Propranolol in the Treatment of Anxiety Neurosis Vasantkumar
T. Tanna,
R. Paul Penningroth,
and Robert F. Woolson
B
ETA-ADRENERGIC BLOCKING AGENTS have been found useful in the treatment of diverse anxiety states: anxiety neurosis ;I-’ public speaking; 7 “exam nerves”;s use of LSD;g anxiety and tension states of chronic alcoholics;‘“,” anxiety of schizophrenics;12 tension state in the withdrawal syndrome of alcoholism;‘3 etc. Unsatisfactory clinical classification of anxiety states, however, in addition to variation in drug, dose, design and assessment technique, makes comparative evaluation of reported studies difficult. In general, somatic symptoms such as tachycardia, palpitations, and tremulousness seem to respond better than psychic symptoms like fears, worry, tension, irritability, difficulty in concentrating.1,4.5 But some studies do report improvement in psychic symptoms as well.3,“’ Anxiety may be considered to be 1) primary when it occurs in the relatively well-defined syndrome of anxiety neurosis, or 2) secondary when it occurs in situational settings such as examinations or public speaking, or in the course of other preexisting psychiatric illnesses such as depression or alcoholism. The focus of the present article is anxiety neurosis. Most previous studies dealing with primary anxiety states or anxiety neurosis have not used rigorous definition or explicit criteria for the diagnosis or selection of the patients. The duration of symptoms in the same study in many instances has ranged widely, suggesting inclusion of both acute and chronic patients. Moreover, no study has compared different doses of the same agent. We present in this article a double-blind controlled study of therapeutic efficacy of two different doses of the beta-adrenergic blocking agent propranolol (Inderal) in moderately to severely ill chronic anxiety neurotic patients selected according to rigorous and specific criteria. MATERIALS
AND
METHODS
Outpatients and inpatients between the ages of 20 and 55 attending Linn County Psychiatric Clinic, Cedar Rapids, Iowa, and psychiatric facilities of the University of Iowa Medical Center, Iowa City, Iowa, with a primary diagnosis of chronic anxiety neurosis were considered for the trial. Patients were selected according to the criteria for anxiety neurosis outlined by Pitts and McClure,‘4 and Wheeler et al.,15 which closely agree with the rigorous research criteria developed by Feighner et al.16 Informed consent, after full explanation of the objective and the nature of procedures, was obtained from all patients accepted in the study. All patients received a standard psychiatric interview to establish the diagnosis as well as presence or absence of specific symptoms. To be accepted in the study, a patient had to meet each of the following four criteria: A) To have had severe feelings of tenseness or free-
Propranolol (Inderal) and placebo were supplied by Ayerst Laboratories. From the Departments of Psychiatr.v and Preventive Medicine and Environmental Health, University of Iowa College of Medicine, and Veterans Adminisrration Hospital, Iowa City, Iowa. Vasantkumar L. Tanna, M.D.: Assistanf Professor, Department of Psychiatry, University ofIowa College of Medicine, Staff Psychiatrist, Iowa City VA Hospital; Robert F. Woolson, Ph.D.: Assistant Professor, Department of Preventive Medicine and Environmental Health, University of Iowa College of Medicine; R. Paul Penningroth, M.D.: Clinical Assistant Professor, Department of Psychiatry, University of Iowa College of Medicine, and Director, Linn County Psychiatric Clinic, Cedar Rapids, Iowa. Reprint requests should be addressed to Dr. Tanna, VA Hospital, Iowa City, Iowa, 52240. fc 1977 by Grune & Strarron. Inc.
Comprehensive
Psychiatry,
Vol 18, No. 4 (July/August), 1977
319
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TANNA,
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AND WOOLSON
Table 1. Previous Hospitalizations Numberof Hospitalizations
Numberof Patients 11 7 4 4 2 Total
28
floating anxiety nearly daily for at least two years. B) Must have had frequent anxiety attacks manifested by apprehension, fearfulness, or sense of impending doom, and during the majority of the anxiety attacks the following symptoms must be present: I) at least two of the following: dyspnea, smothering, sighing, chest discomfort or chestpain, and lump in throat; 2) at least three of the following: dizziness or giddiness, faintness, weakness, fatigue, inner shakiness, tremor, paresthesias, vascular throbbing, and palpitations. C) Aside from anxiety attacks, must have had at least IO of the following I6 symptoms: headache, dizziness, blurred vision, dyspnea, sighing, tiredness, easy fatigueability. paresthesias, depressed mood, trembling, shakiness, weakness, fears, initial insomnia, chest pain, and palpitations. D) The onset of the syndrome must have been before the age of 40. Patients with schizophrenia, organic brain syndrome, primary affective illness, asthma, cardiac disease, and pregnancy were excluded. Of the 30 patients that began the study, 2 dropped out (this will be discussed later) so that 28 patients, I3 male and 15 female, completed the study. Depressive (I4 patients), phobic (15), and obsessive-compulsive (16) features were common. A few of the patients showed hysterical (2). antisocial (2), and alcoholic (3) traits. In 4 patients possibility of schizophrenia was raised based on replies to screening questions for schizophrenia, but was satisfactorily ruled out on further investigation of their history and clinical picture. Twenty-two were outpatients and six were inpatients. The mean age at admission to the study was 34.3 years and the mean age at onset of the illness was 22.1 years. In 8 patients the duration of illness was 2-3 years, in 7 patients 4410 years, and in I3 the illness had been present for more than IO years. Table I shows the number of previous hospitalizations. In general, few of the patients had derived lasting benefit from prior treatments, including benzodiazepines. Each patient was randomly assigned to one of two groups in which the sequence of drug and placebo administered differed. The drug or an identical appearing placebo were given orally in four divided doses. The I4 patients in group A were drug-free the first week, received 40 mg/day of propranolol the second week, placebo the third week, and 120 mg/day of propranolol the fourth week. The I4 patients in group B were drug-free the first week, received 120 mg/day of propranolol the second week, 40 mg/day of propranolol the third week, and placebo the fourth week. Patients were assessed by selfreport on a weekly basis at the end of each one week trial period. Assessment was by interview rating of the following I7 symptoms on a five point scale indicating the severity of the symptoms: headache, dizziness, blurred vision, dyspnea, sighing, tiredness, easy fatigueability, paresthesias, depressed mood, chest pain, palpitations, and tension or trembling, shakiness, weakness, fears, initial insomnia, nervousness. The five point scale was: O-not experienced; l-just noticeable (in ordinary circumstances); 2-definite but not uncomfortable; 3-definite and quite uncomfortable; &intolerable or severe enough for medical consultation in ordinary circumstances.
