- Email: [email protected]
Some Comments on Non-Drug Factors In Psychiatric Drug Therapy
Some Comments on Non-Drug Factors In Psychiatric Drug Therapy KARL RICKELS,
• Clinical controlled psychophannacological research has led during the past years to a more intense focus on factors other than drugs, Le., non-drug factors, and on their relative importance in affecting drug and placebo responses. Our research group at the University of Pennsylvania and the Philadelphia General Hospital has been particularly interested in such non-drug factors and in the role, if any, that such factors may play in drug therapy outcome in general, and in the outcome of placebo controlled studies in particular. A number of such non-drug, or non-specific factors, have been discussed in recent years by several investigators, including our group, and today I should like to present some evidence collected in recent studies carried out with neurotic, non-psychotic patients which demonstrate that several demographic and symptom related factors indeed affect outcome in controlled drug studies. In particular, I should like to discuss the influence and role which sex, age, intelligence, patient's main symptom focus, symptom pattern and degree of psychopathology may have on the patient's response to drug therapy. All data are based on double-blind controlled studies carried out by us with anxious, often mildly depressed neurotic or character neurotic outpatients. SEX
Table I presents data on side reactions for male and female drug and placebo patients. The data demonstrate that males reported Doctor Rickels is Associate Professor of Psychiatry, University of Pennsylvania and Director of Psychopharmacological Research, Philadelphia General Hospital. Preparation of this paper was supported by USPHS Grants MH04731 and MH08957-8. September-October, 1965
M.D.
fewer side reactions than females in both treatment groups, and that men reported primarily side effects when on drug, while females when on drugs and on placebo. Also, side effects of females included a variety of unrelated vague symptoms, and were often not drug related, while men reported primarily such drug related side effects as "drowsiness." This reporting of side effects on drugs was found not to be related to weight in our studies, and in fact female patients reporting side reactions while on drugs were slightly heavier (mean weight: 140.3 pounds, N =35) than females not reporting side reactions (mean weight: 133.5, N=73). The data supports Green's findings who also reported higher placebo induced incidences of side reactions in female than in male non-psychotic subjects. 1 Elsewhere we have reported that side reactions are frequently psychological in nature and represent an expression of disappointment with therapy, without having to say so straightforwardly.2 It appears, that the more passive female patient uses more indirect means, i.e., side reactions, in this case, to express anger and dissatisfaction with therapy or, in other words, even here, as so frequently in life, the female uses more devious ways in her responses than does the male. Earlier findings by us that less directly hostile patients report more frequently side effects than the more direct hostile patients lend further support to the above.' Some of the implications of these findings are quite obvious. For example, studies being conducted primarily with female patients may differ from studies conducted with male patients in incidences of observed side reactions simply because of differential sex distributions. Turning our focus of attention from side 303
PSYCHOSOMATICS TABLE I. DIFFERENTIAL REPORTING OF SIDE REACTIO:\S FOR MALE AND FEMALE PATIENTS (Fi~res
Dru!l: Patients
Given in PercenlaJtes)
Placeoo Patients
Dru~ &
Placebo
Patients
Male Female
24{4J)· 35(112) X '= 1.50. n .s.
*1'Olal !': is ,'(in'n in
3(31) 15(72) 32(75) 34(187) X'=8.54. p=.OI X'=17.99. p=.OOI
parenth~("s.
