychosis
patients had to meet the criteria for based on the presence of a delusion,
which was defined as a fixed false belief not shared by the patient’s family or cultural group. Patients
with
schizophrenia,
previous
or present
organic brain syndrome,
diagnoses
of
or anorexia
nervosa were excluded. Patients with a diagnosis of drug abuse or alcoholism were excluded unless they had been abstinent for 2 years prior to entering the study. Patients
who had a medical
illness
or were on a medication that affected the central nervous system were also excluded. The basic design of the two studies included a 2-week drug-free ‘wash-out’ period. During that time, approximately 20% of the potential patients had a spontaneous remission of their symptoms. Accurate records on these patients were not kept so no comment can be made on the presence or absence of psychotic features in this group. To enter the study, patients had to have a Hamilton Rating Scale (HRS) score of 30 or more based on the sum of two raters’ scores using the 17-item HRS (Hamilton, 1960). Patients were subsequently rated twice weekly. All patients received one placebo capsule 4 times a day for 7 days on a single-blind basis. They were then assigned on a random double-blind basis to either amitriptyline or to continuance of placebo for 4 additional weeks. Patients were not given any other psychoactive medications during the 5-week study. All patients gave informed consent to participate in the trial. Thirty-six patients (13 male, 23 female) with a mean (+ SD) age of 45.5 & 13.9 years and an HRS score of 43.0 + 10.4 were assigned to amitriptyline. Thirty-one patients (11 male, 20 female) with
Nonpsychotic Placebo Amitriptyline
AND TREATMENT
Responder
Nonresponder
0 4
10 6
2 11
13 9
only
Ps.ychotlc and nonpsychotlc Placebo 2 Amitriptyline 15
23 15
score 2 20 or who were still psychotic at the end of the protocol were considered nonresponders. If the patient’s HRS score was 13-19 and he or she was not psychotic, the patient was considered to be a responder if the final HRS score was one third or less than the entering
score.
Results Of the 67 patients who entered protocol, six patients on amitriptyline
the 35-day and six on
placebo were dropped. Four of the six amitriptyline noncompleters were psychotic compared to three of the six placebo noncompleters. Two of the amitriptyline patients were dropped because they became manic. The responses of the 55 completers are shown in Table 1. The overall placebo response rate was 8%. The placebo response rate for the psychotic
patients
was 0% and for the nonpsy-
chotic patients 13.3%. There is no significant difference between these response rates. Patients treated with amitriptyline responded at a significantly higher rate than those treated with placebo regardless of whether one looks at psychotic patients (Fisher’s exact test, P I 0.05, l-tailed), nonpsychotic patients (x2 = 6.37, P I 0.05) or the combined group (x2 = 11.26, P 5 0.001).
a mean ( f SD) age of 41.3 f 15.0 years and an HRS score of 43.5 + 10.7 were assigned to placebo.
Discussion
To be considered a reseponder, the patient had to have an HRS score I 12 and, if they were in the
The 55% response rate for the nonpsychotic patients treated with amitriptyline is similar to the
psychotic group, no longer be psychotic at the end of the 35-day protocol. Patients with an HRS
response rate reported over the last 15 years for studies using inpatient populations (Potter and
23 Goodwin,
1978). More importantly,
this reanalysis
of data from two older studies clearly demonstrates that patients with a psychotic depression do not respond to placebo. We were unable to find any other articles that present their results in a similar manner. As noted by Kantor and Glassman (1977) this is primarily because earlier studies did not differentiate between delusional and nondelusional depressives. The only report that attempts to do so is by Quitkin and associates (1978) who considered any patient with a positive rating on the F factor of the LORR Multidimensional
Scale for Rating
Psychiatric
Patients
to be
psychotic. psychotic
Four psychotic patients and nine nonpatients were assigned to placebo; nine
psychotic
patients
and 12 nonpsychotic
patients
were assigned to imipramine. They reported patients treated with imipramine responded significantly higher rate than those treated
that at a with
placebo regardless of the presence or absence of psychosis. However, their patient population is probably not the same as in this report as a positive rating on the F factor of the LORR Multidimensional Scale is not necessarily equivalent to the presence of a delusion (Minter, 1979). We hypothesized that our design using a 14-day drug-free period before beginning the protocol would yield a low placebo response rate. This was indeed the case. Of the 25 patients assigned to placebo only two (8%) were responders. Even if one excludes
the psychotic
patients,
the response
rate is still only 13.3%. This is substantially
below
the placebo response rate reported in other inpatient double-blind placebo controlled studies (Rogers and Clay, 1975, Kantor and Glassman,
1977).
We
believe
that
this
1Cday
drug-free
‘wash-out’ period should be given serious consideration when researchers are designing inpatient treatment studies for depressed patients that do not use a placebo control. References Coble, P.A., Kupfer, D.J., Spiker, D.G., Neil, J.F. and McPartland, R.J. (1979) EEG sleep in primary depression. A longitudinal placebo study. J. Affect. Disord. 1, 131-138. Coble, P.A., Kupfer, D.J. and Shaw, D.H. (1981) Distribution of REM latency in depression. Biol. Psychiatry 16,453-466. Hamilton, M. (1960) A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56-62. Kantor, S.J. and Classman, A.H. (1977) Delusional depressions: natural history and response to treatment. Br. J. Psychiatry 131, 351-360. Kupfer, D.J., Foster, F.G., Reich, L., Thompson, K.S. and Weiss, B. (1976) EEG sleep changes as predictors in depression. Am. J. Psychiatry 133, 622-626. Kupfer, D.J., Spiker, D.G., Cable, P.A., Neil, J.F., Ulrich, R. and Shaw, D.H. (1980) Depression, EEG sleep, and clinical response, Compr. Psychiatry 21, 212-220. Minter, R.E. (1979) Predicting imipramine response. Am. J. Psychiatry 136, 731. Potter, W.Z. and Goodwin, F.K. (1978) Antidepressant drug levels and clinical response, Lancet i, 1049-1050. Quitkin, F., Rifkin, A. and Klein, D.F. (1978) Imipramine response in deluded depressive patients. Am. J. Psychiatry 135, 806-811. Rogers, S.C. and Clay, P.M. (1975) A statistical review of controlled trials of imipramine and placebo in the treatment of depressive illnesses. Br. J. Psychiatry 127, 599-603. Spiker, D.G., Weiss, J.C., Dealy, R.S. et al. (1985) The pharmacological treatment of delusional depression. Am. J. Psychiatry 142, 430-436. Spiker, D.G., Dealy, R.S., Hanin, I., Weiss, J.C. and Kupfer, D.J. (1986) Treating delusional depressives with amitriptyline. J. Clin. Psychiatry 47, 243-246.