Statistical
Analysis
The standard statistical model for a cross-over design is assumed to be an adequate representation for each symptom.” Specifically, an observed score for a symptom is an additive model with a grand mean, a week effect, the direct effect of the treatment received during the week, the residual effect of the treatment received the previous week, and the random effects of the patient and the error in the measurement of the response. Only two of the six possible sequences of ordering the doses have been studied in this trial, thus it is clear that one dose is absent for each of the treatment weeks. It would require all six sequences (viz. two 3 x 3 latin square arrangements) to have a balanced design with regard to the residual effects of treatments on the observed scores the following week. This lack of balance in our design and the absence of one treatment each week indicates that certain parameters in the
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assumed cross-over model are not statistically estimable. These facts make it unreasonable to analyze the data as an aggregate in a single linear statistical model as certain untestable assumptions regarding the week and the residual effects would be required to perform the analysis. We propose instead performing an analysis of the 17 symptoms at each time point separately. AS the symptoms may be expected to be correlated and the data may not be assumed to be normal, a nonparametric multivariate comparison of the two groups is performed at each time point. We proceed by first comparing the two groups during the drug-free period by applying the multivariate Wilcoxon statistic of Puri and Sen’* to the 17 symptoms, then eliminate those symptoms which yield a significant group difference. By a trivial extension of Koch’s” model to this design. we observe that the only residual effects which we can test are the residual effects of placebo and 120 mg; this test is performed
by
summing the scores
for each patient across the three weeks for each symptom separately, then applying the same rank order statistic to these sums to compare the two sequence groups. This comparison is a test for equality
of the two previously
symptoms which are significantly yield a group difference
during the drug-free
plied to the resulting symptoms carry-over
different
mentioned
residual effects. This is repeated
are eliminated.
Having eliminated
after
those
those symptoms which
period or in residual effects, the rank order tests are ap-
at each specific time point; these comparisons
effect (assuming the residual effect of 40 mg is intermediate
would be free of an)
between placebo and 120 mg).
and time effect. We may lose power with this procedure but the risk of bias is minimized. All test statistics are compared
to their appropriate
asymptotic
chi-square
distribution
for signifi-
cance.‘” RESULTS
A difference between the two sequences (groups A and B) was detected in the drug-free period with respect to dyspnea and depressed mood (XI of 9.75and 4.00. respectively). Carry-over effects (i.e., the residual effects of a treatment in a given week on the observed scores of the following week) of 120 mg and placebo differed with regard to tension (X: of 3.84); hence this symptom, dyspnea, and depressed mood were eliminated from the remaining analyses. Comparing the two sequences during the drug-free period, there is no overall difference (X:a = 10.67), nor is there a difference detected on any of the fourteen symptoms (all individual chi-squares less than 1.13). Thus, the groups were initially comparable on these 14 symptoms. Examining the carry-over effects of Table
2.
of Mean
Mean
Symptom
Difference’
Scores
by Treatment
and
Standard
and
Treatment
Error Week
Week 1 Tri?atmC?llt Symptom
40 mg
120mg
Week 3
Week 2 Treatment SE
Placebo
40mg
Treatment SE
120 mg
Placebo
12
1.9
S E 50
9 6 1 1 1.8 14 11 1 .o 13 1.3 16 IO 14 9
13 9 1.4 25 19 1.1 1.7 24 1.7 1.6 21 .6 1.5
46 38 41 33 49 42 49 49 49 44 57 47 49
Headache
16
1.4
4%
Dizziness Blurred Vision
1.2 1.2
1.6 IO 1.2 23 1.8 1 .o .a 1.8 2.0 1.8 1.6 .7 2.6
45 46 38 42 .45 46 .39 .44 .44 .50 .57 42 43
SIghrIg
1.4
Tiredness Easy Fatigue Paresthesias Tremblmg Shakmess Weakness Fears lnsomma Chest Pain Palpitations
2.1 17 1.1 16 1.6 1.6 17 1.2 11 1.2
‘Standard
22
2.0
17 1.4 15 2.5 2.2 16 17 2.3 1.6 1.9 11 .9 1.4
1.5 11 1.4 28 21 .9 1.4 25 2.3 20 1.9 8 1.6
53
45 .47 42 .33 .47 .49 .49 41 .46 .43 .52 .51 50
error computed from wlthtn group vanance for each symptom
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AND WOOLSON
Table 3. Overall Mean Symptom Scores and Their Standard
Symptoms
Errors for Each Treatment
Drug Free
Placebo
40 mg
120mg
Headache
2.1 1 t.25)
2.07 l.26)
1.82 l.26)
1.32 t.22)
Dizziness
2.14 1.23)
1.50 L22)
1.36 t.24)
1.29 t.221 0.82 L2 1)
Blurred Vision
1.36 1.20)
1.141.23)
1.14 (.22)
Sighing
1.61 t.14)
1.43 (.22)
1.39 (.17)
1 .18 t.20)
Tiredness
2.79 (.I 8)
2.50 t.17)
2.43 t.18)
2.04 1.20)
Easy Fatigue
2.32 t.18)
2.07 t.24)
1.93 1.24)
1.61 1.23)
Paresthesias
1.46 t.24)
1.32 L231
1.04 t.241
1.04 (‘21)
Depression
2.43 f.23)
1.89 f.28)
1.71 t.25)
1.61 t.23)
Trembling
2.25 t.20)
1.71 i.26)
1.50 t.23)
0.89 t.18)
Shakiness
2.71 C.15)
2.32 t.24)
2.04 t.20)
1.54 t.24)
Weakness
2.50 t.12)
1.64 1.24)
1.93 1.22)
1.64 t.24)
Fears
2 36 f.19)
1.75 L21)
1.86 C.22)
1.7 1 t.24)
Chest Pain
2 07 t.25)
0.75 L21)
0.93 t.25)
1.07 t.25)
Palpitations
2.18 t.23)
1.46 L25)
1.39 (.22)
0.96 1.23)
120 mg and placebo there was also no evidence of a difference in these two effects (see Table 4, column 4). Hence, assuming the residual effect of 40 mg is between the placebo and 120, we conclude that all residual effects are equal for these 14 symptoms. In Table 2, mean scores for each symptom by treatment and treatment week are summarized along with the standard error of the mean difference between groups. Summary mean scores across all time points for each treatment are also summarized in Table 3. In Table 4, the results of the multivariate nonparametric analyses are summarized. It is noteworthy that the two sequence groups differ significantly with regard to the entire set of symptoms at each time point using the large sample chi-square test. The difference at time 1 and at time 2 in which we Table 4.