reactions to drop outs, we found that sex distribution did not afl'ect the total group of drop-out patients significantly, even if in earlier studies by us we did observe fewer drop outs with male than with female patients. 4 Graph No. 1 demonstrates that females predominated in patients who dropped out from therapy after their initial visit, but not when dropping out at later visits. These drop out data include drug and placebo patients. If one looks at drug and placebo patients separately, one observes the interesting fact that females tend to drop out more frequently on drug and males on placebo. In fact, in the "later drop out group" male patients on placebo contributed mainly to the increase in drop out rate. One may hypothesize that men tend to adhere more rigidly and conscientiously to a ~lales: N-72 Females: S-220
so
40
)0
20
10
Male !='emale ArTCR 1st VISIT
ArTCR 2 HEEl'S
~1ale
Female
TOTAL
started program of treatment if such treatment shows some effect, thus explaining, at least in part, the fewer drop outs observed, and the fewer side reactions reported. Further support for the fact that males might do better with psychopharmacological drugs, has been shown by data reported by Jenner et aI, who reported significantly more clinical improvement in males than females in a chlordiazepoxide-placebo controlled study." Thus our data show that incidences of clinical improvement, dropping out of therapy and reporting of side reactions differ for males and females and indicate that males may do better than females with certain psychopharmacological agents, but not with placebo. AGE
Results from a recently conducted doubleblind evaluation of protriptyline (MK240) and placebo will be used to exemplify the importance that such a simple factor as age may have on clinical outcome in studies carried out with depressed patients.'; Table II presents strong evidence for the existence of a differential response to drug and placebo in patients 40 years and younger and patients 41 years and older. In the older age group, drug effect is most marked and placebo effect least marked, producing a significant drug-placebo difference in improvement rate, while in the younger age group, drug effect decreases and placebo effect increases, so that drug-placebo differences become insignificant. This phenomenon is not a function of different psychopathology levels since pre-scores for both age groups did not differ significantly. The observation of differential drop out rates in these two populations, (i.e., older patients dropped out less frequently than did younger patients, and the fact that in the older age group most drop out patients were on placebo, while this did not hold true for the TABLE II. AGE vs. IMPROVEMENT (DEPRESSED PSYCHIATRIC CLINIC PATIENTS) ARe
o
~
t
Patients on Placeoo
,
Patients on Drury
Graph No. 1. Drop-out rate for male and female neurotic patients.
304
Population Completed Aurited
41 and Above 40 and Below
30
8
16
20
X·=9.36, p=.OI
Depre..ion Scale ChanRe Score (pre· 4 weeks) Dru~·.
10.3 Placebo· 2.8 Dru~ • 6.8 Placebo· 6.8 ·Protriptyline (Merck)
SiKnificance p
.01 n.s. Student', t test
Volume VI
THIRD SYMPOSIUM: ANXIETY AND DEPRESSION
younger age group), can be considered as further evidence for the fact that older patients responded better to protriptyline than did the younger patient group. Time does not allow to discuss the numerous implications of these findings. Suffice it to say here that while pre-psychopathology levels do not differ for both age groups, one may suspect that causes for depressive manifestations, and possibly even etiology may differ for both age groups. INTELLIGENCE
Graph No.2 gives data from a study of about 180 neurotic patients and demonstrates that patients with low intelligence improved more than patients with slightly higher intelligcnce. 7 This differential improvement rate was found in patients treated with placebo or with clinically inactive drugs but not in patients treated with active psychopharmacologic agents. This increased placebo response observed in the lower intelligence group may at times contribute to a decrease in drug-placebo differences in such populations and one may speculate that this response is related to the higher degree of suggestibility, compliance, dependency in relation to authority figures, as well as to the more appropriate drug treatment expectations found in this patient group. It should be added here, however, that intelligence, as measured in this case by a vocabulary test,S was very low for the total patient population (median 86), which is lower than the I.Q. for unskilled workers. It may therefore well be, that intelligence plays a more important role in this very low intelligence group than in patients with an I.Q. of 100 and above.
chotherapy but only "nerve medication" and sometimes not even such, as they did not understand the emotional nature of their problems. Psychiatric clinic patients, on the other hand, were more emotionally focused, expected psychiatric help, often as a combination of drug and psychotherapy, and were usually aware of the emotional nature of their problems. Table III shows main symptom focus of patients, participating in one of our studies in which two active agents were used and in which both groups of patients were seen by the same psychiatrist and the same nurse. One can observe that a very significant difference exists between psychiatric and medical clinic neurotic patients, psychiatric clinic patients presenting primarily psychological symptoms and medical clinic patients primarily somatic ones. 9 This differential symptom focus may well be one of the major factors in explaining the significantly higher improvement rate found in the psychiatric clinic population, when compared with medical clinic patients (Table III). Some further indication of why medical, somatically focused patients improved less and dropped out more than psychiatric clinic
so
40
30
20
SOMATIC VS. EMOTIONAL SYMPTOM FOCUS
Turning now to a discussion of the influence which the patient's main symptom focus may have on his improvement rate, data collected in studies conducted with neurotic patients from the medical and psychiatric clinics of a large city hospital, both of low intelligence and low socio-economic (class IV and V) background, may serve as examples. Neurotic medical clinic patients were primarily somatically focused, did not expect psySeptember-October, 1965
10
BELOW HEOIArl
~
o
I~ITELLIGE~lCE
lWOVE ~U:OIA."t
I:'"lprovcd Unimproved
Graph No.2. Frequencies of improved and unimproved placebo treated anxious patients with high and low intelliltence (N-84).
