A Double-Blind Study of Prazepam Versus Placebo in Single Daily Doses in the Treatment of Anxiety H. L. Goldberg and R. J. Finnerty
P
RAZEPAM (@Verstran, Warner-Chilcott.) is a new benzodiazepine tranquilizer that differs from diazepam only by a cyclopropyl group (Fig. 1). In 15 double-blind placebo-controlled studies with the same protocol, all the data were pooled to evaluate the efficacy of Prazepam administered on a T.I.D. schedule in the treatment of anxiety. On final global evaluations and for the target symptom of anxiety in 432 patients treated with Prazepam and 346 on placebo, improvement in both spheres was significant for patients with anxiety as their primary diagnosis. In addition, the Prazepam group always fared better than the placebotreated group, regardless of pretreatment symptom severity.’ In summarizing the results of the self-administered rating scales in 8 of the 15 studies, several scales did demonstrate between-group differences on 1 or a few factors, but usually did not differentiate between treatments on most of the factors of the scale. After 7 days of Prazepam, 10 mg t.i.d. administered orally to healthy men, ‘*CPrazepam (10 mg) was administered orally on the eighth day. The half-life for total radioactivity in the plasma was 70 + 10 hr.” This long half-life suggested that once-a-day dosage of Prazepam would probably be effective. A double-blind randomized, tolerance study of single daily bedtime doses of Prazepam, 30,40,50, and 60 mg, and placebo administered orally for 2 weeks was done in normal male volunteers .3 All doses were well tolerated with morning drowsiness occurring more frequently in those taking Prazepam than those taking placebo, but not severe at any dose. In a recent well controlled study, Brauzer4 studied single daily bedtime doses of Prazepam for relief of anxiety in 132 symptomatic volunteers with target symptoms of anxiety of at least moderate severity. This was a double-blind study with patients randomly assigned to three treatment groups; one received 40 mg Prazepam, another 60 mg Prazepam, and another placebo for 4 weeks. The two Prazepam groups, 40 mg and 60 mg, produced generally similar results. Patients on Prazepam, 40 and 60 mg, did significantly better than those on placebo on ratings of global improvement or measured by the psychiatrist’s evaluation of global psychopathology, change in patient since the study onset rated separately by the psychiatrist and patient, and the therapeutic effect of the drug rated separately by the psychiatrist and the patient. On the profile of mood states (POMS) and SCL-56, there were significant From the Outpatient Psychopharmacology Research Group, West-Ros-Park Mental Health Cenrer, Hyde Park. Mass. H. L. Goldberg, M.D.: Director. West-Ros-Park Mental Health Center and Co-Director. Outpatient Psychopharmacology Research Group: R. J. Finnerty. Ph.D.: Co-Director. Outpatienr PSTchopharmacology Research Group. Reprint requests should be addressed to H. L. Goldberg, M.D., West-Ros-Park Mental Health Center. 26 Central Avenue, Hyde Park, Mass. 02136. 1~1 1977 by Grune & Stratton. Inc. Comprehensive Psychiatry, Vol. 18. No. 2 (March/April), 1977
147
148
GOLDBERG
Diazepam
Prazepam Fig. 1.
Comparison
AND FINNERTY
of chemical structure of Prazepam and Diazepam.
improvements in mean scores for anxiety and depression for patients in all three groups, but there were no significant differences between any two groups on these two symptoms. It is interesting to note that the anger-hostility (POMS), and the interpersonal/sensitivity (SCL) factors showed statistically significant greater mean decreases in the placebo group than in the two Prazepam groups during the first 3 weeks of the study. The fatigue/inertia factor of the POMS also showed significant differences in favor of placebo, as well as the obsessive/compulsive factor on the XL at week 1 and 2. In another well controlled study, Rickels5 studied 97 patients in a design very similar to Brauzer’s. The study lasted 4 weeks, and patients were seen every 2 weeks. Patients on Prazepam, 40 mg and 60 mg, did significantly better than those on placebo on ratings of global improvement by the physician, on global psychopathology, change in patient since study onset, and the therapeutic effect of the drug. Significant differences in favor of Prazepam over placebo were also seen on Physician’s Questionnaire Emotional and Somatic cluster total scores and on the Emotional and Somatic clusters of the Hamilton Anxiety Scale. On the SCL-56, both drug groups were combined because of the small numbers in each group. The only factor showing improvement was the anxiety cluster at 2 weeks in favor of Prazepam. MATERIALS
AND METHODS