Mean Rank Sumst
Multivariate
Symptom
and Nonparametric
Test Statistics by Treatment
Week 1 140t “S 1201
Week 2 (Pt “540)
Week Week 3 1120t
“SP)
Carry-over Effects
-
Headache
15.0
15.5
12.5
Dizziness
13.1
15.2
13.5
13.6
Blurred Vision
15.2
15.6
13.6
15.1
Sighing
15.1
14.7
13.4
14.7
Tiredness
13.5
13.5
11.7‘
12.4
Easy Fatigue
14.6
14.6
12.9
14.0
Paresthesias
14.4
16.2
14.0
15.7
Trembling
16.9
15.3
12.5
14.7
Shakiness
14.0
145
11.4’
13.0
Weakness
13.2
12.4
13.0
12.5
Fears
14.4
14.0
14.7
14.2
Insomnia
13.5
11.9
11.7’
12.2
Chest Pain
15.7
15.2
16.4
15.4
Palpitations
15.0
14.1
12.4
19.8
Multivariate Trace Statistic
42.8
32.2
29.6
19.2
Multivariate P (Asymptotic X2 (14)) -
14.7
.0002
.0044
*Significant at 0.05 using unwariate test.t Mean Rank sum for sequence A
.0094
.1610
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PROPRANOLOL
have 40 mg vs 120 mg and placebo vs 40 mg, respectively, are in favor of no particular treatment. Specifically, at time 1 40 mg has a higher mean rank for seven of the symptoms, and 120 mg is higher for the remaining seven; while at time 2, placebo has a mean rank higher than 40 mg for 8 of the 14 symptoms. Thus, an overall statistical difference has been determined but the direction is clearly not in favor of one or the other treatment at either of these two times. None of the univariate rank order tests are significant for week 1 or 2. At week 3, an overall statistical difference is found; however, with the exception of two of the symptoms (fears and chest pain) the direction of the difference is in favor of a lower mean rank sum for the 120 mg for all symptoms. Univariate differences are detected for tiredness, shakiness and initial insomnia. As the mean rank sum for each of these three is lower for 120 mg as compared to placebo this is suggestive of efficacy for the 120 mg regimen. It is also of interest to note that the mean scores for each symptom (Table 3) show a trend in reduction of severity with higher doses of propranolol. DISCUSSION
Within the limitations of our design, our results show that propranolol is effective in the treatment of chronic severe anxiety neurosis defined according to rigorous and specific criteria. The 14 symptoms of anxiety neurosis tested showed, at week 3, a significant difference (p < 0.01) in intensity with 120 mg of propranolol as compared to placebo. Twelve symptoms, namely, headache, dizziness, blurred vision, sighing, tiredness, easy fatigue, paresthesias, trembling, shakiness, weakness, initial insomnia, and palpitations showed a decrease in intensity with the drug and only two symptoms, fears and chest pain, failed to show such a decrease. Moreover, three symptoms, namely, tiredness, shakiness and initial insomnia, each considered separately showed a significant decrease (p < 0.05) in intensity with 120 mg of propranolol. The reasons that the decrease in intensity of the remaining 9 symptoms, when each was considered separately, failed to reach statistical significance may be various, e.g. severity and chronicity of our patients, use of only moderate doses (maximum 120 mg) of propranolol insufficient to cause adequate peripheral beta blockade. Granted that it has not been established that all of the effects of the drug in reducing anxiety are mediated by peripheral beta blockade (see the discussion below), but as many of them very likely are, it would make sense clinically to achieve optimum beta blockade. The dose range of propranolol for adequate beta blockade in most individuals is considered to be from 160-200 mg or more. 3.13This dosage range is of course subject, in different individuals, to such factors as variable bioavailability, variations in resting or stimulated sympathetic tone, variations in plasma drug binding as well as differences in actual receptor sensitivity. The usefulness of monitoring plasma levels of the drug is debated as its interpretation is fraught with difficulties and there may not be a simple correlation between plasma levels and therapeutic effects. Shand,‘g,20 however, contends that plasma level of 100 mg/ml of propranolol at the end of the usual 6 hour dosage interval would produce a high degree of beta blockade in most patients. Therefore, monitoring plasma levels may help institution of proper dosage. Our study did not find 40 mg of propranolol/day to be an effective dose, which is consistent with the above discussion.
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AND WOOLSON
There were no side effects of any importance. Two patients dropped out, one from each of the two groups A and B. Prior to the study the first patient was on six different psychoactive drugs including diazepam, trifluoperazine, and amitriptyline. His anxiety symptoms became exacerbated during the first, drug-free week. He became restless and unable to sleep, requiring bedtime hypnotics. He continued anxious and agitated and dropped out in the beginning of the second week. After taking the experimental drug on the first day of the second week, the second patient complained of chest pain, upset stomach, and inability to work or sleep. The pain was localized to the left breast, was steady and sharp, beginning 45 minutes after the pills and lasting until 30 minutes before the next pill. She stated she had had similar attacks of chest pain in the past. She felt the experimental drug did not help at all and withdrew from the study, also during the early part of the second week. In both of these patients precipitation or worsening of their anxiety symptoms rather than adverse effects of propranolol were considered to be the reasons for their not completing the study. This assumption is strengthened by the fact that the first patient subsequent to dropping out from the study has been followed as an outpatient on much higher doses (320 mg) of propranolol without significant undesirable side effects and with moderate improvement. It should be mentioned here that although this study was not designed as a follow-up study, we have had some follow-up information on a few of the patients. Although all the patients fulfilled the specific criteria for anxiety neurosis outlined earlier and we are certain that we have excluded mania, schizophrenia, organic brain disease, gross character disorders and addictions, and situational anxiety, in retrospect, in a few patients we are not certain that we have satisfactorily and completely excluded a primary obsessive-compulsive illness, a primary depressive illness, or hysteria. In the 3 neurotic illnesses, i.e., anxiety neurosis, obsessivecompulsive neurosis, and hysteria, the ages of onset can be similar and even though the illness may be predominantly of one type, features of theother two are quite common in the same individual. Similarly, depressive symptoms occur quite commonly in these neurotic illnesses (when it would be called secondary depression), and further, neurotic features such as anxiety symptoms, obsessions, etc., can occur as secondary phenomena in the course of a primary depressive illness. Thus unravelling of the primary diagnosis and secondary features can present difficult diagnostic problems in a given patient. Not much can be said from our study regarding whether propranolol is effective in relieving only autonomic symptoms of anxiety or whether it relieves psychic symptoms as well, as two of the psychic symptoms, depressed mood and tension or nervousness, were eliminated from the analysis in order to exclude sequence and carry-over effects as mentioned earlier. The only remaining psychic symptom, fears, failed to show improvement with propranolol. Rational treatment of anxiety neurosis is handicapped as there is little reliable knowledge about its etiology except that heredity probably plays an important ro1e.21 Similarly, the mechanism of production of anxiety symptoms or of the action of beta blockers in the relief of these symptoms is not clear. The lactate theory of anxiety proposed by Pitts and McClure14 though heuristically useful has serious flaws.22 That learning theory principles are probably involved is underlined by a review of the psychophysiology of anxiety: “sympathomimetic symptoms of anxiety are both a response to the central nervous system state of anxiety (as Cannon postulated) and a reinforcement of further anxiety (as James postulated). The
