Treatment of Emotional Disturbances in Clinic Patients

Treatment of emotional disturbances Emotions in clinic patients

JENNIE TRIPSIN BUTTON, B.A., D.O. St. Louis, Missouri W. V. COLE, D.O. Kansas City, Missouri

Fifty-three patients with neuroses medium-duration study was done to determine participated in a double-blind, the effectiveness of this agent in such patients. placebo-controlled study to evaluate Symptomatic control, over-all improvement, and incidence of side effects were the primary deter- the usefulness of tybamate. Dizziness minants in the evaluation. or slight sedation, which was reported occasionally. with a high-dosage Procedure regimen, disappeared on reduction of A double-blind study was performed on 53 out- the dosage. Length of treatment patients, all suffering from neuroses. There were 48 females and 5 males, including 49 Cau- periods averaged 45 days, with a casians, 3 Mexicans, and 1 Japanese, whose maximum of about 70 days. Quantitative ages ranged from 14 to 84 years (average response was measured by grading of 40.8) . They were divided randomly into two initial and final symptom scores, groups. At study termination it was revealed qualitative response by investigators' that 27 patients had been given tybamate and the remaining 26 had been treated with a judgment of degree of relief obtained. placebo. There was moderate to complete relief Anxiety neurosis was the prominent feature in 82 per cent of tybamate patients in most of these patients. For many the dis- and 23 per cent of placebo patients. turbance was associated with other conditions, Symptomatic improvement in patients such as menopause, migraine, obesity, hyper- tension, allergy, skin disease, or postpartum receiving tybamate was found to syndrome. The history profile pattern shown in be statistically significant. Tybamate Table 1 illustrates that the treatment groups was of particular value where symptoms were generally comparable in parameters im- of anxiety or mild depression were portant for valid statistical analysis. accompanied by gastrointestinal At the beginning of the study, the patients were observed and graded for neurotic symp- somatization, headache, hostility, and toms : anxiety, depression, tension, headache, obsessiveness or compulsiveness. obsessive-compulsiveness, hostility, gastrointestinal somatization, and hypochondriasis. During weekly visits, the above symptoms were checked and recorded. They were graded as absent, mild, moderate, severe, or very severe on an equivalent scale of 0 to 5 with intermediate fractions. Re- It has been reported-3 that tybamate (Solacen, sponses to the test drugs were evaluated as ob- Wallace Laboratories, Cranbury, N. J.) , a new jectively as possible by the clinician and sub- psychotropic drug, is effective in relieving many jectively through verbal expressions by the pa- symptoms common to neurotic disturbances. tients. Over-all responses were graded according Since patients with emotional disturbances, to relief obtained : complete, marked, moderate, whether primary or secondary to physical ill- slight, none, or worse. Side effects also were ness, are frequently encountered, a controlled recorded at each visit. During the study, the

812/86 TABLE 1: COMPARATIVE CHARACTERISTICS OF STUDY daily, divided into four equal doses of two 250 GROUPS mg. capsules each. An equal number of placebo Tybamate Placebo capsules was administred. During the weekly visits dosage levels were adjusted upward or Sex (number) downward, depending upon each patients clini- Male 3 2 Female 24 24 cal progress. Duration of therapy ranged from Age (years) 7 to 69 days (average 44.5) for tybamate and Minimum 13 22 from 16 to 71 days (average 42) for placebo. Maximum 84 63 Median 43 37.5 Thus there was no significant difference in length Average 41.5 40 of therapy for each group. Weight (pounds) Minimum 105 102 Results Maximum 268.5 213.5 Median 142 139.5 Dosage Average 148.5 146.2 A review of changes in dosage during the study Previous sedative, shows that 18 of the 27 patients receiving ty- tranquilizer, or related bamate had a reduction in drug dosage require- therapy (number) ments after 1 week of therapy, in contrast with Antispasmodics 1 2 a reduction in 5 of 26 patients given placebo. Phenobarbital 1 3 Meprobamate 1 2 During the course of the study there were an 5 3 Chlordiazepoxide additional 14 dosage reductions for the patients Skeletal muscle relaxants 1 Trifluoperazine 2 treated with tybamate. In the placebo group 1 Rauwolfia there were 2 reductions and 2 increases in dos- 2 Antihistamines age. Results of previous The early reductions in dosage usually were therapy (number) prompted by complaints of occasional dizziness Complete relief 0 0 Marked relief 1 1 or slight sedation. When the dose was cut in Moderate relief 5 3 half, clinical progress continued, but side effects 5 4 Slight relief were no longer a problem. The dose was re- No relief 1 4 Some patients received various combinations duced subsequently when it was thought that of these agents. the point was reached where less medication was required to maintain the improved status. This hypothesis was generally found to be cor- rect, although, as would be expected, there were patients received no other tranquilizers, seda- still some transient fluctuations in scores ; in tives, or related drugs. However, drugs neces- some cases, further improvement was obtained sary for treatment of existing pathologic condi- at the reduced dosage levels. tions, such as a diuretic (chlorthalidone) for one hypertensive patient, nitroglycerine for Relief of symptoms coronary insufficiency in another patient, and an Initially there was no statistically significant dif- appetite suppressant (phenmetrazine) for two ference in the over-all severity symptom scores extreme cases of obesity, were continued. of the two groups (p = 0.2-0.3, t test) . How- The initial dose of tybamate was 2,000 mg. ever, analysis of the scores tabulated at the

