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A controlled trial of phenelzine in posttraumatic stress disorder
149
Psychiarry Research. 24, I49- I55 Elsevier
A Controlled Disorder
Trial of Phenelzine
Miguel
Shestatzky,
David Greenberg,
Received
November ZI, 1986; accepted
in Posttraumatic
Stress
and Bernard Lerer
February 17, 1987.
Abstract. Thirteen patients meeting DSM-III criteria for posttraumatic stress disorder participated in a random-assignment, double-blind crossover trial comparing phenelzine (45-75 mg/day) and placebo. Ten patients completed at least 4 weeks of each treatment phase. Clinical response to phenelzine did not differ from placebo, and overall improvement by the end of the study could not be attributed to the active drug. The findings are discussed in the light of preliminary reports suggesting that phenelzine may be an effective treatment for posttraumatic stress disorder. Key Words. Posttraumatic
stress disorder, monoamine
oxidase, phenelzine.
It has long been recognized that exposure to severe psychological trauma may be followed by long-lasting emotional symptoms and pervasive adjustment difficulties. This syndrome, defined by DSM-III (American Psychiatric Association, 1980) as posttraumatic stress disorder (PTSD), is often resistant to standard psychotherapeutic interventions. Although the core features of PTSD are related to reexperiencing of the original traumatic event and avoidance of situations reminiscent of it, symptoms suggestive of affective disorder are often prominent. These include diminished interest in significant activities, detachment or estrangement from others, constricted affect, hyperalertness or exaggerated startle response, sleep disturbance, and impairment of memory or concentration. The potential efficacy of antidepressant agents in treating PTSD has therefore aroused increasing interest. lnitial reports focused on the monoamine oxidase (MAO) inhibitor phenelzine. Hogben and Cornfield (1981) described five cases of “traumatic war neurosis” in whom phenelzine (45-75 mg/day) improved traumatic dreams, flashbacks, startle reactions, and violent outbursts. In an open prospective trial, Davidson et al. (1987) recently administered phenelzine (45-60 mg) to 1 I combat veterans with PTSD and observed a 50% response rate by 2 weeks of treatment and a 70% response rate by 4 weeks. Similar positive effects were noted in three patients by
Miguel Shestatzky, M.D., is Research Fellow, Jerusalem Mental Health Center. David Greenberg, M.D., is Director, Outpatient Department, Jerusalem Mental Health Center. Bernard Lerer, M.D., is Director of Research, Jerusalem Mental Health Center. (Reprint requests to Prof. B. Lerer, Director of Research, Jerusalem Mental Health Center-Ezrath Nashim Hospital, P.O.B. 140, Jerusalem, Israel.) 01651781/88/$03.50
@ 1988 Elsevier Scientific
Publishers
Ireland
Ltd.
150 Walker (1982) and in single cases by other authors (Levenson et al., 1982; Shen and Park, 1983). Recent uncontrolled reports have suggested that imipramine (Burstein, 1983; Marshall, 1975) and other tricyclic antidepressants (Boehnlein et al., 1985; Falcon et al., 1985; Bleich et al., 1986) may also be effective in alleviating the symptoms of PTSD and as an adjunct to psychotherapy (Bleich et al., 1986). These positive reports prompted us to undertake a double-blind crossover trial comparing phenelzine and placebo in the treatment of PTSD.
Methods Patients referred to the Jerusalem Mental Health Center Outpatient Clinic were considered eligible for the study provided that they met DSM-III criteria for PTSD, were medically healthy, and had not suffered significant head injury or other physical trauma. Before beginning treatment, subjects were withdrawn from all psychotropic medication for at least 2 weeks; during this period the diagnosis was confirmed by semistructured interview, and baseline psychiatric ratings were performed. The subjects were then randomly assigned to treatment with phenelzine or placebo. Phenelzine was begun at 30 mg/day and was increased to the maximum tolerated dosage. After 5 weeks of treatment, all subjects were switched to placebo for a 2-week period and were then, under double-blind conditions, crossed over to the alternate treatment (phenelzine or placebo) for a further 5 weeks. Patients were followed by the same therapist (MS), and psychotherapeutic intervention was of a supportive nature only. Clinical response was monitored by the following observer-rated scales, administered at baseline and then weekly throughout the trial by a rater (MS) without knowledge of treatment assignment: (I) Clinical Global Inventory (Guy, 1976). (2) PTSD Scale consisting of each of the 12 items making up the DSM-IIIcriteria; the items were rated on a O-5 scale of severity. (3) Hamilton Rating Scale for Anxiety (Guy, 1976). (4) Hamilton Rating Scale for Depression (Guy, 1976). (5) Psychosocial Function Scale rating each of the following items on a O-5 scale of severity: (a) occupational adjustment, (b) leisure activities, (c) sexual function, (d) interpersonal relationships with spouse and (e) children, and (f) general social interactions. In addition, the following self-rating instruments were administered: (I) Impact of Events Scale (Zilberg et al., 1982). (2) Visual Analog Scale (IO cm) reflecting the subject’s overall subjective impression of his clinical state. Statistical analyses of the outcome data compared ratings.during treatment with phenelzine to those recorded during the placebo phase (Wilcoxon Signed Ranks Test) and also scores during each of the two legs of the trial without regard to the treatment administered.