The purpose of this study was to evaluate the efficacy of a once-a-day bedtime dose of Prazepam for the treatment of anxiety. The patients were anxious private outpatients who were considered acceptable for entrance into the study according to the normal inclusion and exclusion criteria one would follow for benzodiazepinetype medications. Of 59 patients who were entered into the study, 30 were assigned to Prazepam and 29 to placebo, according to a double-blind randomization procedure. Any psychotropic agent that the patient had been taking was stopped at least 7 days prior to enrollment in the study, and concomitant psychotropic agents were not permitted during the study. Patients were started on two tablets (two IO-mg Prazepam tablets or two placebo tablets) once-aday at bedtime during the first week of treatment. The once-a-day dose was increased by one tablet weekly, unless the patient reported feeling very much better since the onset of the study or there were severe side effects. Each patient was treated for no more than 3 weeks with Prazepam or placebo. The maximum possible daily dose during this 3-week treatment period was four tablets at bedtime (40 mg
PRAZEPAM
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149
of Prazepam or 4 placebo tablets). The patients were required to return all unconsumed tablets at each weekly visit after the first visit. Two psychiatrists evaluated the patients. Each patient was evaluated weekly by the same psychiatrist throughout the study. The following psychiatric forms were completed at the times indicated: (I) intake information, on entering the study; (2) Physician Questionnaire, pretreatment and weekly during the study; (3) Hamilton Anxiety Rating Scale,B pretreatment and weekly during the study; (4) Patient Symptom Checklist,7 56 items (SCL-56) pretreatment and weekly during the study; (5) Profile of Mood States (POMS),” pretreatment and weekly during the study; (6) Doctor Disposition, at the last patient visit. RESULTS
The psychiatric diagnoses of the patients in the study were:
Anxiety neurosis Anxiety neurosis with significant depression Phobic neurosis
Prazepam 19 11 0
Placebo 17 11 1
Twenty-five of 30 patients on Prazepam (83.3%) and 23 of 29 patients on placebo (79.3%) completed the study (3 patients on placebo who did not take any medication during week 3 because they felt no better, but had the psychiatric tests done at the end of week 3 when they returned for reevaluation, were considered completers). The most common daily bedtime dose of Prazepam during the third (last) week of the study was 30 mg. Demography
Seventy percent of the patients were female. The average age was 35.8 years for the patients on Prazepam and 38.3 years for those on placebo. Two-thirds of the patients were married. Fifty-four percent had at least some college education. White collar workers comprised 30% of the patients, skilled and semiskilled workers lo%, housewives 24%, and occupation was not stated in 27%. The difference between the two groups in stated characteristics is within the range of what one would expect from a randomization procedure. No statistically significant differences between the groups were found at baseline. Global Evaluations
The psychiatrist was asked on the PhyDegree of global psychopathology. sician Questionnaire to rate on a scale of 1 (not ill) to 7 (extremely severe), “How ill is this patient now, compared to your experience with other neurotic outpatients?” Pretreatment Moderate Severe
Prazepam 20 (66.7 %) 10 (33.3%)
The degree of global psychopathology the two treatment groups.
pretreatment
Placebo 20 (69.0%) 9 (31.0%) was essentially the same in
GOLDBERG
150
AND
FINNEATY
Treatment Improvement Prazepam Placebo
Week 1 18/30 (0.60)* 9/28 (0.32)*
Ratios Week 2 19/26 (0.73) 12/25 (0.48)
Week 3 20/24 (0.83)* 13/23 (0.57)*
*p < 0.05
The patients on Prazepam had higher improvement ratios (number of patients with reduced global psychopathology ratings divided by the total number of patients evaluated at time indicated) than the patients on placebo at all 3 weeks, and at weeks 1 and 3 the differences were statistically significant (p < 0.05). At each follow-up visit, the psyChange in patient since study onset (Table I). chiatrist and the patient were asked on the Physician Questionnaire to rate on a scale of 1 (very much better) to 7 (very much worse), “How much has patient changed since study onset?” In the psychiatrist’s opinion, at weeks 1,2, and 3, and in the patient’s opinion, at weeks 2 and 3, significantly higher proportions of patients on Prazepam than on placebo were rated as much or very much better since the study onset. At week 1, a significantly-higher proportion of patients on Prazepam than on placebo rated themselves as better since the study onset. Therapeutic effect of study drug. Both the physician and patient evaluations showed that significantly higher proportions of patients on Prazepam had at least a moderate therapeutic effect from their medication, in contrast to those on placebo. Physician Evaluation Prazepam 19 (0.66)* 1 (0.03) 20 (0.69) 9 (0.3 1)
Therapeutic Effect Marked or moderate Minima1 Total showing effect Unchanged or worse
Placebo 8 (0.28)* 5 (0.18) 13 (0.46) 15 (0.54)
Patient Evaluation Drug Helped Very much, much, or moderately A little Total helped Not at all
Prazepam
Placebo
19 (0.66)* 1 (0.03) 20 (0.69) 9 (0.3 1)
7 (0.25)* 6 (0.21) 13 (0.46) 15 (0.54)
*Significant difference between 2 groups.