305
PSYCHOSOMATICS TABLE
III.
DRUG
INDUCED
CLINICAL IMPROVEMENT NEUROTIC POPULATIONS
Symptom Population
Focus
Somatic
Psychiatric Clinic Patients Medical Clinic Patients
22 40
SYMPTOM
PAYFERN OF
AND
DECREE
PSYCHOPATHOLOGY
Table IV gives the mean doctor ratings of anxiety, depression, irritability, and hypochondriasis (on seven point scales) for anxious private psychiatric patients of upper middle socio-economic class, for anxious medical clinic patients of lowest socio-economic class (class 5 and less) and for depressed psychiatric clinic patients of low socio-economic class (class 4 and 5). Several interesting findings stand out: 1. Depressed as well as anxious patients, show mixed symptomatology, i.e., suffer from some degrees of psychopathology in the four symptom areas concerned in this table. 2. While anxious patients are significantly more anxious than depressed patients (p < .001 [N = 185]) (Student’s t-test), and depressed patients significantly more depressed
TABLE
IV.
SYMTOM
RATINGS POPULATIONS
TN
THREE
Anxious Private Anxious Medical Psychiatric Patients Clinic Patients (N=112) (N=95)
NEUROTIC
Depressed Psychiatric Clinic Patients (N=73)
Anxiety Depression
4.44 3.48
4.05 3.08
Irritability Hypochondriasin
4.07
2.57
2.68
2.30
4.64
3.18
306
3.27 4.96
Improved
48
42
9
16
ANXIOUS
Unimproved 22 29 X2=9.60,
p<.OO1
patients is provided by the observation that somatically focused medical clinic patients complained significantly more about the many research forms used. While psychiatric clinic patients evaluated these research forms largely as positive, medical clinic patients evaluated them as negative. One may well expect the less educated, less intelligent patient who is more concrete in his thinking and unable to see the emotionality of his complaints to be more threatened and upset by such research forms, not only because these forms are emotionally oriented but also because the patients’ low I.Q. often does not allow them to understand many of the questions asked.
TWO
Patients
Emotional
X229.1l,
IN
than both, present
anxious anxiety in the
p<.Ol
patients (p<.00l [N=185]), and depression are definitely two patient populations.
3. Hypochondriasis scores are highest in anxious, somatizing, low socio-economic medical clinic patients and lowest in middle to middle-upper class psychiatric private patients ( p < .001 [N = 207] ) Since it is a wellestablished fact that hypochondriasis is hard to influence therapeutically, one may observe another factor which contributes to the poorer clinical improvement rate found in the medical clinic patient group. Also, there may exist evidence for a selective process, that is, patients are either referred or accepted for psychotherapy only if they have none or little somatic or hypochondriacal complaints. It was also of interest to us to find that hypochondriasis is significantly lower in the depressed clinic group as compared with the anxious clinic group (p<.OO1 [N168]) thus throwing doubt on the belief by many that hypochondriasis as well as somatizations can be considered pure depressive equivalents. .