Results Seven subjects were randomly assigned to phenelzine treatment during the first leg of the trial, and six subjects received placebo. Three subjects dropped out during this phase, after 1, 2, and 5 weeks, respectively. All were receiving phenelzine and complained of lassitude, dizziness, and lack of therapeutic benefit. Following crossover, four subjects (all receiving phenelzine) failed to complete week 5 of treatment. One developed urticaria which was attributed to phenelzine and three refused further treatment on the grounds that it was ineffective. Ten subjects completed at least 4 weeks of treatment during both legs of the trials and were included in the data analysis. Their background and clinical characteristics are summarized in Table 1. Table 2 summarizes the response to treatment during each leg of the trial as reflected in the rating scales used. Mean (*SD) baseline and week 4 ratings are given. Week 5 ratings for the six subjects who completed both legs of the trial in full
151 did not significantly differ from those recorded at the end of week 4 and also showed no advantage for phenelzine over placebo (PTSD Scale Il.3 f 5.68 vs. 10.8 + 8.00; Clinical Global Inventory 3.3 + 0.8 I vs. 3.0 + I .54; Hamilton depression 6.5 _+ I .04 Table 1. Background and clinical characteristics traumatic stress disorder (PTSD)
Patient No.
Age W)
1
31
Time No. of since PTSD trauma items (yr) (DSM-III)
Nature of trauma Aircraft crashpresumed
12
9
with
post-
Concurrent DSM-III diagnosis
Maximum phenelzine dose (mg)
Generalized
75
anxiety disorder
responsibility
31
Automobile
accident
2
10
-
75
26
Automobile
accident
2
10
-
45
28
Military combat
48
Automobile
stress
accident-
3
9
-
60
2
11
Major depressive
75
disorder
death of son 6
of patients
Military combat
42
stress
12
11
Generalized
60
anxiety disorder 50
Military combat
stress
12
11
-
75
45
Terrorist attack in city
1
10
-
60
50
Military combat
3
12
Major depressive
75
stress
disorder 10
Terrorist
34
Table 2. Treatment
bomb in bus
response
7
11
as assessed
-
by rating scales
Phenelzine Rating scales
Baseline
60
Placebo
Week 4
Baseline
Week 4
Observer-rated Posttraumatic Clinical
stress disorder
Global Inventory
Hamilton
depression
Hamilton
anxiety
Psychosocial
Function
Scale
20.0 +
2.7
13.0 +
7.6
4.0 +
0
3.5 *
1.06
19.0 + 11.7 3.7 +
1.77
12.2 +
8.6
3.2 +
1.40
11.0 f
3.4
9.0 +
5.5
12.0 t
9.2
7.0 f
6.4
9.5 *
6.69
6.9 f
4.46
11.2 4
7.41
6.7 +
4.68
15.0 f
4.4
11.0 *
4.7
14.0 f
5.9
11.0 +
6.0
Self-rated Impact of Events Intrusion
21,.0 f
4.9
17.0 f 10.2
20.0 + 11.4
15.0 *
9.1
Avoidance
13.0 f
7.5
16.0 +
15.0 +
15.0 +
5.9
Total
34.0 f 11.6
Visual Analog
(Global)
5.9 +
1.45
6.6
33.0 * 11.6 5.0 *
1.66
9.1
36.0 + 19.0 6.1 f
2.71
30.0 f 12.0 5.4 f
2.42
Figures represent mean + SD for the respective scale units. No differences between phenelzme and placebo were statistically significant.