Physician Questionnaire (PQ)
Fourteen symptoms in the PQ were evaluated. A x2 test of these variables revealed a good balance between the two groups at baseline. All patients had at least moderate anxiety. All the patients on placebo and 93% of the patients on Prazepam had at least moderate tension. Fisher’s exact test showed statistically significant differences favoring
PRAZEPAM
VERSUS
151
PLACEBO
Table 1. Change in Patient Since Study Onset Doctor’sOpinron Week
1
2
3 (0.1 1)’
10
10.33)’
Placebo
Prazepam
4 (0.14)
10 (0.33)
A llttle better
10 (0.36)
11
(0.37)
8 (0.29)
11 (0.37)
Total better (improvement ratio)
13 (0.46)
21 (0.70)
12 (0.43)’
21 (0 70)’
No change or worse
15 (0.54)
9 (0.30)
16 (0.57)
9 (0 30)
7 (0.28)’
15 (0.58)’
7 (0.28)’
15 (0.58)’
Much or very much better A llttle better Total better (improvement ratio)
3
Prazepam
Placebo
Much or very much better
Patient’s Opmmn
9 (0.36)
5 (0.19)
6 (0.241
5(0 19)
16 (0.64)
20 (0.77)
13 (0.52)
20 (0 77)
12 (0.48)
No change or worse
9 (0.36)
6 (0.23)
Much or very much better
7 (0.37)’
18 10.72)’
6 (0.23) 19 (0 761’
6 (0.32)
2 (0 08)
6 (0.27)
1 (0.041
13 (0.69)
20 (0.80)
13 (0.59)
20 (0.80)
6 (0.32)
5 (0.20)
9 (0.411
5 (0.20)
A lIttIe better Total better (improvement ratio)
7 10.32)’
No change or worse
‘Significant difference in improvement ratio between two groups at indicated time (p < 0.05).
Prazepam
over placebo
for the following
symptoms
at the times indicated:
Symptom
Week
Phobia Insomnia Headaches
I, 3 I I
The other PQ symptoms, except hostility at each visit and obsession-compulsion at week 1. showed greater improvement ratios in the Prazepam group than in the placebo group at each interval, but the Prazepam-placebo differences were not statistically significant. Hamilton
Anxiety Rating Scale
The 14 items in the Hamilton Anxiety Rating Scale, which is also completed by the physician, were evaluated. The random assignment of patients to the two groups resulted in a good balance of the variables at baseline, as indicated by a x2 test. On the Hamilton Anxiety Scale, Fisher’s exact test showed statistically significant differences favoring Prazepam over placebo on the following variables at the times indicated: Variable
Week
Anxious mood Fears Depressed mood Autonomic symptoms Cardiovascular symptoms
1, 3 1, 3 3 2 I
The other variables, except genitourinary symptoms, showed greater ment ratios in the Prazepam group than in the placebo group, Prazepam-placebo differences were not statistically significant.
improvebut the
POMS The variables examined in the POMS total mood disturbance, tension-anxiety,
self-report symptom depression-dejection,
rating scale were anger-hostility,
152
GOLDBERG
Table 2.
AND FINNERTY
POMS Sample Size-and Mean Change Week 1
Week 2
Week 3
Sample size Prazepam
30
26
24
Placebo
28
25
23
Mean Change Treatment Score Minus Pretreatment Score Total mood disturbance Prazepam
-33.6’
-46.2’
- 52.5’
Placebo
- 12.3
-29.9’
-34.5’
Prazepam
-7.8’
-10.1’
-11.0'
Placebo
-2.8’
Tension-anxiety - 6.8’
- 7.3’
Depression-dejection
-
Prazepam
-8.9’
Placebo
-4.5’
-8.5’
12.6’
Prazepam
-7.4’
- 10.7’
Placebo
-2.4
- 5.4’
-
14.0’
-
10.3’
Anger-hostility -11.6’ - 7.6’
Vigor-activity Prazepam
1.9
2.1
3.3
Placebo
0.4
2.8
1.4
Fatigue-inertia Prazepam
-2.9’
-4.9’
-6.2’
Placebo
- 1.4
-3.2’
-3.6’
Prazepam
-4.6’
-
-6.3’
Placebo
- 1.6’
-3.3’
Confusion-bewilderment 5.9’
-4.0’
‘Significant change from pretreatment fp < 0.05)
vigor-activity, fatigue-inertia, and confusion-bewilderment. The mean changes of the scores of these variables from the baseline scores at each weekly visit are shown in Table 2. Except for vigor-activity, a greater decrease in score means greater improvement. Statistically significant improvements compared to baseline in all of the factors, except vigor-activity, were achieved by the patients on Prazepam at week, 1, 2, and 3. The patients on placebo also showed statistically significant improvements in the same variables as the patients on Prazepam except that their improvements during week 1 were not significant for total mood disturbance, anger-hostility, and fatigue-inertia. Analyses of covariance showed statistically significant differences between the Prazepam and placebo groups in favor of the Prazepam group in the improvements from baseline of the following variables: total mood disturbance, tensionanxiety, and confusion-bewilderment at week 1 only and anger-hostility at weeks 1,2, and 3. All the other variables, except vigor-activity at week 2, showed greater mean improvements in the Prazepam group than in the placebo group at each visit, but the differences between Prazepam and placebo were not statistically significant. XL-56
Derogatis
Factors (Table 3)
The Derogatis factors of the SCL-56 self-report symptom rating scale that were analyzed were: somatization, obsessive-compulsive behavior, interpersonal
PRAZEPAM
VERSUS
PLACEBO
Table 3.
153
Patient Symptom
Checklist (56 Items): Derogatis
Factors
Week 1
Week 2
Week 3
Prazepam
30
26
24
Placebo
28
25
23
Sample size
Mean Change Treatment Score Minus Pretreatment Score Somatizatlon *
-0.68’
Prazepam
- 0.45’
-0.61
Placebo
-0.15‘
-0
48’
-0.51.
