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Treating Psychical Disturbances Induced by Physical Disorders
Treating Psychical Disturbances Induced by Physical Disorders A Double-Blind Study of Perphenazine-Amitriptyline in Anxiety and Depression W.
GRAYBURN DAVIS, M.D.
• As medicine approaches the prophylactic era, the concept of total medicine becomes more and more important. This comprehensive idea finds its greatest expression in psychosomatic medicine, where the mindbody, body-mind relationship is so tightly intertwined. One has but to observe the majority of his patients to confirm the existence of this very relationship. Anxiety and depression more often than not are secondary manifestations of some chronic illness such as asthma, allergy, cardiovascular disturbances, etc. The relations of psychial and physical influences sometimes confuse the etiology, manifestations and management of the disorder, making it extremely difficult for the physician to cope with the problem. In recent years, however, clinical studies of psychotropic agents have demonstrated the effectiveness of tranquilizers for anxiety and antidepressants for episodes involving depression. One of the most effective antidepressants, amitriptyline, has been found extremely valuable in a number of clinical trials. J-' Likewise, the efficacy and safety of the phenothiazine tranquilizer, perphenazine, has become widely recognized. A tablet combining these two agents (Etrafon®) 0 has recently become available and appears to be valuable in treating psychical disorders of various types and severities revolving around the depressive anxieties.
The present study compares the effects of this combination (2 mg perphenazine and 25 mg amitriptyline) with those of amitriptyline alone, and of placebo, in management of anxiety and depression in patients. MATERIALS AND METIIODS
Forty-eight subjects were selected on the basis of diagnosis of depression and anxiety for a double-blind, cross-over evaluation of amitriptyline-perphenazine, designated as "e," amitriptyline alone as "A," and a placebo, designated as "B." There were 11 males and 37 females ranging in age from 27 to 80. Almost all the patients had been known to me for a long time; five to ten years or more. The situational stress promoting emotional disturbance in these patients involved physical illness or financial, social, or domestic problems. Physical disorders in 28 patients included asthma, peptic ulcer, cancer, pruritus, hypertension, eczema, arthritis, atopic dermatitis and other afflictions. Other signs of disease included headaches in 11 patients, insomnia in 11 patients, hypochondriasis in five, and hysteria in four. One patient presented manicdepressive tendencies, another paranoid tendencies, and a third was schizophrenic. Each subject received one of the two active medications for the initial six weeks of the study; this was followed by two weeks either of placebo medication or of no medication at all; for the final six weeks completing the study, each patient was then crossed over to Dr. Davis is Ass()(:iate Clinical Professor, Univer- medication with the other active drug. Idensity of Colorado School of Medicine, Denver Clinic. tical capsules contained either 25 mg amitripPresf'nted at the 14th Annual Meeting, Academy tyline; 25 mg amitriptyline and 2 mg perphenof Psychosomatic ~1edicine, Houston, Texas, Novem- azine; or inert placebo. Dosages of all medicaher 30, 1967. tions ranged from two to four capsules per o Product of Schering Corporation, Bloomfield/ day. Similar capsules were used in order to Union. N. J. 44
Volume IX
TREATING PSYCHICAL DISTURBANCES-DAVIS
keep the patient or physician from recognizing any of the compounds. Evaluations of the improvements effected by each active drug were made on at least two occasions during each six weeks of active medication. On these occasions, laboratory and physical findings pertinent to side effects were duly recorded. At the end of the 14 weeks of study, a general preference among the medications was determined according to the relevant findings in each case. RESULTS AND DISCUSSION
Final evaluation of responses to the different medications showed that the combination of perphenazine and amitriptyline controll{'(] emotional disturbance best in 32 subjects (66.6)f); amitriptyline alone was favored in seven cases (14.6%); and no medication appeared superior, for any of various reasons, in nine cases. No subject favored placebo. The nine subjects with no preference among medications included three who could not tolerate either of the active drugs, alleging adverse reactions; three who were too anxious or fearful to complete the active-treatment trials; and three who could distinguish no advantage between the active drugs' effects. Aside from the drugs' direct effects on primary depression and anxiety, the greater frequency of improvement with the combined agent can be attributed largely to Etrafon's general superiority in relieving headaches and insomnia, which prevailed among many members of the present subject group. It might be noted, for example, that two patients habitually requiring large amounts of codeine for headache experienced appreciable reductions in this need during therapy with Etrafon. The finding of Etrafon's notable efficacy in relieving insomnia has been reported by previous investigators concerned with the drug's use in general practice}'" Of the seven subjects reported to favor medication with amitriptyline alone, it should be remarked that emotional disturbance in three cases was diagnosed in association with cancerous organic disease. This suggests a tendency of the antidepressant medication alone to be more appropriate in such a disturbance. Medication apparently effected considerable relief of the symptoms of asthma in nine patients receiving Etrafon and in two on amiJanuary-February, 1968