152 vs. 7.7 f 7.13; Hamilton anxiety 7.0 + 2.75 vs. 6.3 + 5.61; Psychosocial Scale 9.5 f 2.58 vs. 9.3 f 3.71; Impact of Events total 31.7 + 13.93 vs. 31.5 + 13.0; Visual Analog 6.2 * 1.89 vs. 6.0 + 1.41). There was no evident difference in response between subjects administered phenelzine during the first leg of the trial and those administered placebo during this phase. Subjects who received phenelzine during the first phase did not relapse when switched to placebo while those who received placebo first did not show an accelerated response when switched to the active drug. Fig. 1 shows, in chronological order and irrespective of treatment, ratings recorded throughout the trial on PTSD, Impact of Events, Hamilton anxiety and Hamilton depression scales. A consistent improvement is evident, unrelated to the nature of the treatment administered. A similar trend was observed on all the other rating scales used. A detailed analysis of the individual items on the rating scales was performed, as well as a comparison between intrusion and avoidance symptoms as reflected on the
Fig. 1. Mean Posttraumatic Stress Disorder Scale, Impact of Events, Hamilton anxiety, and Hamilton depression scores in patients treated with phenelzine or placebo
Post
Traumatic Stress Disorder Scale
of Events State
30_ Trial
A
20 -“\,O
-0
,O _
30 -
\ o-0
\/‘%
Trial
El
4./.,* ‘A“*...*
&.-b--A,
*.‘.&.’.A.._*
20_-
0 Hamilton Scale Depression
15
E
,O 5 “a 0
pN/”
I
. ..-A.--4 \
0 1 2 3 2 5 om Weeks
of Treatment
Note. n = 10 for all points other than week 5 of trial B when n = 6.
-I-
...’
_.
‘S. ‘r
153 PTSD and Impact of Events Scales. Results for the PTSD Scale (Table 3) showed a nonsignificant differential effect favoring phenelzine on 9 out of 12 items, but this was not of clinically meaningful magnitude except in the case of items #I (recollections of the event) and #7 (hyperalertness/startle response). When intrusion (#I, 2, 3, 7, 8, 10, 12) and avoidance (#4, 5, 6, 9, II) clusters were compared, phenelzine was superior on five out of seven intrusion items and three of the five avoidance items. However, overall response to treatment over the entire trial period exceeded that on either phenelzine or placebo for 10 of the 12 categories. The same trends were present on the Impact of Events Scale.
Table 3. Mean improvement scores on Posttraumetic Stress Disorder scale Overall Phenelzine (baselineweek 4) n=lO
Item
Placebo (baselineweek 4) n=lO
(baselineweek4of phase 2) n=lO
Reexperiencing of the trauma 1. Recollections 2. Dreams
of the event
of the event
3. Reexperiencing
of the event
1 .o
0.4
1.0
0.6
0.7
1.1
0.1
0.3
0.6
Numbed responsiveness 4. Diminished
interest
1.0
0.8
0.9
5. Detachment/estrangement
1.0
0.9
1.7
6. Constricted
0.5
0.8
1.0
1.1
0.5
1.8
0.8
0.5
1.1
0.2
0.1
0.3
0.5
0.3
0.7
1.0
0.6
1.5
0.7
0.5
1.3
affect
Symptoms not present before the trauma 7. Hyperalertness/startle
response
8. Sleep disturbance 9. Survivor guiit 10. Memory/concentration 11. Avoidance
difficulties
of reminiscent
12. Intensification
by exposure
activities
Discussion On the basis of previous reports (Hogben and Cornfield, 1981; Levenson et al., 1982; Shen and Park, 1983; Walker, 1982) we hypothesized that phenelzine would be superior to placebo and would have a specific effect on intrusive reexperiencing of the trauma and symptoms such as sleep disturbance, hyperalertness, and startle response. These expectations were not fulfilled, and overall improvement observed during the study period (Fig. 1) could not be attributed to the active drug. These negative conclusions are mitigated by methodological considerations, primarily the small sample size which is vulnerable to a Type I I statistical error (Cohen, 1969). The results suggest, however, that an extremely large sample would be needed to disprove the null hypothesis (e.g., 2,000 subjects for a difference at p < 0.05 with a power of 0.80 on the PTSD Scale). Note, also, that patients treated with phenelzine in the first