4. Finally, irritability is high in anxious, private patients, belonging to the middle socio-economic class, who also dropped out least and reported lowest incidences of side effects in our studies; irritability is low in patient populations of low socio-economic status (p< .001 [N = 207]), in whom we also observed higher incidences of drop outs and side effects, but less clinical improvement. Earlier we interpreted dropping out of therapy as well as the reporting of side efects, particularly when occurring on placebo, as frequently representing an indirect expression of hostility, to be associated with lower hostility scores on the Buss-Durkee hostility scale, and to occur primarily in patients who could not express direct hostility or, in other words, were unable to tell the physician that he was not helping them and/or that they disliked participating in research.2’3 Volume
VI
THIRD SYMPOSIUM: ANXIETY AND DEPRESSION TABLE V. CLINICAL IMPROVEMENT PRODUCED BY TYBAMATE AND PLACEBO AS RELATED TO INITIAL SYMPTOM LEVEL
Initial Symptom Level
Difference Seor.. pre-pool 2 weeb)
DruR
Hilth
-2.92"
Low N
-0.50
:-.;
Global Improvement
(~
Anxiety Placebo
-1.12 29 +0.17 12
p'
DruR
.01
-1.75
n.s.
-1.25
Irritability Placebo
+0.40 14 -0.67 17
p
DruR
.05
0
n.s.
-1.35
Depression Placebo
+0.20 13 0 32
(post 2 weeb) Placebo
p
Drult
n.s.
-0.78
.02
-0.90
+0.67 18 -0.78 18
*p values derived by Student's t-tests, or chi square where Studrnt's t-test not appropriate because of excessive drnotes improvement.
p
.02 n.s.
skewin~.
**~tinus si~
The differential level of observed irritability in Table IV confirms these interpretations. The more irritable, less somatizing, private patient expresses discontent and anger more easily and directly and does not have to resort to dropping out or reporting of side reactions, while the low socio-economic, more somatizing and less irritable medical or psychiatric clinic patient cannot do so. Unable to show dissatisfaction, anger, or hostility directly, he must resort to such indirect hostility expressions as side effects and/or dropping out. Consequently, drop out rates for example, differ significantly between anxious clinic and anxious private patients (X 2 = 6.12, p<.02, N=207). The above findings make it appear obvious that clinical improvement observed in controlled studies can well be influenced significantly by existing patterns and degree of psychopathology; particularly if drug and placebo exert differential effects on different symptom clusters or patterns of psychopathology. Earlier we reported on such influence of different symptom focus on study outcome; we found that Deprol (meprobamate, 400 mgm., and benactyzine, 1 mgm., produced most and Tofranil (imipramine) least improvement in mildly to moderately depressed medical clinic patients, while the reverse was observed for more affectively oriented depressed, psychiatric clinic patients. tO Data collected in a controlled study of tybamate (Solacen, 2000 mgm./d) and placebo may serve as an illustration as to how levels of pre-study psychopathology as well as of several symptom clusters may affect drug study outcome.H Results found with the "dizzy" factor of the September-October, 1965
Clyde Mood Scale,t2 a factor being heavily loaded by such items as dizzy, sick to the stomach, jittery, and shaky, is presented in Graph 3, and demonstrates that homogeneity of regression does not exist here and that the slopes of tybamate and placebo scores differ significantly from each other. Since only tybamate but not placebo responses were affected by initial level, and since tybamate produced largest improvement in patients with high pre-scores on this "dizzy" factor, one can easily understand why significant drug-placebo differences occur only in this "high symptom" patient group. Similar results, related to differences in the slopes of regression lines, were found in several other symptom clusters, rated by the physician on seven point scales. Dividing the
CHANGE IN ··DIZZY·· FACTOR OF THE CLYDE MOOD SCALE OVER A 2 WEEK PERIOD (Dizzy, Sick to ~tomoch, Jittery, Shaky) (N = 51)
/
Placebo
/
70
/
/ /
Tybomote
/
6S
/ /
/ IIJ
"/
F 0 8.10
/ 55
IIJ
6S
70
Pre - Score
Graph. No.3. 307
PSYCHOSOMATICS