Prazepam
-0.52’
- 0.60’
-0.74’
Placebo
-0.26’
-0.97’
-0.52’
Prazepam
-0.57
-0.85’
-0.83‘
Placebo
-0.28’
-0.46’
-0.51.
Prazepam
-0.55’
-0
-0
Placebo
-0.23’
-037’
Obsessive-compulsive behavior
Interpersonal sensitivity
Depression 72’
80’
-0.49’
Anxiety Prszepam
-0.61
Placebo
-0.38’
*
-0.84’
-0.89’
-0.54’
-0
69’
*Significant change from pretreatment (p < 0.05)
sensitivity, depression, and anxiety. On all of these factors, there were significant improvements from the baseline scores in both the Prazepam and the placebo groups at weeks 1,2, and 3. An analysis of covariance showed statistically significant differences between the Prazepam and placebo groups in favor of the Prazepam group in the improvements on interpersonal sensitivity and depression at weeks 1 and 2. All the other Derogatis factors, except obsessive-compulsive behavior at week 2, showed greater mean improvements in the Prazepam group than in the placebo group at each visit, but the differences between Prazepam and placebo were not statistically significant. Side E&CO Due to the Study Medications
Patients were questioned about side effects listed on the Physician’s Questionnaire. Side effects that arose de novo during treatment or a preexistent symptom that worsened during treatment were included as side effects. The most frequent side effects were drowsiness, 16 on Prazepam, 5 on placebo; dry mouth, 14 Prazepam, 5 placebo; lightheadedness and blurred vision, also higher in the drug group compared to the placebo group. There were no significant changes in the patients’ blood pressures or pulse rates during the study. DISCUSSION
On both the patients’ and psychiatrist’s ratings of global improvement, Prazepam, taken once-a-day at bedtime in doses of 20-40 mg, was significantly better than placebo in these private patients with anxiety symptoms. The patient ratings of global improvement, on which Prazepam was shown to be better than placebo, were (1) the patient’s opinion of how much he or she had changed at each
154
GOLDBERG
AND
FINNERTY
visit since the study onset, and (2) the patient’s evaluation at the end of treatment of how much the study drug helped. The psychiatrist ratings of global improvement, on which Prazepam was shown to be better than placebo, were (1) the psychiatrist’s evaluation of the degree of global psychopathology at each patient visit, (2) the psychiatrist’s opinion of the change in the patient at each visit since the study onset, and (3) the psychiatrist’s evaluation at the end of treatment of the therapeutic effect of the study drug. On the Physician Questionnaire, the Prazepam group showed statistically significant greater improvement ratios than the placebo group on the symptoms of phobia, insomnia, and headaches at some visits. On the Hamilton Anxiety Rating Scale, the patients on Prazepam showed statistically significant higher improvement ratios than those on placebo on the target symptoms anxious mood, fears, depressed mood, autonomic symptoms, and cardiovascular symptoms at various visits in the study. The Prazepam group showed greater improvement than the placebo group on nearly all the other PQ and Hamilton variables, but the Prazepam-placebo differences were not statistically significant. On the self-rating POMS, the Prazepam group showed statistically significant greater mean improvements from the baseline than the placebo group at 1 week on total mood disturbance, tension-anxiety, and confusion-bewilderment and at 1, 2, and 3 weeks on anger-hostility. This study’s findings that most drug-placebo differences on symptom items or clusters occur in the first week or two is shared by a number of other studies with other benzodiazepines; significant drug-placebo differences are usually shown to be present early in the trial, but then diminish or disappear as the study continues for several weeks. The probable explanation for this observation is the intermittent nature of the anxiety symptoms in patients with situational anxiety and the tendency to recovery, which occurs both in the drug- and placebo-treated groups.g On the self-rating SCL-56, the Derogatis factors interpersonal sensitivity and depression at 1 and 2 weeks showed significantly greater mean improvements in the Prazepam group than in the placebo group. Over 90% of the patients in this study were rated by the psychiatrists on the Physician Questionnaire and Hamilton Anxiety Rating Scale as having some degree of depressive mood accompanying their anxiety. Some degree of depression is quite common in patients with anxiety neurosis, and with improvement in their anxiety, there is concomitant improvement in their depressive mood. The patients on Prazepam showed greater improvement than those on placebo on nearly all the other mood states of the POMS and SCL-56 Derogatis factors, but the Prazepam-placebo differences were not statistically significant. Statistical significance in favor of Prazepam might have been attained for some of these variables if a larger number of patients had been in the study.
CONCLUSION
In this double-blind placebo-controlled study in anxious private outpatients, the data indicate that Prazepam, taken orally once-a-day at bedtime in doses of 20-40 mg, is effective in relieving symptoms of anxiety.
PRAZEPAM
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PLACEBO
REFERENCES I. Weir JH: Prazepam Clinical Morris Plains, NJ, Warner-Lambert Institute, 1975 2. Viau JP, Epps JE, DiCarlo
Summary. Research FJ: Prazepam
metabolism after chronic administration to humans. Xenobiotica 3:58ll587, 1973 3. Cohen AB: Unpublished study. Morris Plains, NJ, Warner-Lambert Research Institute, RR No. 934-0037, 1972 4. Brauzer B: Evaluation of single daily doseof Prazepam for relief of anxiety. Unpublished article. 5. Rickels K, Sablosky L, Silverman H, et al: Prazepam in anxiety: A controlled Compr Psychiatry (in press)
clinical
trial.