154 leg of the trial did not relapse when withdrawn from the active drug, while patients who initially received placebo did not show an enhanced response when switched to phenelzine. The dose of phenelzine and the length of administration of the drug are further potential drawbacks. The dose used was dictated by the limit of clinical tolerance and, in the absence of facilities for monitoring platelet monoamine oxidase activity, every effort was made to achieve maximum levels (90 mg/day). In practice, five patients received 75 mg/day and only one patient received < 60 mg per day (Table 1). Maximum dose was reached in all subjects within 14 days and was maintained for a further 21 days in the six subjects who completed 5 weeks of phenelzine treatment and for 14 days in the four subjects who completed 4 weeks. The dosage range resembled that reported by Hogben and Cornfield (1981) who observed resolution of panic symptoms within 1 to 7 days, anxiety symptoms within 7 to 21 days, nightmares within 5 days to 1 month, and flashbacks within 7 to 18 days. A similarly rapid response was observed by Davidson et al. (1987) in 11 veterans with PTSD who were administered phenelzine (45-60 mg/day). The findings of Hogben and Cornfield (1981) and of Davidson et al. (1987) suggest that both the phenelzine dose and the length of phenelzine treatment in our patient group were sufficient to permit reasonable conclusions to be drawn about the efficacy of the active drug relative to placebo. The clinical characteristics of the subject group are a further consideration. Chronicity could have influenced therapeutic response; three of our subjects had a 12-year history of symptoms since the initial trauma, and one subject had been ill for 7 years. However, the five patients reported by Hogben and Cornfield (1981) as responding well to phenelzine had a median illness duration of 10 years (range 5-30 years). Severity of illness should also be considered. As measured by number of DSM-III items fulfilled (range 9-12, mean 10.4) and level of psychosocial functioning, our subjects were severely impaired. They were, however, an outpatient group and, although chronically ill, had no hospitalization history and appeared to have had less dramatic symptomatology than the patients described by Hogben and Cornfield (198 1). The degree to which intrusion symptoms characterized the clinical picture could also have influenced therapeutic response. Previous reports have stressed improvement in symptoms of this type following phenelzine (Hogben and Cornfield, 1981; Levenson et al., 1982; Shen and Park, 1983; Walker, 1982) and Burstein (1983) observed a similar differential response in 10 patients treated with imipramine. The total Impact of Events score in our group (mean = 40, SD = 13.2) was lower than that reported by Burstein (1983) (mean = 57.7). The difference for intrusion items was, however, less striking (present study: mean = 22, SD = 7.0; Burstein (1983): mean = 29.7). Comparable data of this kind are, unfortunately, not available from previous reports of patients treated with phenelzine. It is also noteworthy that the baseline Hamilton anxiety score in our patient group (mean = 14, SD = 7.3) was lower than might have been expected. The possibility that a group of patients with more striking positive or intrusion symptoms might have responded better to phenelzine cannot be excluded.
155
Over the full length of the study period, substantial clinical improvement was noted on a number of the rating scales used. This improvement was unrelated to drug treatment and may reflect a placebo effect or a response to supportive psychotherapy. Such factors may clearly influence the outcome of medication trials in PTSD. Acknowledgment.
The authors
thank Dr. Y. Ciivant for preparing
the trial medications.