325
PROPRANOLOL
acute anxiety reaction can become selfgenerating, since the symptoms of the anxiety reaction can reinforce the reaction, causing it to spiral.“23 But whether these or other mechanisms are the pathogenetic mechanisms in anxiety neurosis is not known. Furthermore, the question of central vs peripheral mode of action of beta blockers is not settled. Practolol, a cardioselective beta blocker that enters the central nervous system poorly, has been shown to afford relief of anxiety symptoms suggesting the peripheral beta blockade to be of primary importance.” The situation is complex, however, especially in regard to drugs like propranolol that freely penetrate the central nervous system, and because: 1) beta blockers have two additional actions, i.e., membrane stabilizing and intrinsic sympathomimetic actions, the roles of which in reducing anxiety are not completely clear; 2) we have limited knowlege of central beta-adrenergic receptors, study of which is impeded by difficult technical problems. A word of caution is in order here. Failure in the past of most of our patients to derive lasting benefit from prior treatments including benzodiazepines and improvement with propranolol in this study does not imply that patients would get lasting benefit from propranolol administered over a long period. We do not know the long-term efficacy of propranolol or such factors as development of tolerance in the treatment of anxiety neurosis in a systematic way. Suzman” mentions that he has maintained anxiety patients on propranolol for up to 6 years without undesirable consequences and indications from the literature on use of propranolol in the treatment of medical disorders are that long-term use of propranolol is unattended by serious hazards provided patients have been selected carefully. Nonetheless, more systematic studies in this direction are needed to better define the placeof beta blockers in the treatment of chronic anxiety neurosis. We have taken here chronic anxiety neurosis in the sense of Wheeler et al.‘” Among its many synonyms are: neurocirculatory asthenia, effort syndrome, soldier’s heart, cardiac neurosis, DaCosta’s syndrome, irritable heart, and vasomotor neurosis, and it is very likely that such functional cardiac conditions as “hyperkinetic heart syndrome.” “ hyperdynamic beta-adrenergic circulatory state,” and “vasoregulatory asthenia,” in which beta blockade has been found effective, are either synonyms for chronic anxiety neurosis or variants of it. Introduction of propranolol is an important addition to the existing methods of treatment of anxiety neurosis such as psychotherapy, relaxation training and behavior therapy, benzodiazepines and other anxiolytic drugs, and in extreme cases, some form of localized stereotaxic leucotomy. Propranolol is a safe drug as this study shows provided patients are carefully selected, i.e., by excluding those patients who are prone to beta blocking side effects, namely, those with previous history of cardiac failure or with existing cardiac failure, hypotension, bradycardia, heart block, asthma, or bronchitis. It is in many instances preferable to benzodiazepines as it rarely produces sedation and is not prone to abuse.
SUMMARY In a double-blind controlled propranolol at the dose level of the treatment of 28 moderately diagnosed and selected according i.e., 40 mg/day, of propranolol
trial the beta-adrenergic blocking agent 120 mg/day was found to be safe and effective in to severely ill chronic anxiety neurosis patients to rigorous and specific criteria. A reduced dose, was found to be ineffective. Both univariate and
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AND WOOLSON
multivariate nonparametric statistics were used in the analysis. Problems such as pathogenetic mechanisms in the production of anxiety symptoms, mode of action of beta blockers and their place in the treatment of anxiety states, optimum dose, monitoring plasma level of the drug, and long-term use have been discussed. ACKNOWLEDGMENTS We are indebted to Kathleen Buckwalter and Randee Fieselmann for their assistance at all stages of the study. We are grateful to Jim Leeper, M.S., of the Department of Preventive Medicine and Environmental Health of the University of Iowa College of Medicine for his help in statistical analysis. Robert Kyle, Ayerst Laboratories Research Associate, provided generous assistance.
REFERENCES I. Granville-Grossman KL, Turner P: The effect of propranolol on anxiety. Lancet I :788-790, 1966 2. Wheatley D: Comparative effects of propranolol and chlordiazepoxide. Br J Psychiatr ll5:141 l-1412, 1969 3. Suzman MM: The use of beta-adrenergic blockade with propranolol in anxiety syndromes. Postgrad Med J 47: I04 108, 197 I 4. Bonn JA, Turner P, Hicks DC: Betaadrenergic-receptor blockade with practolol in treatmentof anxiety. Lancet 1:814815, 1972 5. Tyrer PJ, Lader MH: Response to propranolol and diazepam in somatic anxiety. Br Med J 2:14- 16, 1974 6. Kellner R, Collins C, Shulman RS, et al: The short-term antianxiety effects of propranolol HCI. J Clin Pharmacol5:301-304, 1974 7. Taggart P, Carruthers M, Somerville W: Electrocardiogram, plasma catecholamines, and lipids, and their modification by oxprenolol when speaking before an audience. Lancet 2:341-346, 1973 8. Brewer C: Beneficial effect of betaadrenergic blockade on “exam nerves.” Lancet 2:435, 1972 9. Linken A: Propranolol for LSD-induced anxiety states. Lancet 2: lO39- 1040, 197 I 10. Carlsson C, Johansson T: Effects of propranolol (Inderal) on psychiatric symptoms in chronic alcoholism. Acta Psychiatr Stand 217:58, 1970 11. Gallant DM, Swanson WC, GuerreroFigueroa R: A controlled evaluation of propranolol in chronic alcoholic patients presenting the symptomatology of anxiety and tension. J Clin Pharmacol 13:41-43, 1973 12. Gardos G, Cole JO, Volicer L, et al: A dose-response study of propranolol in chronic schizophrenics. Curr Ther Res 15:314-323, 1973
13. Carlsson C, Johansson psychological effects of propranolol stinence phase of chronic alcoholics. chiatr 119:605-606, 197 I
T: The in the abBr J Psy-
14. Pitts FN, McClure JN: Lactate metabolism in anxiety neurosis. N Engl J Med 277: 1329- 1336, 1967 15. Wheeler EO, White PD, Reed EW, et al: Neurocirculatory asthenia (anxiety neurosis, effort syndrome, neurasthenia). J A M A 142:878- 888, 1950 16. Feighner JP, Robins E, Guze SB, et al: Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57-63, 1972 17. Koch GG: The use of the nonparametric methods in the statistical analysis of the twoperiod change-over design. Biometrics 28:577-584, 1972 18. Puri ML, multisample rank Non-parametric Analysis, chap 5. 181-206
Sen PK: Multivariate and test for location and scale, in Methods in Multivariate New York, Wiley, 1971, pp
19. Shand DC: Propranolol. Chicago, October 1974
Dis
Month,