6. Hamilton M: The assessment of anxiety states by rating. Br J Med Psycho1 32:50-55. 1959 7. Lipman RS, Cole JO, Park LC, et al: Sensitivity of symptoms and nonsymptoms -Focused criteria of outpatient drug efficacy. Am J Psychiatry 12?:24-27. 1965 8. McNair DN, Lorr M: An analysis of mood in neurotics. J Abnorm Sot Psycho1 69:620 627, 1964 9. Greenblatt in Clinical 1974. p 74
DJ, Shader
Practice.
New
RI: Benzodiazepines York.
Raven
Press.
P
RAZEPAM (@Verstran, Warner-Chilcott.) is a new benzodiazepine tranquilizer that differs from diazepam only by a cyclopropyl group (Fig. 1). In 15 double-blind placebo-controlled studies with the same protocol, all the data were pooled to evaluate the efficacy of Prazepam administered on a T.I.D. schedule in the treatment of anxiety. On final global evaluations and for the target symptom of anxiety in 432 patients treated with Prazepam and 346 on placebo, improvement in both spheres was significant for patients with anxiety as their primary diagnosis. In addition, the Prazepam group always fared better than the placebotreated group, regardless of pretreatment symptom severity.’ In summarizing the results of the self-administered rating scales in 8 of the 15 studies, several scales did demonstrate between-group differences on 1 or a few factors, but usually did not differentiate between treatments on most of the factors of the scale. After 7 days of Prazepam, 10 mg t.i.d. administered orally to healthy men, ‘*CPrazepam (10 mg) was administered orally on the eighth day. The half-life for total radioactivity in the plasma was 70 + 10 hr.” This long half-life suggested that once-a-day dosage of Prazepam would probably be effective. A double-blind randomized, tolerance study of single daily bedtime doses of Prazepam, 30,40,50, and 60 mg, and placebo administered orally for 2 weeks was done in normal male volunteers .3 All doses were well tolerated with morning drowsiness occurring more frequently in those taking Prazepam than those taking placebo, but not severe at any dose. In a recent well controlled study, Brauzer4 studied single daily bedtime doses of Prazepam for relief of anxiety in 132 symptomatic volunteers with target symptoms of anxiety of at least moderate severity. This was a double-blind study with patients randomly assigned to three treatment groups; one received 40 mg Prazepam, another 60 mg Prazepam, and another placebo for 4 weeks. The two Prazepam groups, 40 mg and 60 mg, produced generally similar results. Patients on Prazepam, 40 and 60 mg, did significantly better than those on placebo on ratings of global improvement or measured by the psychiatrist’s evaluation of global psychopathology, change in patient since the study onset rated separately by the psychiatrist and patient, and the therapeutic effect of the drug rated separately by the psychiatrist and the patient. On the profile of mood states (POMS) and SCL-56, there were significant From the Outpatient Psychopharmacology Research Group, West-Ros-Park Mental Health Cenrer, Hyde Park. Mass. H. L. Goldberg, M.D.: Director. West-Ros-Park Mental Health Center and Co-Director. Outpatient Psychopharmacology Research Group: R. J. Finnerty. Ph.D.: Co-Director. Outpatienr PSTchopharmacology Research Group. Reprint requests should be addressed to H. L. Goldberg, M.D., West-Ros-Park Mental Health Center. 26 Central Avenue, Hyde Park, Mass. 02136. 1~1 1977 by Grune & Stratton. Inc. Comprehensive Psychiatry, Vol. 18. No. 2 (March/April), 1977
147
148
GOLDBERG
Diazepam
Prazepam Fig. 1.
Comparison
AND FINNERTY
of chemical structure of Prazepam and Diazepam.