References American Psychiatric Association. DSM-III: Diagnostic and Statistical Manual qf Mental Disorders. 3rd ed. APA, Washington, DC (1980). Bleich, A., Siegel, B., and Lerer, B. Post-traumatic stress disorder following combat exposure: Clinical features and psychopharmacological treatment. British Journal of Psychiatry, 149, 356 ( 1986). Boehnlein, J.K., Kinzie, J.D., Ben, R., and Fleck, J. One-year follow-up study of posttraumatic stress disorder among survivors of Cambodian concentration camps. American Journal of’ Psychiatry, 142, 956 (1985). Burstein, A. The treatment of post-traumatic stress disorder with imipramine. fs_vchosomatic.s. 25, 683 ( 1983). Cohen, J. Statistical Power Ana!vsisfor the Behavioral Sciences. Academic Press, New York ( 1969). Davidson, J., Walker, J.I., and Kilts, C. A pilot study of phenelzine in posttraumatic stress disorder. British Journal of Psychiatry. 150, 252 ( 1987). Falcon, S., Ryan, C., Chamberlain, K., and Curtis, G. Tricyclics: Possible treatment for posttraumatic stress disorder. Journal oy Clinical Psychiatry. 46, 385, 1985. Guy, W. ECDEU Assessment Manual for Psychopharmac~ology. George Washington University, Kensington, MD (1976). Hogben, G.L., and Cornfield, R.B. Treatment of traumatic war neurosis with phenelzine. Archives o/’ General fsvc’hiatry. 38,440 ( I98 I). Levenson, H., Lamman, R., and Rankin, M. Traumatic war neurosis and phenelzine. Archives of’ General Psychiatry. 39, 1345 ( 1982). Marshall, J.R. The treatment of night terrors associated with the posttraumatic syndrome. American Journal qf Psychiatry. 132, 293 (1975). Shen, W.W., and Park, S. The use of monamine oxidase inhibitors in the treatment of traumatic war neurosis: Case report. Military Medicine. 148,430 (1983). Walker, J.I. Chemotherapy of traumatic war stress. Military Medicine. 147, 1029 (1982). Zilberg, N.J., Weiss, D.S., and Horowitz, M.J. Impact of Events Scale: A cross-validation study and some empirical evidence supporting a conceptual model of stress response syndromes. Journal of Consulting and Clinical Psychology, 50, 407 ( 1982).
Psychiarry Research. 24, I49- I55 Elsevier
A Controlled Disorder
Trial of Phenelzine
Miguel
Shestatzky,
David Greenberg,
Received
November ZI, 1986; accepted
in Posttraumatic
Stress
and Bernard Lerer
February 17, 1987.
Abstract. Thirteen patients meeting DSM-III criteria for posttraumatic stress disorder participated in a random-assignment, double-blind crossover trial comparing phenelzine (45-75 mg/day) and placebo. Ten patients completed at least 4 weeks of each treatment phase. Clinical response to phenelzine did not differ from placebo, and overall improvement by the end of the study could not be attributed to the active drug. The findings are discussed in the light of preliminary reports suggesting that phenelzine may be an effective treatment for posttraumatic stress disorder. Key Words. Posttraumatic
stress disorder, monoamine
oxidase, phenelzine.
It has long been recognized that exposure to severe psychological trauma may be followed by long-lasting emotional symptoms and pervasive adjustment difficulties. This syndrome, defined by DSM-III (American Psychiatric Association, 1980) as posttraumatic stress disorder (PTSD), is often resistant to standard psychotherapeutic interventions. Although the core features of PTSD are related to reexperiencing of the original traumatic event and avoidance of situations reminiscent of it, symptoms suggestive of affective disorder are often prominent. These include diminished interest in significant activities, detachment or estrangement from others, constricted affect, hyperalertness or exaggerated startle response, sleep disturbance, and impairment of memory or concentration. The potential efficacy of antidepressant agents in treating PTSD has therefore aroused increasing interest. lnitial reports focused on the monoamine oxidase (MAO) inhibitor phenelzine. Hogben and Cornfield (1981) described five cases of “traumatic war neurosis” in whom phenelzine (45-75 mg/day) improved traumatic dreams, flashbacks, startle reactions, and violent outbursts. In an open prospective trial, Davidson et al. (1987) recently administered phenelzine (45-60 mg) to 1 I combat veterans with PTSD and observed a 50% response rate by 2 weeks of treatment and a 70% response rate by 4 weeks. Similar positive effects were noted in three patients by
Miguel Shestatzky, M.D., is Research Fellow, Jerusalem Mental Health Center. David Greenberg, M.D., is Director, Outpatient Department, Jerusalem Mental Health Center. Bernard Lerer, M.D., is Director of Research, Jerusalem Mental Health Center. (Reprint requests to Prof. B. Lerer, Director of Research, Jerusalem Mental Health Center-Ezrath Nashim Hospital, P.O.B. 140, Jerusalem, Israel.) 01651781/88/$03.50
@ 1988 Elsevier Scientific
Publishers
Ireland
Ltd.
150 Walker (1982) and in single cases by other authors (Levenson et al., 1982; Shen and Park, 1983). Recent uncontrolled reports have suggested that imipramine (Burstein, 1983; Marshall, 1975) and other tricyclic antidepressants (Boehnlein et al., 1985; Falcon et al., 1985; Bleich et al., 1986) may also be effective in alleviating the symptoms of PTSD and as an adjunct to psychotherapy (Bleich et al., 1986). These positive reports prompted us to undertake a double-blind crossover trial comparing phenelzine and placebo in the treatment of PTSD.