Shand DC: Plasma 20. Coltart DJ, propranolol levels in the quantitative assessment of beta-adrenergic blockade in man. Br Med J 3:73l-734,197o 21. Cohen ME, Badal DW, Kilpatrick A, et al: The high familial prevalence of neurocirculatory asthenia (anxiety neurosis, effort syndrome). Am J Hum Genet 3:126-158, 1951 22. Ackerman SH, Sachar EJ: The lactate theory of anxiety: A review and reevaluation. Psychosom Med 36:6998 I, 1974 23. Breggin PR: The psychophysiology anxiety. J Nerv Ment Dis 139:558-568, 1964
of
T. Tanna,
R. Paul Penningroth,
and Robert F. Woolson
B
ETA-ADRENERGIC BLOCKING AGENTS have been found useful in the treatment of diverse anxiety states: anxiety neurosis ;I-’ public speaking; 7 “exam nerves”;s use of LSD;g anxiety and tension states of chronic alcoholics;‘“,” anxiety of schizophrenics;12 tension state in the withdrawal syndrome of alcoholism;‘3 etc. Unsatisfactory clinical classification of anxiety states, however, in addition to variation in drug, dose, design and assessment technique, makes comparative evaluation of reported studies difficult. In general, somatic symptoms such as tachycardia, palpitations, and tremulousness seem to respond better than psychic symptoms like fears, worry, tension, irritability, difficulty in concentrating.1,4.5 But some studies do report improvement in psychic symptoms as well.3,“’ Anxiety may be considered to be 1) primary when it occurs in the relatively well-defined syndrome of anxiety neurosis, or 2) secondary when it occurs in situational settings such as examinations or public speaking, or in the course of other preexisting psychiatric illnesses such as depression or alcoholism. The focus of the present article is anxiety neurosis. Most previous studies dealing with primary anxiety states or anxiety neurosis have not used rigorous definition or explicit criteria for the diagnosis or selection of the patients. The duration of symptoms in the same study in many instances has ranged widely, suggesting inclusion of both acute and chronic patients. Moreover, no study has compared different doses of the same agent. We present in this article a double-blind controlled study of therapeutic efficacy of two different doses of the beta-adrenergic blocking agent propranolol (Inderal) in moderately to severely ill chronic anxiety neurotic patients selected according to rigorous and specific criteria. MATERIALS
AND
METHODS
Outpatients and inpatients between the ages of 20 and 55 attending Linn County Psychiatric Clinic, Cedar Rapids, Iowa, and psychiatric facilities of the University of Iowa Medical Center, Iowa City, Iowa, with a primary diagnosis of chronic anxiety neurosis were considered for the trial. Patients were selected according to the criteria for anxiety neurosis outlined by Pitts and McClure,‘4 and Wheeler et al.,15 which closely agree with the rigorous research criteria developed by Feighner et al.16 Informed consent, after full explanation of the objective and the nature of procedures, was obtained from all patients accepted in the study. All patients received a standard psychiatric interview to establish the diagnosis as well as presence or absence of specific symptoms. To be accepted in the study, a patient had to meet each of the following four criteria: A) To have had severe feelings of tenseness or free-
Propranolol (Inderal) and placebo were supplied by Ayerst Laboratories. From the Departments of Psychiatr.v and Preventive Medicine and Environmental Health, University of Iowa College of Medicine, and Veterans Adminisrration Hospital, Iowa City, Iowa. Vasantkumar L. Tanna, M.D.: Assistanf Professor, Department of Psychiatry, University ofIowa College of Medicine, Staff Psychiatrist, Iowa City VA Hospital; Robert F. Woolson, Ph.D.: Assistant Professor, Department of Preventive Medicine and Environmental Health, University of Iowa College of Medicine; R. Paul Penningroth, M.D.: Clinical Assistant Professor, Department of Psychiatry, University of Iowa College of Medicine, and Director, Linn County Psychiatric Clinic, Cedar Rapids, Iowa. Reprint requests should be addressed to Dr. Tanna, VA Hospital, Iowa City, Iowa, 52240. fc 1977 by Grune & Strarron. Inc.
Comprehensive
Psychiatry,
Vol 18, No. 4 (July/August), 1977
319
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TANNA,
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Table 1. Previous Hospitalizations Numberof Hospitalizations
Numberof Patients 11 7 4 4 2 Total
28
floating anxiety nearly daily for at least two years. B) Must have had frequent anxiety attacks manifested by apprehension, fearfulness, or sense of impending doom, and during the majority of the anxiety attacks the following symptoms must be present: I) at least two of the following: dyspnea, smothering, sighing, chest discomfort or chestpain, and lump in throat; 2) at least three of the following: dizziness or giddiness, faintness, weakness, fatigue, inner shakiness, tremor, paresthesias, vascular throbbing, and palpitations. C) Aside from anxiety attacks, must have had at least IO of the following I6 symptoms: headache, dizziness, blurred vision, dyspnea, sighing, tiredness, easy fatigueability. paresthesias, depressed mood, trembling, shakiness, weakness, fears, initial insomnia, chest pain, and palpitations. D) The onset of the syndrome must have been before the age of 40. Patients with schizophrenia, organic brain syndrome, primary affective illness, asthma, cardiac disease, and pregnancy were excluded. Of the 30 patients that began the study, 2 dropped out (this will be discussed later) so that 28 patients, I3 male and 15 female, completed the study. Depressive (I4 patients), phobic (15), and obsessive-compulsive (16) features were common. A few of the patients showed hysterical (2). antisocial (2), and alcoholic (3) traits. In 4 patients possibility of schizophrenia was raised based on replies to screening questions for schizophrenia, but was satisfactorily ruled out on further investigation of their history and clinical picture. Twenty-two were outpatients and six were inpatients. The mean age at admission to the study was 34.3 years and the mean age at onset of the illness was 22.1 years. In 8 patients the duration of illness was 2-3 years, in 7 patients 4410 years, and in I3 the illness had been present for more than IO years. Table I shows the number of previous hospitalizations. In general, few of the patients had derived lasting benefit from prior treatments, including benzodiazepines. Each patient was randomly assigned to one of two groups in which the sequence of drug and placebo administered differed. The drug or an identical appearing placebo were given orally in four divided doses. The I4 patients in group A were drug-free the first week, received 40 mg/day of propranolol the second week, placebo the third week, and 120 mg/day of propranolol the fourth week. The I4 patients in group B were drug-free the first week, received 120 mg/day of propranolol the second week, 40 mg/day of propranolol the third week, and placebo the fourth week. Patients were assessed by selfreport on a weekly basis at the end of each one week trial period. Assessment was by interview rating of the following I7 symptoms on a five point scale indicating the severity of the symptoms: headache, dizziness, blurred vision, dyspnea, sighing, tiredness, easy fatigueability, paresthesias, depressed mood, chest pain, palpitations, and tension or trembling, shakiness, weakness, fears, initial insomnia, nervousness. The five point scale was: O-not experienced; l-just noticeable (in ordinary circumstances); 2-definite but not uncomfortable; 3-definite and quite uncomfortable; &intolerable or severe enough for medical consultation in ordinary circumstances.