triptyline. Combined-drug treatment also appreciably reduced the severity of dermatitis in three patients and reduced the frequency of hyperventilation and/or tachycardia in two others. No remarkable relief of these or other involved physical disorders was obtained with amitriptyline alone. Some illustrative cases follow: Case I.-Mr. S., a 42-year-old asthmatic, has considerable anxiety, some depression and insomnia. He is a compensation case who was a professional weIder. He had his own business in New York but was sent to Colorado because of his asthma. He has now become a stoekbrokt'r-an interesting combination -a very successful ont', I might add. He did better on C than on A. He was a bit too drowsy to tolerate unknown C (perphenazine-amitriptyline) in full dose, so he was maintained on one dose at night and one dose during the day if necessary. With this dosage formula he has done quite well. In fact, he has evidenced less asthma and virtually no problcm with insomnia. Case II.-:\lrs. :\1., a physician's widow with severe atopic dermatitis, asthma, anxiety, depression and menopausal symptoms, was in considerahle difficulty financially and had many other problems, too, including a severe relapse of her dermatitis. She was started with unknown C (perphenazine-amitriptyline) and she did fabulously well. When she was changed to B (placebo), she relapsed. On the A (amitriptyline) she was improved but not as well as with C. It should be noted that while on A additional steroids were required to control her. On C she is not taking any steroids. Case III.-J. C., 24, is an anxious, depressed, confused young man with atopic dermatitis of severe degree and associated asthma. His dermatitis was so severe that he had been turned down for military service. He is disturhed to the degree that his education suffers. He has had six or seven jobs, most of this difficulty stemming back to his severe dermatitis and self-consciousness about his poor appearance. With the A (amitriptyline) preparation, he was improved; but with the C (perphenazine-amitriptyline), he was much improved. His asthma disappeared and his skin was much better. Although he was on steroids at the beginning of this study and continues to take them, he is using very much less (an average dose of prednisone of 5 mg a day whereas initially he had taken as much as 20 to 40, with only fair control).
On the basis of the present findings, it may be asserted that medication combining perphenazine and amitriptyline secures greater therapeutic response among patients with anxiety and depression than does amitriptyline alone. This impression accords with such previous findings as those of Diamond. 6 Also in accord with previous findings is the ability found in this study to maintain therapeutic
45
PSYCHOSO~IA TICS
response while reducing the required dosage of Etrafon. Three patients with favorable responses to one capsule b.i.d., and four to one capsule t.i.d., were reduced to one capsule at bedtime while maintaining superior effects of treatment; two other Etrafon- subjects reduced effective dosage to one capsule b.i.d. No serious side effects resulted from medication in the present study: no blood abnormalities, no significant urinary value changes, no liver function disturhances, etc. The most common side effects reported were drowsines~, occurring in 14 patients on Etrafon and eight on amitriptyline; dry mouth, in nine on Etrafan and two on amitriptyline; and dizziness, in four on Etrafon and one on amitriptyline. Alleged side effects caused one patients to discontinue medication with amitriptyline: two to discontinue Etrafon; and three to stop all medication. Interestingly two subjects discontinued medication because of alleged side effects from both the active and inert medications. A<:<:ordingly, an appreciable degree of interference from somatization and other factors related to emotional disorder must be read into the overall record of "side effects" in the present study. The common occurrence of drowsiness in this study agrees with a similar finding in a previous report hy Ernst.; Another side effect noted with some frequency among subjects receiving Etrafon was weight gain; Cook has reported' his impression that this effect is a function of the patients' improved moods. This opinion is shared hy the present investigator, who, moreover, ruled out the possihility of related edema through testing electrolytes and using diuretic agents.
in nine patients (18.7%). No serious side effects occurred as a result of medication. Some drowsiness and dryness of mouth were reported in both activetreatment groups. It is concluded that combination therapy with Etrafon can be expected to relieve anxiety and depression arising from situational stress, with greater effectiveness than amitriptyline alone, and generally with a valuable consistency and relatively low toxicity. Moreover, the compound is particularly valuable when one realizes that in relieving the psychical problem the accompanying physical dysfunction (gastrointestinal complaints, hypertensive states, etc.), real or imagined, is also relieved. Treating the psychiatric condition may well serve as a preventive measure for a future organic chronic state. As Goldman" noted at a recent symposium on the emotional basis of illness, certain stress "reactions require adequate management with hoth psychotherapeutic support and medication to relieve symptoms which, without medication, could persist and hecome chronic."