Methods Patients referred to the Jerusalem Mental Health Center Outpatient Clinic were considered eligible for the study provided that they met DSM-III criteria for PTSD, were medically healthy, and had not suffered significant head injury or other physical trauma. Before beginning treatment, subjects were withdrawn from all psychotropic medication for at least 2 weeks; during this period the diagnosis was confirmed by semistructured interview, and baseline psychiatric ratings were performed. The subjects were then randomly assigned to treatment with phenelzine or placebo. Phenelzine was begun at 30 mg/day and was increased to the maximum tolerated dosage. After 5 weeks of treatment, all subjects were switched to placebo for a 2-week period and were then, under double-blind conditions, crossed over to the alternate treatment (phenelzine or placebo) for a further 5 weeks. Patients were followed by the same therapist (MS), and psychotherapeutic intervention was of a supportive nature only. Clinical response was monitored by the following observer-rated scales, administered at baseline and then weekly throughout the trial by a rater (MS) without knowledge of treatment assignment: (I) Clinical Global Inventory (Guy, 1976). (2) PTSD Scale consisting of each of the 12 items making up the DSM-IIIcriteria; the items were rated on a O-5 scale of severity. (3) Hamilton Rating Scale for Anxiety (Guy, 1976). (4) Hamilton Rating Scale for Depression (Guy, 1976). (5) Psychosocial Function Scale rating each of the following items on a O-5 scale of severity: (a) occupational adjustment, (b) leisure activities, (c) sexual function, (d) interpersonal relationships with spouse and (e) children, and (f) general social interactions. In addition, the following self-rating instruments were administered: (I) Impact of Events Scale (Zilberg et al., 1982). (2) Visual Analog Scale (IO cm) reflecting the subject’s overall subjective impression of his clinical state. Statistical analyses of the outcome data compared ratings.during treatment with phenelzine to those recorded during the placebo phase (Wilcoxon Signed Ranks Test) and also scores during each of the two legs of the trial without regard to the treatment administered.
Results Seven subjects were randomly assigned to phenelzine treatment during the first leg of the trial, and six subjects received placebo. Three subjects dropped out during this phase, after 1, 2, and 5 weeks, respectively. All were receiving phenelzine and complained of lassitude, dizziness, and lack of therapeutic benefit. Following crossover, four subjects (all receiving phenelzine) failed to complete week 5 of treatment. One developed urticaria which was attributed to phenelzine and three refused further treatment on the grounds that it was ineffective. Ten subjects completed at least 4 weeks of treatment during both legs of the trials and were included in the data analysis. Their background and clinical characteristics are summarized in Table 1. Table 2 summarizes the response to treatment during each leg of the trial as reflected in the rating scales used. Mean (*SD) baseline and week 4 ratings are given. Week 5 ratings for the six subjects who completed both legs of the trial in full
151 did not significantly differ from those recorded at the end of week 4 and also showed no advantage for phenelzine over placebo (PTSD Scale Il.3 f 5.68 vs. 10.8 + 8.00; Clinical Global Inventory 3.3 + 0.8 I vs. 3.0 + I .54; Hamilton depression 6.5 _+ I .04 Table 1. Background and clinical characteristics traumatic stress disorder (PTSD)
Patient No.