improvements in mean scores for anxiety and depression for patients in all three groups, but there were no significant differences between any two groups on these two symptoms. It is interesting to note that the anger-hostility (POMS), and the interpersonal/sensitivity (SCL) factors showed statistically significant greater mean decreases in the placebo group than in the two Prazepam groups during the first 3 weeks of the study. The fatigue/inertia factor of the POMS also showed significant differences in favor of placebo, as well as the obsessive/compulsive factor on the XL at week 1 and 2. In another well controlled study, Rickels5 studied 97 patients in a design very similar to Brauzer’s. The study lasted 4 weeks, and patients were seen every 2 weeks. Patients on Prazepam, 40 mg and 60 mg, did significantly better than those on placebo on ratings of global improvement by the physician, on global psychopathology, change in patient since study onset, and the therapeutic effect of the drug. Significant differences in favor of Prazepam over placebo were also seen on Physician’s Questionnaire Emotional and Somatic cluster total scores and on the Emotional and Somatic clusters of the Hamilton Anxiety Scale. On the SCL-56, both drug groups were combined because of the small numbers in each group. The only factor showing improvement was the anxiety cluster at 2 weeks in favor of Prazepam. MATERIALS
AND METHODS
The purpose of this study was to evaluate the efficacy of a once-a-day bedtime dose of Prazepam for the treatment of anxiety. The patients were anxious private outpatients who were considered acceptable for entrance into the study according to the normal inclusion and exclusion criteria one would follow for benzodiazepinetype medications. Of 59 patients who were entered into the study, 30 were assigned to Prazepam and 29 to placebo, according to a double-blind randomization procedure. Any psychotropic agent that the patient had been taking was stopped at least 7 days prior to enrollment in the study, and concomitant psychotropic agents were not permitted during the study. Patients were started on two tablets (two IO-mg Prazepam tablets or two placebo tablets) once-aday at bedtime during the first week of treatment. The once-a-day dose was increased by one tablet weekly, unless the patient reported feeling very much better since the onset of the study or there were severe side effects. Each patient was treated for no more than 3 weeks with Prazepam or placebo. The maximum possible daily dose during this 3-week treatment period was four tablets at bedtime (40 mg
PRAZEPAM
VERSUS
PLACEBO
149
of Prazepam or 4 placebo tablets). The patients were required to return all unconsumed tablets at each weekly visit after the first visit. Two psychiatrists evaluated the patients. Each patient was evaluated weekly by the same psychiatrist throughout the study. The following psychiatric forms were completed at the times indicated: (I) intake information, on entering the study; (2) Physician Questionnaire, pretreatment and weekly during the study; (3) Hamilton Anxiety Rating Scale,B pretreatment and weekly during the study; (4) Patient Symptom Checklist,7 56 items (SCL-56) pretreatment and weekly during the study; (5) Profile of Mood States (POMS),” pretreatment and weekly during the study; (6) Doctor Disposition, at the last patient visit. RESULTS
The psychiatric diagnoses of the patients in the study were:
Anxiety neurosis Anxiety neurosis with significant depression Phobic neurosis
Prazepam 19 11 0
Placebo 17 11 1
Twenty-five of 30 patients on Prazepam (83.3%) and 23 of 29 patients on placebo (79.3%) completed the study (3 patients on placebo who did not take any medication during week 3 because they felt no better, but had the psychiatric tests done at the end of week 3 when they returned for reevaluation, were considered completers). The most common daily bedtime dose of Prazepam during the third (last) week of the study was 30 mg. Demography
Seventy percent of the patients were female. The average age was 35.8 years for the patients on Prazepam and 38.3 years for those on placebo. Two-thirds of the patients were married. Fifty-four percent had at least some college education. White collar workers comprised 30% of the patients, skilled and semiskilled workers lo%, housewives 24%, and occupation was not stated in 27%. The difference between the two groups in stated characteristics is within the range of what one would expect from a randomization procedure. No statistically significant differences between the groups were found at baseline. Global Evaluations
The psychiatrist was asked on the PhyDegree of global psychopathology. sician Questionnaire to rate on a scale of 1 (not ill) to 7 (extremely severe), “How ill is this patient now, compared to your experience with other neurotic outpatients?” Pretreatment Moderate Severe
Prazepam 20 (66.7 %) 10 (33.3%)
The degree of global psychopathology the two treatment groups.
pretreatment
Placebo 20 (69.0%) 9 (31.0%) was essentially the same in
GOLDBERG
150
AND
FINNEATY
Treatment Improvement Prazepam Placebo
Week 1 18/30 (0.60)* 9/28 (0.32)*
Ratios Week 2 19/26 (0.73) 12/25 (0.48)
Week 3 20/24 (0.83)* 13/23 (0.57)*
*p < 0.05
The patients on Prazepam had higher improvement ratios (number of patients with reduced global psychopathology ratings divided by the total number of patients evaluated at time indicated) than the patients on placebo at all 3 weeks, and at weeks 1 and 3 the differences were statistically significant (p < 0.05). At each follow-up visit, the psyChange in patient since study onset (Table I). chiatrist and the patient were asked on the Physician Questionnaire to rate on a scale of 1 (very much better) to 7 (very much worse), “How much has patient changed since study onset?” In the psychiatrist’s opinion, at weeks 1,2, and 3, and in the patient’s opinion, at weeks 2 and 3, significantly higher proportions of patients on Prazepam than on placebo were rated as much or very much better since the study onset. At week 1, a significantly-higher proportion of patients on Prazepam than on placebo rated themselves as better since the study onset. Therapeutic effect of study drug. Both the physician and patient evaluations showed that significantly higher proportions of patients on Prazepam had at least a moderate therapeutic effect from their medication, in contrast to those on placebo. Physician Evaluation Prazepam 19 (0.66)* 1 (0.03) 20 (0.69) 9 (0.3 1)
Therapeutic Effect Marked or moderate Minima1 Total showing effect Unchanged or worse
Placebo 8 (0.28)* 5 (0.18) 13 (0.46) 15 (0.54)
Patient Evaluation Drug Helped Very much, much, or moderately A little Total helped Not at all
Prazepam
Placebo
19 (0.66)* 1 (0.03) 20 (0.69) 9 (0.3 1)
7 (0.25)* 6 (0.21) 13 (0.46) 15 (0.54)
*Significant difference between 2 groups.