Journal AOA/vol. 64, April 1965 813/87 TABLE 2: SEVERITY OF SYMPTOMS AT START AND AT END OF STUDY FOR TYBAMATE AND PLACEBO PATIENTS Very Severe Severe Moderate Mild Absent Symptom Before After Before After Before After Before After Before After Tybamate Anxiety 6 19 3 2 5 14 5 Depression 3 12 3 8 2 4 8 14 Gastrointestinal somatization 1 4 1 3 2 5 2 14 22 Headache 5 1 8 2 4 3 7 7 3 14 Hostility 1 7 5 2 5 6 9 19 Hypochondriasis 2 1 3 1 5 4 3 5 14 16 Obsessive-compulsive 3 11 4 2 1 4 10 7 12 Tension 9 16 5 2 3 14 5 Placebo Anxiety 11 5 14 11 1 6 4 Depression 3 5 11 6 6 4 4 3 2 8 Gastrointestinal somatization 4 6 4 3 3 3 4 10 16 Headache 3 9 8 4 4 4 10 6 4 Hostility 1 6 2 4 2 3 5 12 17 Hypochondriasis 3 1 5 5 4 3 7 6 7 11 Obsessive-compulsive 4 4 10 5 6 5 3 5 3 6 Tension 10 6 14 13 2 3 4

TABLE 3: WEIGHTED SYMPTOM SEVERITY SCORES AND PER CENT IMPROVEMENT

Improvement Tybamate Placebo per cent Improve- Improve- Tyba- Pla- Symptom Initial Final ment Initial Final ment mate cebo Anxiety 82.5 32.0 50.5 86.0 69.0 17.0 61 20 Depression 65.0 22.5 42.5 59.5 50.0 9.5 65 16 Gastrointestinal somatization 25.5 8.5 17.0 39.5 20.5 19.0 72 54 Headache 58.0 24.0 34.0 49.0 39.0 10.0 59 20 Hostility 37.5 10.5 27.0 35.5 16.5 19.0 72 54 Hypochondriasis 28.5 19.0 9.5 42.0 32.5 9.5 33 23 Obsessive-compulsive 50.5 23.0 27.5 61.5 48.0 13.5 54 22 Tension 89.0 34.0 55.0 87.0 72.0 15.0 62 17 Totals 436.5 173.5 263.0 460.0 347.5 112. 0 25

close of the study reveals that reductions in and the per cent improvements (61 and 62 per severity of symptoms obtained in the patients cent versus 20 and 17 per cent) were signifi- receiving tybamate were significantly greater cantly different. than those recorded for patients of the placebo Depression associated with anxiety also re- group (p < 0.01, t test). Tables 2 and 3 indi- sponded well to tybamate (65 per cent improve- cate the quantitative findings. The figures in ment compared with 16 per cent for placebo), Table 3 were derived by assigning weighting as did functional complaints such as headaches factors to each of the symptom grades: 0 indi- and gastrointestinal symptoms. The only symp- cates absent; 1, mild ; 2, moderate; 3, severe; tom which did not respond appreciably to and 4, very severe. to either tybamate or placebo was hypochon- Table 3 indicates that anxiety and tension driasis. The fact that somatic complaints re- were the major factors in the disturbances of sponded but hypochondriac concern did not both the tybamate-treated and the placebo- is somewhat paradoxical and not in agreement treated patients. The initial anxiety and tension with the findings of Raab and his associates, severity scores for each group were quite close who stated that drug patients improved most (82 and 89 versus 86 and 87, respectively), but and placebo patients least when scoring high on the final values (32 and 34 versus 69 and 70) the MMPI hypochondriac scale (p = 0.05) and

814/88 when rated high by the physician on somatic tion was made of total-patient response. In complaints. The variance in this study can per- other words, considering the various factors, haps be attributed to the relatively low initial what was the over-all degree of relief afforded scores in hypochondriasis and gastrointestinal each patient? The results are shown in Table 4. somatization and to the fact that these were primarily medical patients with a variety of TABLE 4: GENERAL RESPONSE TO TYBAMATE AM) organic diseases in contrast to the primarily PLACEBO neurotic patients of Raab and Rickels. Tybamate Placebo The improvement rates of the placebo pa- Relief No. Per cent No. Per cent tients in the present group fall within the often Complete 8 29.7 0 — quoted range of 20 to 40 per cent anticipated Marked 13 48.1 4 15.4 placebo response. Such observations support in Moderate 1 3.7 2 7.7 part the emphasis today on the need for Slight 1 3.7 3 11.5 double-blind, placebo-controlled studies, which, None 3 11.1 14 53.9 although they can scarcely be relied upon ex- Worse 1 3.7 3 11.5 clusively, are an important facet of the meth- Total 27 100 26 100 odology of studying new drugs, especially those of the psychopharmacologic type used to treat conditions subject to many influential variables.