Age W)
1
31
Time No. of since PTSD trauma items (yr) (DSM-III)
Nature of trauma Aircraft crashpresumed
12
9
with
post-
Concurrent DSM-III diagnosis
Maximum phenelzine dose (mg)
Generalized
75
anxiety disorder
responsibility
31
Automobile
accident
2
10
-
75
26
Automobile
accident
2
10
-
45
28
Military combat
48
Automobile
stress
accident-
3
9
-
60
2
11
Major depressive
75
disorder
death of son 6
of patients
Military combat
42
stress
12
11
Generalized
60
anxiety disorder 50
Military combat
stress
12
11
-
75
45
Terrorist attack in city
1
10
-
60
50
Military combat
3
12
Major depressive
75
stress
disorder 10
Terrorist
34
Table 2. Treatment
bomb in bus
response
7
11
as assessed
-
by rating scales
Phenelzine Rating scales
Baseline
60
Placebo
Week 4
Baseline
Week 4
Observer-rated Posttraumatic Clinical
stress disorder
Global Inventory
Hamilton
depression
Hamilton
anxiety
Psychosocial
Function
Scale
20.0 +
2.7
13.0 +
7.6
4.0 +
0
3.5 *
1.06
19.0 + 11.7 3.7 +
1.77
12.2 +
8.6
3.2 +
1.40
11.0 f
3.4
9.0 +
5.5
12.0 t
9.2
7.0 f
6.4
9.5 *
6.69
6.9 f
4.46
11.2 4
7.41
6.7 +
4.68
15.0 f
4.4
11.0 *
4.7
14.0 f
5.9
11.0 +
6.0
Self-rated Impact of Events Intrusion
21,.0 f
4.9
17.0 f 10.2
20.0 + 11.4
15.0 *
9.1
Avoidance
13.0 f
7.5
16.0 +
15.0 +
15.0 +
5.9
Total
34.0 f 11.6
Visual Analog
(Global)
5.9 +
1.45
6.6
33.0 * 11.6 5.0 *
1.66
9.1
36.0 + 19.0 6.1 f
2.71
30.0 f 12.0 5.4 f
2.42
Figures represent mean + SD for the respective scale units. No differences between phenelzme and placebo were statistically significant.
152 vs. 7.7 f 7.13; Hamilton anxiety 7.0 + 2.75 vs. 6.3 + 5.61; Psychosocial Scale 9.5 f 2.58 vs. 9.3 f 3.71; Impact of Events total 31.7 + 13.93 vs. 31.5 + 13.0; Visual Analog 6.2 * 1.89 vs. 6.0 + 1.41). There was no evident difference in response between subjects administered phenelzine during the first leg of the trial and those administered placebo during this phase. Subjects who received phenelzine during the first phase did not relapse when switched to placebo while those who received placebo first did not show an accelerated response when switched to the active drug. Fig. 1 shows, in chronological order and irrespective of treatment, ratings recorded throughout the trial on PTSD, Impact of Events, Hamilton anxiety and Hamilton depression scales. A consistent improvement is evident, unrelated to the nature of the treatment administered. A similar trend was observed on all the other rating scales used. A detailed analysis of the individual items on the rating scales was performed, as well as a comparison between intrusion and avoidance symptoms as reflected on the
Fig. 1. Mean Posttraumatic Stress Disorder Scale, Impact of Events, Hamilton anxiety, and Hamilton depression scores in patients treated with phenelzine or placebo
Post
Traumatic Stress Disorder Scale
of Events State
30_ Trial
A
20 -“\,O
-0
,O _
30 -
\ o-0
\/‘%
Trial
El
4./.,* ‘A“*...*
&.-b--A,
*.‘.&.’.A.._*
20_-
0 Hamilton Scale Depression
15
E
,O 5 “a 0
pN/”
I
. ..-A.--4 \
0 1 2 3 2 5 om Weeks
of Treatment
Note. n = 10 for all points other than week 5 of trial B when n = 6.
-I-
...’
_.
‘S. ‘r
153 PTSD and Impact of Events Scales. Results for the PTSD Scale (Table 3) showed a nonsignificant differential effect favoring phenelzine on 9 out of 12 items, but this was not of clinically meaningful magnitude except in the case of items #I (recollections of the event) and #7 (hyperalertness/startle response). When intrusion (#I, 2, 3, 7, 8, 10, 12) and avoidance (#4, 5, 6, 9, II) clusters were compared, phenelzine was superior on five out of seven intrusion items and three of the five avoidance items. However, overall response to treatment over the entire trial period exceeded that on either phenelzine or placebo for 10 of the 12 categories. The same trends were present on the Impact of Events Scale.