Physician Questionnaire (PQ)
Fourteen symptoms in the PQ were evaluated. A x2 test of these variables revealed a good balance between the two groups at baseline. All patients had at least moderate anxiety. All the patients on placebo and 93% of the patients on Prazepam had at least moderate tension. Fisher’s exact test showed statistically significant differences favoring
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Table 1. Change in Patient Since Study Onset Doctor’sOpinron Week
1
2
3 (0.1 1)’
10
10.33)’
Placebo
Prazepam
4 (0.14)
10 (0.33)
A llttle better
10 (0.36)
11
(0.37)
8 (0.29)
11 (0.37)
Total better (improvement ratio)
13 (0.46)
21 (0.70)
12 (0.43)’
21 (0 70)’
No change or worse
15 (0.54)
9 (0.30)
16 (0.57)
9 (0 30)
7 (0.28)’
15 (0.58)’
7 (0.28)’
15 (0.58)’
Much or very much better A llttle better Total better (improvement ratio)
3
Prazepam
Placebo
Much or very much better
Patient’s Opmmn
9 (0.36)
5 (0.19)
6 (0.241
5(0 19)
16 (0.64)
20 (0.77)
13 (0.52)
20 (0 77)
12 (0.48)
No change or worse
9 (0.36)
6 (0.23)
Much or very much better
7 (0.37)’
18 10.72)’
6 (0.23) 19 (0 761’
6 (0.32)
2 (0 08)
6 (0.27)
1 (0.041
13 (0.69)
20 (0.80)
13 (0.59)
20 (0.80)
6 (0.32)
5 (0.20)
9 (0.411
5 (0.20)
A lIttIe better Total better (improvement ratio)
7 10.32)’
No change or worse
‘Significant difference in improvement ratio between two groups at indicated time (p < 0.05).
Prazepam
over placebo
for the following
symptoms
at the times indicated:
Symptom
Week
Phobia Insomnia Headaches
I, 3 I I
The other PQ symptoms, except hostility at each visit and obsession-compulsion at week 1. showed greater improvement ratios in the Prazepam group than in the placebo group at each interval, but the Prazepam-placebo differences were not statistically significant. Hamilton
Anxiety Rating Scale
The 14 items in the Hamilton Anxiety Rating Scale, which is also completed by the physician, were evaluated. The random assignment of patients to the two groups resulted in a good balance of the variables at baseline, as indicated by a x2 test. On the Hamilton Anxiety Scale, Fisher’s exact test showed statistically significant differences favoring Prazepam over placebo on the following variables at the times indicated: Variable
Week
Anxious mood Fears Depressed mood Autonomic symptoms Cardiovascular symptoms
1, 3 1, 3 3 2 I
The other variables, except genitourinary symptoms, showed greater ment ratios in the Prazepam group than in the placebo group, Prazepam-placebo differences were not statistically significant.
improvebut the
POMS The variables examined in the POMS total mood disturbance, tension-anxiety,
self-report symptom depression-dejection,
rating scale were anger-hostility,
152
GOLDBERG
Table 2.
AND FINNERTY
POMS Sample Size-and Mean Change Week 1
Week 2
Week 3
Sample size Prazepam
30
26
24
Placebo
28
25
23
Mean Change Treatment Score Minus Pretreatment Score Total mood disturbance Prazepam
-33.6’
-46.2’
- 52.5’
Placebo
- 12.3
-29.9’
-34.5’
Prazepam
-7.8’
-10.1’
-11.0'
Placebo
-2.8’
Tension-anxiety - 6.8’
- 7.3’
Depression-dejection
-
Prazepam
-8.9’
Placebo
-4.5’
-8.5’
12.6’
Prazepam
-7.4’
- 10.7’
Placebo
-2.4
- 5.4’
-
14.0’
-
10.3’
Anger-hostility -11.6’ - 7.6’
Vigor-activity Prazepam
1.9
2.1
3.3
Placebo
0.4
2.8
1.4
Fatigue-inertia Prazepam
-2.9’
-4.9’
-6.2’
Placebo
- 1.4
-3.2’
-3.6’
Prazepam
-4.6’
-
-6.3’
Placebo
- 1.6’
-3.3’
Confusion-bewilderment 5.9’
-4.0’
‘Significant change from pretreatment fp < 0.05)
vigor-activity, fatigue-inertia, and confusion-bewilderment. The mean changes of the scores of these variables from the baseline scores at each weekly visit are shown in Table 2. Except for vigor-activity, a greater decrease in score means greater improvement. Statistically significant improvements compared to baseline in all of the factors, except vigor-activity, were achieved by the patients on Prazepam at week, 1, 2, and 3. The patients on placebo also showed statistically significant improvements in the same variables as the patients on Prazepam except that their improvements during week 1 were not significant for total mood disturbance, anger-hostility, and fatigue-inertia. Analyses of covariance showed statistically significant differences between the Prazepam and placebo groups in favor of the Prazepam group in the improvements from baseline of the following variables: total mood disturbance, tensionanxiety, and confusion-bewilderment at week 1 only and anger-hostility at weeks 1,2, and 3. All the other variables, except vigor-activity at week 2, showed greater mean improvements in the Prazepam group than in the placebo group at each visit, but the differences between Prazepam and placebo were not statistically significant. XL-56
Derogatis
Factors (Table 3)
The Derogatis factors of the SCL-56 self-report symptom rating scale that were analyzed were: somatization, obsessive-compulsive behavior, interpersonal
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Table 3.