total study population into patients with high and low ratings of anxiety, depression, and irritability, it can be observed in Table V that only tybamate patients with high, but not with low initial levels of anxiety and irritability improved significantly more than placebo patients. It can also be observed in the same table that, in contrast to the anxiety and irritability clusters, tybamate produced significantly more improvement over placebo in the low depression cluster, but not in the high depression cluster. Since most patients were only mildly depressed in this study, a significant dmg-placebo difference in this cluster could however also be observed for the total population (p<.05). Table V also demonstrates that dmg patients improved significantly less in the high depressed groups as compared with the low depressed groups (t = 2.46, p. < .05), and significantly more in the high anxious groups as compared with the low anxious groups (t=3.18, p.<.OI). Finally, Table V furthermore gives global improvement data, using the physicians' global judgement of clinical change, executed after two weeks on a +3 to -3 scale, for patients who were high and patients who were low on a 64 Item Neurotic Symptom Check List at study onset. Again, significant drug-placebo differences were observed in high psychopathology patients but not in low psychopathology patients. This fact appears to be related primarily to the high improvement rate observed in placebo patients with low initial levels of psychopathology (improvement: high vs. low psychopathology placebo patients t = 2.54, p<.05). Comparing clinical overall improvement (physicians' global improvement scale) produced by tybamate and placebo for the total study population, no significant differences between dmg and placebo can be observed at the two-week level (XZ = 1.66), but this difference becomes significant at the four-week level (xz=5.57, p.<.02).1I These data were further supported by the finding that for the total study population and over a two-week period, tybamate, as compared to placeho. decreased significantly the total scores of the 64 Item Patient Checklist 308
(dmg-placebo difference = 4.37, p<.OI) and decreased almost significantly the scores on the "sleepy" (p<.IO) and "unhappy" (p <.10) factors of the Clyde Mood Scale. SUMMARY
It could be demonstrated, based on data collected in controlled clinical studies, that several non-dmg variables, such as sex, age, and intelligence, as well as the patient's symptom focus, i.e., whether his neurosis is primarily somatically or emotionally expressed, can indeed affect dmg treatment outcome in general and controlled dmg study outcome in particular. Finally, using data collected in a double-blind study of tybamate ( Solacen) and placebo as an illustration, it could be demonstrated that Initial Levels of total psychopathology as well as of several subclusters, e.g., dizzy, anxiety, irritability, and depression, may influence dmg study outcome. In this particular study, patients with high neurotic overall psychopathology, high anxiety, high irritability, and high scores on the "dizzy" factor, improved most with tybamate when compared with placebo. It was also of interest to find that mildly depressed patients improved significantly. Disregarding initial levels, at least in this tybamate study, decreases the significance of dmgplacebo difference in improvement rate. This influence of initial level on improvement is particularly strong during the first two weeks, so that for the total population only one of many measures shows a significant (p<.05), and only two measures an almost significant (p <.10) dmg-placebo difference for this period. At four weeks, however, most comparisons between dmg and placebo become significant. One therefore can come to the tentative conclusion that tybamate is effective clinically in anxious, irritable, neurotic patients who also suffer from mild elements of depression, that tybamate may produce best results in the "sicker" neurotic patients, and that the dmg may be used successfully in patients presenting a mixed neurotic symptomatology. Data presented today may help to explain some of the divergent findings reported in the literature, and awareness of the possible importance that such factors as age, sex, intelliVolume VI
THIRD SYMPOSIUM: ANXIETY AND DEPRESSION
gence, symptom focus, and level of pathology may have for observed clinical results, may lead to an increased sophistication in psychiatric drug research, and hopefully in drug treatment. REFERE~CES
1. Green, D. \1.: Side effects-quantification. Fed. Pmc., :21: 179, 196:2.
2. Hickels, K.: Psychopharmacologic agents: A clinical psychiatrist's individualistic point of \'iew: patient and doctor variables. ]. Nerv. .\ lCllt. Dis., 136:540 (June) 1963. 3. Downing, R. and Rickels, K.: Self report of hostilitv and the incidence of side reactions in neurotic out-paticnts treated with tranquilizing drugs amI placebo. Submitted. 4. Rickels, K. and Snow, L.: Meprobamate and phenoharhital sodium in anxious neurotic psychiatric and medical clinic out-patients: A controlled study. PSIjc1lOplwrmacologill, 5:339, 1964. 5. Jenner. F. A.. Kerry, R. J. and Parkin, D.: A controllcd trial of methaminodiazepoxide (ChlorI wish to thank all my co-workers, Drs. Downing and Raah in particular, for helping in the research reportcd hcr~n.
6. 7. 8. 9.