Table 3. Mean improvement scores on Posttraumetic Stress Disorder scale Overall Phenelzine (baselineweek 4) n=lO
Item
Placebo (baselineweek 4) n=lO
(baselineweek4of phase 2) n=lO
Reexperiencing of the trauma 1. Recollections 2. Dreams
of the event
of the event
3. Reexperiencing
of the event
1 .o
0.4
1.0
0.6
0.7
1.1
0.1
0.3
0.6
Numbed responsiveness 4. Diminished
interest
1.0
0.8
0.9
5. Detachment/estrangement
1.0
0.9
1.7
6. Constricted
0.5
0.8
1.0
1.1
0.5
1.8
0.8
0.5
1.1
0.2
0.1
0.3
0.5
0.3
0.7
1.0
0.6
1.5
0.7
0.5
1.3
affect
Symptoms not present before the trauma 7. Hyperalertness/startle
response
8. Sleep disturbance 9. Survivor guiit 10. Memory/concentration 11. Avoidance
difficulties
of reminiscent
12. Intensification
by exposure
activities
Discussion On the basis of previous reports (Hogben and Cornfield, 1981; Levenson et al., 1982; Shen and Park, 1983; Walker, 1982) we hypothesized that phenelzine would be superior to placebo and would have a specific effect on intrusive reexperiencing of the trauma and symptoms such as sleep disturbance, hyperalertness, and startle response. These expectations were not fulfilled, and overall improvement observed during the study period (Fig. 1) could not be attributed to the active drug. These negative conclusions are mitigated by methodological considerations, primarily the small sample size which is vulnerable to a Type I I statistical error (Cohen, 1969). The results suggest, however, that an extremely large sample would be needed to disprove the null hypothesis (e.g., 2,000 subjects for a difference at p < 0.05 with a power of 0.80 on the PTSD Scale). Note, also, that patients treated with phenelzine in the first
154 leg of the trial did not relapse when withdrawn from the active drug, while patients who initially received placebo did not show an enhanced response when switched to phenelzine. The dose of phenelzine and the length of administration of the drug are further potential drawbacks. The dose used was dictated by the limit of clinical tolerance and, in the absence of facilities for monitoring platelet monoamine oxidase activity, every effort was made to achieve maximum levels (90 mg/day). In practice, five patients received 75 mg/day and only one patient received < 60 mg per day (Table 1). Maximum dose was reached in all subjects within 14 days and was maintained for a further 21 days in the six subjects who completed 5 weeks of phenelzine treatment and for 14 days in the four subjects who completed 4 weeks. The dosage range resembled that reported by Hogben and Cornfield (1981) who observed resolution of panic symptoms within 1 to 7 days, anxiety symptoms within 7 to 21 days, nightmares within 5 days to 1 month, and flashbacks within 7 to 18 days. A similarly rapid response was observed by Davidson et al. (1987) in 11 veterans with PTSD who were administered phenelzine (45-60 mg/day). The findings of Hogben and Cornfield (1981) and of Davidson et al. (1987) suggest that both the phenelzine dose and the length of phenelzine treatment in our patient group were sufficient to permit reasonable conclusions to be drawn about the efficacy of the active drug relative to placebo. The clinical characteristics of the subject group are a further consideration. Chronicity could have influenced therapeutic response; three of our subjects had a 12-year history of symptoms since the initial trauma, and one subject had been ill for 7 years. However, the five patients reported by Hogben and Cornfield (1981) as responding well to phenelzine had a median illness duration of 10 years (range 5-30 years). Severity of illness should also be considered. As measured by number of DSM-III items fulfilled (range 9-12, mean 10.4) and level of psychosocial functioning, our subjects were severely impaired. They were, however, an outpatient group and, although chronically ill, had no hospitalization history and appeared to have had less dramatic symptomatology than the patients described by Hogben and Cornfield (198 1). The degree to which intrusion symptoms characterized the clinical picture could also have influenced therapeutic response. Previous reports have stressed improvement in symptoms of this type following phenelzine (Hogben and Cornfield, 1981; Levenson et al., 1982; Shen and Park, 1983; Walker, 1982) and Burstein (1983) observed a similar differential response in 10 patients treated with imipramine. The total Impact of Events score in our group (mean = 40, SD = 13.2) was lower than that reported by Burstein (1983) (mean = 57.7). The difference for intrusion items was, however, less striking (present study: mean = 22, SD = 7.0; Burstein (1983): mean = 29.7). Comparable data of this kind are, unfortunately, not available from previous reports of patients treated with phenelzine. It is also noteworthy that the baseline Hamilton anxiety score in our patient group (mean = 14, SD = 7.3) was lower than might have been expected. The possibility that a group of patients with more striking positive or intrusion symptoms might have responded better to phenelzine cannot be excluded.
155
Over the full length of the study period, substantial clinical improvement was noted on a number of the rating scales used. This improvement was unrelated to drug treatment and may reflect a placebo effect or a response to supportive psychotherapy. Such factors may clearly influence the outcome of medication trials in PTSD. Acknowledgment.
The authors
thank Dr. Y. Ciivant for preparing
the trial medications.
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