SU~[MARY
5. Splitter, S. R.: Combined Therapy with a New Drug . . . Amitriptyline and . . . Perphenazine in a ~[edical Office Setting. Psychosomatics, 6:322, 1965. 6. Diamond, S.: Double-Blind Controlled Study of Amitriptylim'-Perphenazine Combination in Medical Office Patients with Depression and Anxiety. Psychosomatics. 7:371-375, 1966. 7. Ernst, E. :\I.: Anxiety and Depression. Pellllsylwnia Med. ]., 66:43-45, 1963. 8. Cook, R. W., Jr.: Etrafon: A Three-Year Study. Pennsylwllia .\Ied.. pagt's 63-65, February 1967. 9. Goldman, D.: Symposium, Emotional Basis of Illness. \Valdorf-Astoria. ~ew York Citv, ~Iarch 29, 1967. .
A double-hlind and crossover procedure was employed in a study comparing the effects of Etrafon, amitriptyline, and placebo in 48 suhjects with anxiety and depression arising from situational stress. Final evaluation demonstrated a preference for Etrafon in 32 patients (66.6':,), and for amitriptyline in seven (14.m). In nine patients, no drug appeared clearly superior to the others. The combined agent tested was particularly effective in relieving insomnia and headaches. Dosage of Etrafon could be reduced to below effective levels of amitriptyline, while maintaining therapeutic responses, 46
REFERENCES
1. Diamond, S.: Use of Amitriptyline Hydrochloride in General Practice. Illinois Med., 123:347-348, 1963. 2. Dorfman, W.: Clinical Experience with Amitriptyline (Elavil). P.\yclUlsomatics, 1: 153-155, 1960. 3. The Medical Letter, Nowmber 7, 1965. 4. Lytton, G. J.: Therapy for Mild Depressive and Anxiety States. Curro Therap. Res., 8:347-350, 1966.
The Dent;er Clinic 701 East Colfax At:enue Dellt:er. Colorado Volume IX
GRAYBURN DAVIS, M.D.
• As medicine approaches the prophylactic era, the concept of total medicine becomes more and more important. This comprehensive idea finds its greatest expression in psychosomatic medicine, where the mindbody, body-mind relationship is so tightly intertwined. One has but to observe the majority of his patients to confirm the existence of this very relationship. Anxiety and depression more often than not are secondary manifestations of some chronic illness such as asthma, allergy, cardiovascular disturbances, etc. The relations of psychial and physical influences sometimes confuse the etiology, manifestations and management of the disorder, making it extremely difficult for the physician to cope with the problem. In recent years, however, clinical studies of psychotropic agents have demonstrated the effectiveness of tranquilizers for anxiety and antidepressants for episodes involving depression. One of the most effective antidepressants, amitriptyline, has been found extremely valuable in a number of clinical trials. J-' Likewise, the efficacy and safety of the phenothiazine tranquilizer, perphenazine, has become widely recognized. A tablet combining these two agents (Etrafon®) 0 has recently become available and appears to be valuable in treating psychical disorders of various types and severities revolving around the depressive anxieties.