10. 11.
l"
diazepoxide, "Libriurn") in the treatment of anxiety in neurotic patients. ]. Ment. Sci., 107 :575 (May) 1961. Rickels, K., Raab, E., DiSilverio, R. and Mock, J.: Double-blind evaluation of protriptyline ( MK-240) and placebo. In preparation. Rickels, K. and Downing, R.: In preparation. Miner, J. B.: Intelligence in the United States. New York: Springer, 1958. Rickels, K. and Anderson, F. L.: Attrited and completed lower socio-economic class outpatients in psychiatric drug treatment. Submitted. Rickels, K., Ward, C. and Schut, L.: Different populations, different drug responses. Am. ] . Med. Sci., 247:328 (March) 1964. Raab, E., Rickels, K. and Moore, E.: A douhleblind evaluation of tybamate in anxious neurotic medical clinic patients. Am. ]. Psyc1liat., 120: 1005 (April) 1964. Clyde, D. J.: Manual for Clyde Mood Scale, Biometric Laboratory, University of Miami, Coral Gables, Florida, 1963.
Dcpartment of PSljclliatTlj 203 Piersol Building Universitlj Hospital 3600 Spruce Street Philodelphia 4, Pennsljlvania
Current Antidepressant Therapy EDWI:-<
DUNLOP, M.D.
INTRODUCTION
METHODS AND MATERIALS
• The subtitle of the Third Symposium on Anxiety and Depression although not appearing on the program, but on yesterday's luncheon tickets, "What's New In Psychophannacology," will limit the presentation of this data to the newer psychopharmaceutical agents used for the treatment of depression. Between December, 1964, and January, 1965, three new antidepressant agents were made avaliable for prescription. These are the first since the new Federal Drug Administration regulations went into effect and are of significance to those interested in the treatment of depression by psychophannacology. The drugs are as follows:
Norpramin and Pertofrane are demethylated metabolites of imipramine, and in extensive clinical trials in this country and abroad appear to be more active antidepressants than the parent substance. The clinical types of depression which have shown the best therapeutic response are endogenous depression, psychotic depressive reaction, involutional depressive reactions, and reactive depressions. Those depressions associated with schizophrenia or schizophrenics going through a depressive response appear to respond less favorably. Since 1961, more than 100 depressed patients have been treated with Desipramine. These include both hospitalized and outpatient cases and represent all varieties of depression ranging from the most severe, some frequently resistant to other antidepressant agents and electro-shock, to those of a mild nature and ambulatory status. Today, many patients are treated in the community by non-
1. desipramine (Pertofrane) (Geigy) 2. desipramine (Norpramin) (Lakeside) 3. nortriptyline (Aventyl) (Lilly) Doctor Dunlop is Director of Research, Fuller Memorial Sanitarium, South Attleboro, \Iassachusetts. September-October, 1965
309
• Clinical controlled psychophannacological research has led during the past years to a more intense focus on factors other than drugs, Le., non-drug factors, and on their relative importance in affecting drug and placebo responses. Our research group at the University of Pennsylvania and the Philadelphia General Hospital has been particularly interested in such non-drug factors and in the role, if any, that such factors may play in drug therapy outcome in general, and in the outcome of placebo controlled studies in particular. A number of such non-drug, or non-specific factors, have been discussed in recent years by several investigators, including our group, and today I should like to present some evidence collected in recent studies carried out with neurotic, non-psychotic patients which demonstrate that several demographic and symptom related factors indeed affect outcome in controlled drug studies. In particular, I should like to discuss the influence and role which sex, age, intelligence, patient's main symptom focus, symptom pattern and degree of psychopathology may have on the patient's response to drug therapy. All data are based on double-blind controlled studies carried out by us with anxious, often mildly depressed neurotic or character neurotic outpatients. SEX
Table I presents data on side reactions for male and female drug and placebo patients. The data demonstrate that males reported Doctor Rickels is Associate Professor of Psychiatry, University of Pennsylvania and Director of Psychopharmacological Research, Philadelphia General Hospital. Preparation of this paper was supported by USPHS Grants MH04731 and MH08957-8. September-October, 1965
M.D.