Statistical
Analysis
The standard statistical model for a cross-over design is assumed to be an adequate representation for each symptom.” Specifically, an observed score for a symptom is an additive model with a grand mean, a week effect, the direct effect of the treatment received during the week, the residual effect of the treatment received the previous week, and the random effects of the patient and the error in the measurement of the response. Only two of the six possible sequences of ordering the doses have been studied in this trial, thus it is clear that one dose is absent for each of the treatment weeks. It would require all six sequences (viz. two 3 x 3 latin square arrangements) to have a balanced design with regard to the residual effects of treatments on the observed scores the following week. This lack of balance in our design and the absence of one treatment each week indicates that certain parameters in the
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PROPRANOLOL
assumed cross-over model are not statistically estimable. These facts make it unreasonable to analyze the data as an aggregate in a single linear statistical model as certain untestable assumptions regarding the week and the residual effects would be required to perform the analysis. We propose instead performing an analysis of the 17 symptoms at each time point separately. AS the symptoms may be expected to be correlated and the data may not be assumed to be normal, a nonparametric multivariate comparison of the two groups is performed at each time point. We proceed by first comparing the two groups during the drug-free period by applying the multivariate Wilcoxon statistic of Puri and Sen’* to the 17 symptoms, then eliminate those symptoms which yield a significant group difference. By a trivial extension of Koch’s” model to this design. we observe that the only residual effects which we can test are the residual effects of placebo and 120 mg; this test is performed
by
summing the scores
for each patient across the three weeks for each symptom separately, then applying the same rank order statistic to these sums to compare the two sequence groups. This comparison is a test for equality
of the two previously
symptoms which are significantly yield a group difference
during the drug-free
plied to the resulting symptoms carry-over
different
mentioned
residual effects. This is repeated
are eliminated.
Having eliminated
after
those
those symptoms which
period or in residual effects, the rank order tests are ap-
at each specific time point; these comparisons
effect (assuming the residual effect of 40 mg is intermediate
would be free of an)
between placebo and 120 mg).
and time effect. We may lose power with this procedure but the risk of bias is minimized. All test statistics are compared
to their appropriate
asymptotic
chi-square
distribution
for signifi-
cance.‘” RESULTS
A difference between the two sequences (groups A and B) was detected in the drug-free period with respect to dyspnea and depressed mood (XI of 9.75and 4.00. respectively). Carry-over effects (i.e., the residual effects of a treatment in a given week on the observed scores of the following week) of 120 mg and placebo differed with regard to tension (X: of 3.84); hence this symptom, dyspnea, and depressed mood were eliminated from the remaining analyses. Comparing the two sequences during the drug-free period, there is no overall difference (X:a = 10.67), nor is there a difference detected on any of the fourteen symptoms (all individual chi-squares less than 1.13). Thus, the groups were initially comparable on these 14 symptoms. Examining the carry-over effects of Table
2.
of Mean
Mean
Symptom
Difference’
Scores
by Treatment
and
Standard
and
Treatment
Error Week
Week 1 Tri?atmC?llt Symptom
40 mg
120mg
Week 3
Week 2 Treatment SE
Placebo
40mg
Treatment SE
120 mg
Placebo
12
1.9
S E 50
9 6 1 1 1.8 14 11 1 .o 13 1.3 16 IO 14 9
13 9 1.4 25 19 1.1 1.7 24 1.7 1.6 21 .6 1.5
46 38 41 33 49 42 49 49 49 44 57 47 49
Headache
16
1.4
4%
Dizziness Blurred Vision
1.2 1.2
1.6 IO 1.2 23 1.8 1 .o .a 1.8 2.0 1.8 1.6 .7 2.6
45 46 38 42 .45 46 .39 .44 .44 .50 .57 42 43
SIghrIg
1.4
Tiredness Easy Fatigue Paresthesias Tremblmg Shakmess Weakness Fears lnsomma Chest Pain Palpitations
2.1 17 1.1 16 1.6 1.6 17 1.2 11 1.2
‘Standard
22
2.0
17 1.4 15 2.5 2.2 16 17 2.3 1.6 1.9 11 .9 1.4
1.5 11 1.4 28 21 .9 1.4 25 2.3 20 1.9 8 1.6
53
45 .47 42 .33 .47 .49 .49 41 .46 .43 .52 .51 50
error computed from wlthtn group vanance for each symptom
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AND WOOLSON
Table 3. Overall Mean Symptom Scores and Their Standard
Symptoms
Errors for Each Treatment
Drug Free
Placebo
40 mg
120mg
Headache
2.1 1 t.25)
2.07 l.26)
1.82 l.26)
1.32 t.22)
Dizziness
2.14 1.23)
1.50 L22)
1.36 t.24)
1.29 t.221 0.82 L2 1)
Blurred Vision
1.36 1.20)
1.141.23)
1.14 (.22)
Sighing
1.61 t.14)
1.43 (.22)
1.39 (.17)
1 .18 t.20)
Tiredness
2.79 (.I 8)
2.50 t.17)
2.43 t.18)
2.04 1.20)
Easy Fatigue
2.32 t.18)
2.07 t.24)
1.93 1.24)
1.61 1.23)
Paresthesias
1.46 t.24)
1.32 L231
1.04 t.241
1.04 (‘21)
Depression
2.43 f.23)
1.89 f.28)
1.71 t.25)
1.61 t.23)
Trembling
2.25 t.20)
1.71 i.26)
1.50 t.23)
0.89 t.18)
Shakiness
2.71 C.15)
2.32 t.24)
2.04 t.20)
1.54 t.24)
Weakness
2.50 t.12)
1.64 1.24)
1.93 1.22)
1.64 t.24)
Fears
2 36 f.19)
1.75 L21)
1.86 C.22)
1.7 1 t.24)
Chest Pain
2 07 t.25)
0.75 L21)
0.93 t.25)
1.07 t.25)
Palpitations
2.18 t.23)
1.46 L25)
1.39 (.22)
0.96 1.23)
120 mg and placebo there was also no evidence of a difference in these two effects (see Table 4, column 4). Hence, assuming the residual effect of 40 mg is between the placebo and 120, we conclude that all residual effects are equal for these 14 symptoms. In Table 2, mean scores for each symptom by treatment and treatment week are summarized along with the standard error of the mean difference between groups. Summary mean scores across all time points for each treatment are also summarized in Table 3. In Table 4, the results of the multivariate nonparametric analyses are summarized. It is noteworthy that the two sequence groups differ significantly with regard to the entire set of symptoms at each time point using the large sample chi-square test. The difference at time 1 and at time 2 in which we Table 4.