The present study compares the effects of this combination (2 mg perphenazine and 25 mg amitriptyline) with those of amitriptyline alone, and of placebo, in management of anxiety and depression in patients. MATERIALS AND METIIODS
Forty-eight subjects were selected on the basis of diagnosis of depression and anxiety for a double-blind, cross-over evaluation of amitriptyline-perphenazine, designated as "e," amitriptyline alone as "A," and a placebo, designated as "B." There were 11 males and 37 females ranging in age from 27 to 80. Almost all the patients had been known to me for a long time; five to ten years or more. The situational stress promoting emotional disturbance in these patients involved physical illness or financial, social, or domestic problems. Physical disorders in 28 patients included asthma, peptic ulcer, cancer, pruritus, hypertension, eczema, arthritis, atopic dermatitis and other afflictions. Other signs of disease included headaches in 11 patients, insomnia in 11 patients, hypochondriasis in five, and hysteria in four. One patient presented manicdepressive tendencies, another paranoid tendencies, and a third was schizophrenic. Each subject received one of the two active medications for the initial six weeks of the study; this was followed by two weeks either of placebo medication or of no medication at all; for the final six weeks completing the study, each patient was then crossed over to Dr. Davis is Ass()(:iate Clinical Professor, Univer- medication with the other active drug. Idensity of Colorado School of Medicine, Denver Clinic. tical capsules contained either 25 mg amitripPresf'nted at the 14th Annual Meeting, Academy tyline; 25 mg amitriptyline and 2 mg perphenof Psychosomatic ~1edicine, Houston, Texas, Novem- azine; or inert placebo. Dosages of all medicaher 30, 1967. tions ranged from two to four capsules per o Product of Schering Corporation, Bloomfield/ day. Similar capsules were used in order to Union. N. J. 44
Volume IX
TREATING PSYCHICAL DISTURBANCES-DAVIS
keep the patient or physician from recognizing any of the compounds. Evaluations of the improvements effected by each active drug were made on at least two occasions during each six weeks of active medication. On these occasions, laboratory and physical findings pertinent to side effects were duly recorded. At the end of the 14 weeks of study, a general preference among the medications was determined according to the relevant findings in each case. RESULTS AND DISCUSSION
Final evaluation of responses to the different medications showed that the combination of perphenazine and amitriptyline controll{'(] emotional disturbance best in 32 subjects (66.6)f); amitriptyline alone was favored in seven cases (14.6%); and no medication appeared superior, for any of various reasons, in nine cases. No subject favored placebo. The nine subjects with no preference among medications included three who could not tolerate either of the active drugs, alleging adverse reactions; three who were too anxious or fearful to complete the active-treatment trials; and three who could distinguish no advantage between the active drugs' effects. Aside from the drugs' direct effects on primary depression and anxiety, the greater frequency of improvement with the combined agent can be attributed largely to Etrafon's general superiority in relieving headaches and insomnia, which prevailed among many members of the present subject group. It might be noted, for example, that two patients habitually requiring large amounts of codeine for headache experienced appreciable reductions in this need during therapy with Etrafon. The finding of Etrafon's notable efficacy in relieving insomnia has been reported by previous investigators concerned with the drug's use in general practice}'" Of the seven subjects reported to favor medication with amitriptyline alone, it should be remarked that emotional disturbance in three cases was diagnosed in association with cancerous organic disease. This suggests a tendency of the antidepressant medication alone to be more appropriate in such a disturbance. Medication apparently effected considerable relief of the symptoms of asthma in nine patients receiving Etrafon and in two on amiJanuary-February, 1968
triptyline. Combined-drug treatment also appreciably reduced the severity of dermatitis in three patients and reduced the frequency of hyperventilation and/or tachycardia in two others. No remarkable relief of these or other involved physical disorders was obtained with amitriptyline alone. Some illustrative cases follow: Case I.-Mr. S., a 42-year-old asthmatic, has considerable anxiety, some depression and insomnia. He is a compensation case who was a professional weIder. He had his own business in New York but was sent to Colorado because of his asthma. He has now become a stoekbrokt'r-an interesting combination -a very successful ont', I might add. He did better on C than on A. He was a bit too drowsy to tolerate unknown C (perphenazine-amitriptyline) in full dose, so he was maintained on one dose at night and one dose during the day if necessary. With this dosage formula he has done quite well. In fact, he has evidenced less asthma and virtually no problcm with insomnia. Case II.-:\lrs. :\1., a physician's widow with severe atopic dermatitis, asthma, anxiety, depression and menopausal symptoms, was in considerahle difficulty financially and had many other problems, too, including a severe relapse of her dermatitis. She was started with unknown C (perphenazine-amitriptyline) and she did fabulously well. When she was changed to B (placebo), she relapsed. On the A (amitriptyline) she was improved but not as well as with C. It should be noted that while on A additional steroids were required to control her. On C she is not taking any steroids. Case III.-J. C., 24, is an anxious, depressed, confused young man with atopic dermatitis of severe degree and associated asthma. His dermatitis was so severe that he had been turned down for military service. He is disturhed to the degree that his education suffers. He has had six or seven jobs, most of this difficulty stemming back to his severe dermatitis and self-consciousness about his poor appearance. With the A (amitriptyline) preparation, he was improved; but with the C (perphenazine-amitriptyline), he was much improved. His asthma disappeared and his skin was much better. Although he was on steroids at the beginning of this study and continues to take them, he is using very much less (an average dose of prednisone of 5 mg a day whereas initially he had taken as much as 20 to 40, with only fair control).