fewer side reactions than females in both treatment groups, and that men reported primarily side effects when on drug, while females when on drugs and on placebo. Also, side effects of females included a variety of unrelated vague symptoms, and were often not drug related, while men reported primarily such drug related side effects as "drowsiness." This reporting of side effects on drugs was found not to be related to weight in our studies, and in fact female patients reporting side reactions while on drugs were slightly heavier (mean weight: 140.3 pounds, N =35) than females not reporting side reactions (mean weight: 133.5, N=73). The data supports Green's findings who also reported higher placebo induced incidences of side reactions in female than in male non-psychotic subjects. 1 Elsewhere we have reported that side reactions are frequently psychological in nature and represent an expression of disappointment with therapy, without having to say so straightforwardly.2 It appears, that the more passive female patient uses more indirect means, i.e., side reactions, in this case, to express anger and dissatisfaction with therapy or, in other words, even here, as so frequently in life, the female uses more devious ways in her responses than does the male. Earlier findings by us that less directly hostile patients report more frequently side effects than the more direct hostile patients lend further support to the above.' Some of the implications of these findings are quite obvious. For example, studies being conducted primarily with female patients may differ from studies conducted with male patients in incidences of observed side reactions simply because of differential sex distributions. Turning our focus of attention from side 303
PSYCHOSOMATICS TABLE I. DIFFERENTIAL REPORTING OF SIDE REACTIO:\S FOR MALE AND FEMALE PATIENTS (Fi~res
Dru!l: Patients
Given in PercenlaJtes)
Placeoo Patients
Dru~ &
Placebo
Patients
Male Female
24{4J)· 35(112) X '= 1.50. n .s.
*1'Olal !': is ,'(in'n in
3(31) 15(72) 32(75) 34(187) X'=8.54. p=.OI X'=17.99. p=.OOI
parenth~("s.
reactions to drop outs, we found that sex distribution did not afl'ect the total group of drop-out patients significantly, even if in earlier studies by us we did observe fewer drop outs with male than with female patients. 4 Graph No. 1 demonstrates that females predominated in patients who dropped out from therapy after their initial visit, but not when dropping out at later visits. These drop out data include drug and placebo patients. If one looks at drug and placebo patients separately, one observes the interesting fact that females tend to drop out more frequently on drug and males on placebo. In fact, in the "later drop out group" male patients on placebo contributed mainly to the increase in drop out rate. One may hypothesize that men tend to adhere more rigidly and conscientiously to a ~lales: N-72 Females: S-220
so
40
)0
20
10
Male !='emale ArTCR 1st VISIT
ArTCR 2 HEEl'S
~1ale
Female
TOTAL
started program of treatment if such treatment shows some effect, thus explaining, at least in part, the fewer drop outs observed, and the fewer side reactions reported. Further support for the fact that males might do better with psychopharmacological drugs, has been shown by data reported by Jenner et aI, who reported significantly more clinical improvement in males than females in a chlordiazepoxide-placebo controlled study." Thus our data show that incidences of clinical improvement, dropping out of therapy and reporting of side reactions differ for males and females and indicate that males may do better than females with certain psychopharmacological agents, but not with placebo. AGE
Results from a recently conducted doubleblind evaluation of protriptyline (MK240) and placebo will be used to exemplify the importance that such a simple factor as age may have on clinical outcome in studies carried out with depressed patients.'; Table II presents strong evidence for the existence of a differential response to drug and placebo in patients 40 years and younger and patients 41 years and older. In the older age group, drug effect is most marked and placebo effect least marked, producing a significant drug-placebo difference in improvement rate, while in the younger age group, drug effect decreases and placebo effect increases, so that drug-placebo differences become insignificant. This phenomenon is not a function of different psychopathology levels since pre-scores for both age groups did not differ significantly. The observation of differential drop out rates in these two populations, (i.e., older patients dropped out less frequently than did younger patients, and the fact that in the older age group most drop out patients were on placebo, while this did not hold true for the TABLE II. AGE vs. IMPROVEMENT (DEPRESSED PSYCHIATRIC CLINIC PATIENTS) ARe
o
~
t
Patients on Placeoo
,
Patients on Drury
Graph No. 1. Drop-out rate for male and female neurotic patients.
304
Population Completed Aurited
41 and Above 40 and Below
30
8
16
20
X·=9.36, p=.OI
Depre..ion Scale ChanRe Score (pre· 4 weeks) Dru~·.