Side effects and general response Comment As stated previously, side effects did not cause On the basis of the results of this medium-dura- any problem once the proper dosage level had tion study, it appears that tybamate may be been established. At the initial dosage of 2,000 used effectively to reduce or control many of the mg. daily, dizziness (8 patients) was a promi- neurotic expressions which are so often pre- nent but not disabling effect. There were also sented in practice, either as primary complaints scattered complaints of transient, mild drowsi- or secondary to organic dysfunctions. Before ness, (4 patients) and feelings of lightheaded- therapy, 25 of the 27 patients who eventually re- ness (4 patients) . These effects disappeared ceived tybamate had suffered from severe (or with continued administration at reduced levels. very severe) anxiety. At conclusion, it was Almost one third of the placebo patients also found that "very severe" could not be used to complained of side effects, such as dizziness, describe the anxiety of any of these patients, drowsiness, headaches, and euphoria, indicating and only 3 remained in the severe category. In that this entire group may have been particu- contrast, 16 patients treated with placebo still larly suggestible, although no conscious attempt demonstrated anxiety of severe or very severe was made to elicit reports of side effects. At no intensity at the termination of the study. Com- time were there any signs of depression result- parable results were observed for the other ing from the medication. major symptoms, depression and tension (Table Finally, before breaking the code, in addition 2). to analyses of dosage-response observations, Experience with other drugs in the same pa- symptomatic improvement, incidence of side tients is often a good criterion for comparison effects, and subjective observations, an evalua- of new agents. In this case, about half of the

Journal ADA/vol. 64, April 1966 815/89 Treatment of emotional disturbances

patients in each group had received related sedation, which disappeared when the dose therapy previously (Table 1) . Only 1 in the was reduced. Response was measured quantita- tybamate group had obtained marked relief, tively by grading of initial and final symptom and none was judged to have been adequately scores and qualitatively by the investigators relieved, whereas in this study 21 of 27 pa- judgment of the degree of relief obtained. Al- tients (78 per cent) given tybamate were though there was no significant difference in judged to have obtained marked or adequate re- the pretherapy symptom severity scores of lief. The impression should not be that per- either group, the final tallies revealed statisti- manent remissions were obtained in all of these cally significant symptomatic improvement in patients. The passage of considerable time is the patients receiving the active drug. Over-all necessary to ascertain the duration of the relief moderate to complete relief was obtained in 82 obtained. Where anxiety is an established pat- per cent of the tybamate patients and in 23 per tern or accompanies chronic disease, it is to be cent of the placebo. patients. In the initial study expected that patients will return from time to this new tranquilizer was of value in various time for renewed supportive therapy. On the neurotic states, particularly where symptoms of other hand, relief of acute anxiety, tension, or anxiety or mild depression were primary con- depression triggered by a specific stimulus may tributing factors and were accompanied by be permanent. Nevertheless, it was encouraging symptoms such as gastrointestinal somatization, to observe that tybamate produced moderate to headache, hostility, and obsessiveness or com- complete relief in over 80 per cent of the pa- pulsiveness. tients, and its effects did not seem to dissipate after 2 months of treatment in some patients.

Summary 1. Splitter, S.A.: A new psychotropic drug: Evaluation of tybamate in the treatment of anxiety and tension states. Psychoso- Fifty-three patients with neuroses compounded matics 5:292-4, Sep-Oct 64 of anxiety, tension, depression, and other less 2. Seeherman, R.: Evaluation of tybamate in the clinical manage- ment of anxiety. Delaware Med J 36:213-20, Oct 64 frequent symptoms, such as somatization, head- 3. Dunlop, E.: Tybamate, a new tranquilizer. Mind 2:115-7, Apr ache, and hostility, participated in a double- 64 4. Raab, E., Rickels, K., and Moore, E.: A double-blind evaluation blind, placebo-controlled study designed to eval- of tybamate in anxious neurotic medical clinical patients. Amer uate the usefulness of tybamate. The average J Psychiat 120:1005-7, Apr 64 length of the treatment periods was 45 days, extending to a maximum of approximately 70 This paper was written while Dr. Button was Clinical Instructor days. The initial dose of tybamate was 2,000 at Kansas City College of Osteopathy and Surgery. Dr. Cole is Professor of Osteopathic Theory and Practice and Director of mg. daily. On this high-dosage regimen there Research, Kansas City College of Osteopathy and Surgery. were occasional reports of dizziness or slight Dr. Button. 1444 Bayonne Drive. St. Louis. 63188.

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