On the basis of the present findings, it may be asserted that medication combining perphenazine and amitriptyline secures greater therapeutic response among patients with anxiety and depression than does amitriptyline alone. This impression accords with such previous findings as those of Diamond. 6 Also in accord with previous findings is the ability found in this study to maintain therapeutic
45
PSYCHOSO~IA TICS
response while reducing the required dosage of Etrafon. Three patients with favorable responses to one capsule b.i.d., and four to one capsule t.i.d., were reduced to one capsule at bedtime while maintaining superior effects of treatment; two other Etrafon- subjects reduced effective dosage to one capsule b.i.d. No serious side effects resulted from medication in the present study: no blood abnormalities, no significant urinary value changes, no liver function disturhances, etc. The most common side effects reported were drowsines~, occurring in 14 patients on Etrafon and eight on amitriptyline; dry mouth, in nine on Etrafan and two on amitriptyline; and dizziness, in four on Etrafon and one on amitriptyline. Alleged side effects caused one patients to discontinue medication with amitriptyline: two to discontinue Etrafon; and three to stop all medication. Interestingly two subjects discontinued medication because of alleged side effects from both the active and inert medications. A<:<:ordingly, an appreciable degree of interference from somatization and other factors related to emotional disorder must be read into the overall record of "side effects" in the present study. The common occurrence of drowsiness in this study agrees with a similar finding in a previous report hy Ernst.; Another side effect noted with some frequency among subjects receiving Etrafon was weight gain; Cook has reported' his impression that this effect is a function of the patients' improved moods. This opinion is shared hy the present investigator, who, moreover, ruled out the possihility of related edema through testing electrolytes and using diuretic agents.
in nine patients (18.7%). No serious side effects occurred as a result of medication. Some drowsiness and dryness of mouth were reported in both activetreatment groups. It is concluded that combination therapy with Etrafon can be expected to relieve anxiety and depression arising from situational stress, with greater effectiveness than amitriptyline alone, and generally with a valuable consistency and relatively low toxicity. Moreover, the compound is particularly valuable when one realizes that in relieving the psychical problem the accompanying physical dysfunction (gastrointestinal complaints, hypertensive states, etc.), real or imagined, is also relieved. Treating the psychiatric condition may well serve as a preventive measure for a future organic chronic state. As Goldman" noted at a recent symposium on the emotional basis of illness, certain stress "reactions require adequate management with hoth psychotherapeutic support and medication to relieve symptoms which, without medication, could persist and hecome chronic."
SU~[MARY
5. Splitter, S. R.: Combined Therapy with a New Drug . . . Amitriptyline and . . . Perphenazine in a ~[edical Office Setting. Psychosomatics, 6:322, 1965. 6. Diamond, S.: Double-Blind Controlled Study of Amitriptylim'-Perphenazine Combination in Medical Office Patients with Depression and Anxiety. Psychosomatics. 7:371-375, 1966. 7. Ernst, E. :\I.: Anxiety and Depression. Pellllsylwnia Med. ]., 66:43-45, 1963. 8. Cook, R. W., Jr.: Etrafon: A Three-Year Study. Pennsylwllia .\Ied.. pagt's 63-65, February 1967. 9. Goldman, D.: Symposium, Emotional Basis of Illness. \Valdorf-Astoria. ~ew York Citv, ~Iarch 29, 1967. .
A double-hlind and crossover procedure was employed in a study comparing the effects of Etrafon, amitriptyline, and placebo in 48 suhjects with anxiety and depression arising from situational stress. Final evaluation demonstrated a preference for Etrafon in 32 patients (66.6':,), and for amitriptyline in seven (14.m). In nine patients, no drug appeared clearly superior to the others. The combined agent tested was particularly effective in relieving insomnia and headaches. Dosage of Etrafon could be reduced to below effective levels of amitriptyline, while maintaining therapeutic responses, 46
REFERENCES
1. Diamond, S.: Use of Amitriptyline Hydrochloride in General Practice. Illinois Med., 123:347-348, 1963. 2. Dorfman, W.: Clinical Experience with Amitriptyline (Elavil). P.\yclUlsomatics, 1: 153-155, 1960. 3. The Medical Letter, Nowmber 7, 1965. 4. Lytton, G. J.: Therapy for Mild Depressive and Anxiety States. Curro Therap. Res., 8:347-350, 1966.
The Dent;er Clinic 701 East Colfax At:enue Dellt:er. Colorado Volume IX