Mean Rank Sumst
Multivariate
Symptom
and Nonparametric
Test Statistics by Treatment
Week 1 140t “S 1201
Week 2 (Pt “540)
Week Week 3 1120t
“SP)
Carry-over Effects
-
Headache
15.0
15.5
12.5
Dizziness
13.1
15.2
13.5
13.6
Blurred Vision
15.2
15.6
13.6
15.1
Sighing
15.1
14.7
13.4
14.7
Tiredness
13.5
13.5
11.7‘
12.4
Easy Fatigue
14.6
14.6
12.9
14.0
Paresthesias
14.4
16.2
14.0
15.7
Trembling
16.9
15.3
12.5
14.7
Shakiness
14.0
145
11.4’
13.0
Weakness
13.2
12.4
13.0
12.5
Fears
14.4
14.0
14.7
14.2
Insomnia
13.5
11.9
11.7’
12.2
Chest Pain
15.7
15.2
16.4
15.4
Palpitations
15.0
14.1
12.4
19.8
Multivariate Trace Statistic
42.8
32.2
29.6
19.2
Multivariate P (Asymptotic X2 (14)) -
14.7
.0002
.0044
*Significant at 0.05 using unwariate test.t Mean Rank sum for sequence A
.0094
.1610
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PROPRANOLOL
have 40 mg vs 120 mg and placebo vs 40 mg, respectively, are in favor of no particular treatment. Specifically, at time 1 40 mg has a higher mean rank for seven of the symptoms, and 120 mg is higher for the remaining seven; while at time 2, placebo has a mean rank higher than 40 mg for 8 of the 14 symptoms. Thus, an overall statistical difference has been determined but the direction is clearly not in favor of one or the other treatment at either of these two times. None of the univariate rank order tests are significant for week 1 or 2. At week 3, an overall statistical difference is found; however, with the exception of two of the symptoms (fears and chest pain) the direction of the difference is in favor of a lower mean rank sum for the 120 mg for all symptoms. Univariate differences are detected for tiredness, shakiness and initial insomnia. As the mean rank sum for each of these three is lower for 120 mg as compared to placebo this is suggestive of efficacy for the 120 mg regimen. It is also of interest to note that the mean scores for each symptom (Table 3) show a trend in reduction of severity with higher doses of propranolol. DISCUSSION
Within the limitations of our design, our results show that propranolol is effective in the treatment of chronic severe anxiety neurosis defined according to rigorous and specific criteria. The 14 symptoms of anxiety neurosis tested showed, at week 3, a significant difference (p < 0.01) in intensity with 120 mg of propranolol as compared to placebo. Twelve symptoms, namely, headache, dizziness, blurred vision, sighing, tiredness, easy fatigue, paresthesias, trembling, shakiness, weakness, initial insomnia, and palpitations showed a decrease in intensity with the drug and only two symptoms, fears and chest pain, failed to show such a decrease. Moreover, three symptoms, namely, tiredness, shakiness and initial insomnia, each considered separately showed a significant decrease (p < 0.05) in intensity with 120 mg of propranolol. The reasons that the decrease in intensity of the remaining 9 symptoms, when each was considered separately, failed to reach statistical significance may be various, e.g. severity and chronicity of our patients, use of only moderate doses (maximum 120 mg) of propranolol insufficient to cause adequate peripheral beta blockade. Granted that it has not been established that all of the effects of the drug in reducing anxiety are mediated by peripheral beta blockade (see the discussion below), but as many of them very likely are, it would make sense clinically to achieve optimum beta blockade. The dose range of propranolol for adequate beta blockade in most individuals is considered to be from 160-200 mg or more. 3.13This dosage range is of course subject, in different individuals, to such factors as variable bioavailability, variations in resting or stimulated sympathetic tone, variations in plasma drug binding as well as differences in actual receptor sensitivity. The usefulness of monitoring plasma levels of the drug is debated as its interpretation is fraught with difficulties and there may not be a simple correlation between plasma levels and therapeutic effects. Shand,‘g,20 however, contends that plasma level of 100 mg/ml of propranolol at the end of the usual 6 hour dosage interval would produce a high degree of beta blockade in most patients. Therefore, monitoring plasma levels may help institution of proper dosage. Our study did not find 40 mg of propranolol/day to be an effective dose, which is consistent with the above discussion.
324
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AND WOOLSON
There were no side effects of any importance. Two patients dropped out, one from each of the two groups A and B. Prior to the study the first patient was on six different psychoactive drugs including diazepam, trifluoperazine, and amitriptyline. His anxiety symptoms became exacerbated during the first, drug-free week. He became restless and unable to sleep, requiring bedtime hypnotics. He continued anxious and agitated and dropped out in the beginning of the second week. After taking the experimental drug on the first day of the second week, the second patient complained of chest pain, upset stomach, and inability to work or sleep. The pain was localized to the left breast, was steady and sharp, beginning 45 minutes after the pills and lasting until 30 minutes before the next pill. She stated she had had similar attacks of chest pain in the past. She felt the experimental drug did not help at all and withdrew from the study, also during the early part of the second week. In both of these patients precipitation or worsening of their anxiety symptoms rather than adverse effects of propranolol were considered to be the reasons for their not completing the study. This assumption is strengthened by the fact that the first patient subsequent to dropping out from the study has been followed as an outpatient on much higher doses (320 mg) of propranolol without significant undesirable side effects and with moderate improvement. It should be mentioned here that although this study was not designed as a follow-up study, we have had some follow-up information on a few of the patients. Although all the patients fulfilled the specific criteria for anxiety neurosis outlined earlier and we are certain that we have excluded mania, schizophrenia, organic brain disease, gross character disorders and addictions, and situational anxiety, in retrospect, in a few patients we are not certain that we have satisfactorily and completely excluded a primary obsessive-compulsive illness, a primary depressive illness, or hysteria. In the 3 neurotic illnesses, i.e., anxiety neurosis, obsessivecompulsive neurosis, and hysteria, the ages of onset can be similar and even though the illness may be predominantly of one type, features of theother two are quite common in the same individual. Similarly, depressive symptoms occur quite commonly in these neurotic illnesses (when it would be called secondary depression), and further, neurotic features such as anxiety symptoms, obsessions, etc., can occur as secondary phenomena in the course of a primary depressive illness. Thus unravelling of the primary diagnosis and secondary features can present difficult diagnostic problems in a given patient. Not much can be said from our study regarding whether propranolol is effective in relieving only autonomic symptoms of anxiety or whether it relieves psychic symptoms as well, as two of the psychic symptoms, depressed mood and tension or nervousness, were eliminated from the analysis in order to exclude sequence and carry-over effects as mentioned earlier. The only remaining psychic symptom, fears, failed to show improvement with propranolol. Rational treatment of anxiety neurosis is handicapped as there is little reliable knowledge about its etiology except that heredity probably plays an important ro1e.21 Similarly, the mechanism of production of anxiety symptoms or of the action of beta blockers in the relief of these symptoms is not clear. The lactate theory of anxiety proposed by Pitts and McClure14 though heuristically useful has serious flaws.22 That learning theory principles are probably involved is underlined by a review of the psychophysiology of anxiety: “sympathomimetic symptoms of anxiety are both a response to the central nervous system state of anxiety (as Cannon postulated) and a reinforcement of further anxiety (as James postulated). The