153
Patient Symptom
Checklist (56 Items): Derogatis
Factors
Week 1
Week 2
Week 3
Prazepam
30
26
24
Placebo
28
25
23
Sample size
Mean Change Treatment Score Minus Pretreatment Score Somatizatlon *
-0.68’
Prazepam
- 0.45’
-0.61
Placebo
-0.15‘
-0
48’
-0.51.
Prazepam
-0.52’
- 0.60’
-0.74’
Placebo
-0.26’
-0.97’
-0.52’
Prazepam
-0.57
-0.85’
-0.83‘
Placebo
-0.28’
-0.46’
-0.51.
Prazepam
-0.55’
-0
-0
Placebo
-0.23’
-037’
Obsessive-compulsive behavior
Interpersonal sensitivity
Depression 72’
80’
-0.49’
Anxiety Prszepam
-0.61
Placebo
-0.38’
*
-0.84’
-0.89’
-0.54’
-0
69’
*Significant change from pretreatment (p < 0.05)
sensitivity, depression, and anxiety. On all of these factors, there were significant improvements from the baseline scores in both the Prazepam and the placebo groups at weeks 1,2, and 3. An analysis of covariance showed statistically significant differences between the Prazepam and placebo groups in favor of the Prazepam group in the improvements on interpersonal sensitivity and depression at weeks 1 and 2. All the other Derogatis factors, except obsessive-compulsive behavior at week 2, showed greater mean improvements in the Prazepam group than in the placebo group at each visit, but the differences between Prazepam and placebo were not statistically significant. Side E&CO Due to the Study Medications
Patients were questioned about side effects listed on the Physician’s Questionnaire. Side effects that arose de novo during treatment or a preexistent symptom that worsened during treatment were included as side effects. The most frequent side effects were drowsiness, 16 on Prazepam, 5 on placebo; dry mouth, 14 Prazepam, 5 placebo; lightheadedness and blurred vision, also higher in the drug group compared to the placebo group. There were no significant changes in the patients’ blood pressures or pulse rates during the study. DISCUSSION
On both the patients’ and psychiatrist’s ratings of global improvement, Prazepam, taken once-a-day at bedtime in doses of 20-40 mg, was significantly better than placebo in these private patients with anxiety symptoms. The patient ratings of global improvement, on which Prazepam was shown to be better than placebo, were (1) the patient’s opinion of how much he or she had changed at each
154
GOLDBERG
AND
FINNERTY
visit since the study onset, and (2) the patient’s evaluation at the end of treatment of how much the study drug helped. The psychiatrist ratings of global improvement, on which Prazepam was shown to be better than placebo, were (1) the psychiatrist’s evaluation of the degree of global psychopathology at each patient visit, (2) the psychiatrist’s opinion of the change in the patient at each visit since the study onset, and (3) the psychiatrist’s evaluation at the end of treatment of the therapeutic effect of the study drug. On the Physician Questionnaire, the Prazepam group showed statistically significant greater improvement ratios than the placebo group on the symptoms of phobia, insomnia, and headaches at some visits. On the Hamilton Anxiety Rating Scale, the patients on Prazepam showed statistically significant higher improvement ratios than those on placebo on the target symptoms anxious mood, fears, depressed mood, autonomic symptoms, and cardiovascular symptoms at various visits in the study. The Prazepam group showed greater improvement than the placebo group on nearly all the other PQ and Hamilton variables, but the Prazepam-placebo differences were not statistically significant. On the self-rating POMS, the Prazepam group showed statistically significant greater mean improvements from the baseline than the placebo group at 1 week on total mood disturbance, tension-anxiety, and confusion-bewilderment and at 1, 2, and 3 weeks on anger-hostility. This study’s findings that most drug-placebo differences on symptom items or clusters occur in the first week or two is shared by a number of other studies with other benzodiazepines; significant drug-placebo differences are usually shown to be present early in the trial, but then diminish or disappear as the study continues for several weeks. The probable explanation for this observation is the intermittent nature of the anxiety symptoms in patients with situational anxiety and the tendency to recovery, which occurs both in the drug- and placebo-treated groups.g On the self-rating SCL-56, the Derogatis factors interpersonal sensitivity and depression at 1 and 2 weeks showed significantly greater mean improvements in the Prazepam group than in the placebo group. Over 90% of the patients in this study were rated by the psychiatrists on the Physician Questionnaire and Hamilton Anxiety Rating Scale as having some degree of depressive mood accompanying their anxiety. Some degree of depression is quite common in patients with anxiety neurosis, and with improvement in their anxiety, there is concomitant improvement in their depressive mood. The patients on Prazepam showed greater improvement than those on placebo on nearly all the other mood states of the POMS and SCL-56 Derogatis factors, but the Prazepam-placebo differences were not statistically significant. Statistical significance in favor of Prazepam might have been attained for some of these variables if a larger number of patients had been in the study.
CONCLUSION
In this double-blind placebo-controlled study in anxious private outpatients, the data indicate that Prazepam, taken orally once-a-day at bedtime in doses of 20-40 mg, is effective in relieving symptoms of anxiety.
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