325
PROPRANOLOL
acute anxiety reaction can become selfgenerating, since the symptoms of the anxiety reaction can reinforce the reaction, causing it to spiral.“23 But whether these or other mechanisms are the pathogenetic mechanisms in anxiety neurosis is not known. Furthermore, the question of central vs peripheral mode of action of beta blockers is not settled. Practolol, a cardioselective beta blocker that enters the central nervous system poorly, has been shown to afford relief of anxiety symptoms suggesting the peripheral beta blockade to be of primary importance.” The situation is complex, however, especially in regard to drugs like propranolol that freely penetrate the central nervous system, and because: 1) beta blockers have two additional actions, i.e., membrane stabilizing and intrinsic sympathomimetic actions, the roles of which in reducing anxiety are not completely clear; 2) we have limited knowlege of central beta-adrenergic receptors, study of which is impeded by difficult technical problems. A word of caution is in order here. Failure in the past of most of our patients to derive lasting benefit from prior treatments including benzodiazepines and improvement with propranolol in this study does not imply that patients would get lasting benefit from propranolol administered over a long period. We do not know the long-term efficacy of propranolol or such factors as development of tolerance in the treatment of anxiety neurosis in a systematic way. Suzman” mentions that he has maintained anxiety patients on propranolol for up to 6 years without undesirable consequences and indications from the literature on use of propranolol in the treatment of medical disorders are that long-term use of propranolol is unattended by serious hazards provided patients have been selected carefully. Nonetheless, more systematic studies in this direction are needed to better define the placeof beta blockers in the treatment of chronic anxiety neurosis. We have taken here chronic anxiety neurosis in the sense of Wheeler et al.‘” Among its many synonyms are: neurocirculatory asthenia, effort syndrome, soldier’s heart, cardiac neurosis, DaCosta’s syndrome, irritable heart, and vasomotor neurosis, and it is very likely that such functional cardiac conditions as “hyperkinetic heart syndrome.” “ hyperdynamic beta-adrenergic circulatory state,” and “vasoregulatory asthenia,” in which beta blockade has been found effective, are either synonyms for chronic anxiety neurosis or variants of it. Introduction of propranolol is an important addition to the existing methods of treatment of anxiety neurosis such as psychotherapy, relaxation training and behavior therapy, benzodiazepines and other anxiolytic drugs, and in extreme cases, some form of localized stereotaxic leucotomy. Propranolol is a safe drug as this study shows provided patients are carefully selected, i.e., by excluding those patients who are prone to beta blocking side effects, namely, those with previous history of cardiac failure or with existing cardiac failure, hypotension, bradycardia, heart block, asthma, or bronchitis. It is in many instances preferable to benzodiazepines as it rarely produces sedation and is not prone to abuse.
SUMMARY In a double-blind controlled propranolol at the dose level of the treatment of 28 moderately diagnosed and selected according i.e., 40 mg/day, of propranolol
trial the beta-adrenergic blocking agent 120 mg/day was found to be safe and effective in to severely ill chronic anxiety neurosis patients to rigorous and specific criteria. A reduced dose, was found to be ineffective. Both univariate and
326
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AND WOOLSON
multivariate nonparametric statistics were used in the analysis. Problems such as pathogenetic mechanisms in the production of anxiety symptoms, mode of action of beta blockers and their place in the treatment of anxiety states, optimum dose, monitoring plasma level of the drug, and long-term use have been discussed. ACKNOWLEDGMENTS We are indebted to Kathleen Buckwalter and Randee Fieselmann for their assistance at all stages of the study. We are grateful to Jim Leeper, M.S., of the Department of Preventive Medicine and Environmental Health of the University of Iowa College of Medicine for his help in statistical analysis. Robert Kyle, Ayerst Laboratories Research Associate, provided generous assistance.
REFERENCES I. Granville-Grossman KL, Turner P: The effect of propranolol on anxiety. Lancet I :788-790, 1966 2. Wheatley D: Comparative effects of propranolol and chlordiazepoxide. Br J Psychiatr ll5:141 l-1412, 1969 3. Suzman MM: The use of beta-adrenergic blockade with propranolol in anxiety syndromes. Postgrad Med J 47: I04 108, 197 I 4. Bonn JA, Turner P, Hicks DC: Betaadrenergic-receptor blockade with practolol in treatmentof anxiety. Lancet 1:814815, 1972 5. Tyrer PJ, Lader MH: Response to propranolol and diazepam in somatic anxiety. Br Med J 2:14- 16, 1974 6. Kellner R, Collins C, Shulman RS, et al: The short-term antianxiety effects of propranolol HCI. J Clin Pharmacol5:301-304, 1974 7. Taggart P, Carruthers M, Somerville W: Electrocardiogram, plasma catecholamines, and lipids, and their modification by oxprenolol when speaking before an audience. Lancet 2:341-346, 1973 8. Brewer C: Beneficial effect of betaadrenergic blockade on “exam nerves.” Lancet 2:435, 1972 9. Linken A: Propranolol for LSD-induced anxiety states. Lancet 2: lO39- 1040, 197 I 10. Carlsson C, Johansson T: Effects of propranolol (Inderal) on psychiatric symptoms in chronic alcoholism. Acta Psychiatr Stand 217:58, 1970 11. Gallant DM, Swanson WC, GuerreroFigueroa R: A controlled evaluation of propranolol in chronic alcoholic patients presenting the symptomatology of anxiety and tension. J Clin Pharmacol 13:41-43, 1973 12. Gardos G, Cole JO, Volicer L, et al: A dose-response study of propranolol in chronic schizophrenics. Curr Ther Res 15:314-323, 1973
13. Carlsson C, Johansson psychological effects of propranolol stinence phase of chronic alcoholics. chiatr 119:605-606, 197 I
T: The in the abBr J Psy-
14. Pitts FN, McClure JN: Lactate metabolism in anxiety neurosis. N Engl J Med 277: 1329- 1336, 1967 15. Wheeler EO, White PD, Reed EW, et al: Neurocirculatory asthenia (anxiety neurosis, effort syndrome, neurasthenia). J A M A 142:878- 888, 1950 16. Feighner JP, Robins E, Guze SB, et al: Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57-63, 1972 17. Koch GG: The use of the nonparametric methods in the statistical analysis of the twoperiod change-over design. Biometrics 28:577-584, 1972 18. Puri ML, multisample rank Non-parametric Analysis, chap 5. 181-206
Sen PK: Multivariate and test for location and scale, in Methods in Multivariate New York, Wiley, 1971, pp
19. Shand DC: Propranolol. Chicago, October 1974
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of