10.3 Placebo· 2.8 Dru~ • 6.8 Placebo· 6.8 ·Protriptyline (Merck)
SiKnificance p
.01 n.s. Student', t test
Volume VI
THIRD SYMPOSIUM: ANXIETY AND DEPRESSION
younger age group), can be considered as further evidence for the fact that older patients responded better to protriptyline than did the younger patient group. Time does not allow to discuss the numerous implications of these findings. Suffice it to say here that while pre-psychopathology levels do not differ for both age groups, one may suspect that causes for depressive manifestations, and possibly even etiology may differ for both age groups. INTELLIGENCE
Graph No.2 gives data from a study of about 180 neurotic patients and demonstrates that patients with low intelligence improved more than patients with slightly higher intelligcnce. 7 This differential improvement rate was found in patients treated with placebo or with clinically inactive drugs but not in patients treated with active psychopharmacologic agents. This increased placebo response observed in the lower intelligence group may at times contribute to a decrease in drug-placebo differences in such populations and one may speculate that this response is related to the higher degree of suggestibility, compliance, dependency in relation to authority figures, as well as to the more appropriate drug treatment expectations found in this patient group. It should be added here, however, that intelligence, as measured in this case by a vocabulary test,S was very low for the total patient population (median 86), which is lower than the I.Q. for unskilled workers. It may therefore well be, that intelligence plays a more important role in this very low intelligence group than in patients with an I.Q. of 100 and above.
chotherapy but only "nerve medication" and sometimes not even such, as they did not understand the emotional nature of their problems. Psychiatric clinic patients, on the other hand, were more emotionally focused, expected psychiatric help, often as a combination of drug and psychotherapy, and were usually aware of the emotional nature of their problems. Table III shows main symptom focus of patients, participating in one of our studies in which two active agents were used and in which both groups of patients were seen by the same psychiatrist and the same nurse. One can observe that a very significant difference exists between psychiatric and medical clinic neurotic patients, psychiatric clinic patients presenting primarily psychological symptoms and medical clinic patients primarily somatic ones. 9 This differential symptom focus may well be one of the major factors in explaining the significantly higher improvement rate found in the psychiatric clinic population, when compared with medical clinic patients (Table III). Some further indication of why medical, somatically focused patients improved less and dropped out more than psychiatric clinic
so
40
30
20
SOMATIC VS. EMOTIONAL SYMPTOM FOCUS
Turning now to a discussion of the influence which the patient's main symptom focus may have on his improvement rate, data collected in studies conducted with neurotic patients from the medical and psychiatric clinics of a large city hospital, both of low intelligence and low socio-economic (class IV and V) background, may serve as examples. Neurotic medical clinic patients were primarily somatically focused, did not expect psySeptember-October, 1965
10
BELOW HEOIArl
~
o
I~ITELLIGE~lCE
lWOVE ~U:OIA."t
I:'"lprovcd Unimproved
Graph No.2. Frequencies of improved and unimproved placebo treated anxious patients with high and low intelliltence (N-84).
305
PSYCHOSOMATICS TABLE
III.
DRUG
INDUCED
CLINICAL IMPROVEMENT NEUROTIC POPULATIONS
Symptom Population
Focus
Somatic
Psychiatric Clinic Patients Medical Clinic Patients
22 40
SYMPTOM
PAYFERN OF
AND
DECREE
PSYCHOPATHOLOGY
Table IV gives the mean doctor ratings of anxiety, depression, irritability, and hypochondriasis (on seven point scales) for anxious private psychiatric patients of upper middle socio-economic class, for anxious medical clinic patients of lowest socio-economic class (class 5 and less) and for depressed psychiatric clinic patients of low socio-economic class (class 4 and 5). Several interesting findings stand out: 1. Depressed as well as anxious patients, show mixed symptomatology, i.e., suffer from some degrees of psychopathology in the four symptom areas concerned in this table. 2. While anxious patients are significantly more anxious than depressed patients (p < .001 [N = 185]) (Student’s t-test), and depressed patients significantly more depressed
TABLE
IV.
SYMTOM
RATINGS POPULATIONS
TN
THREE
Anxious Private Anxious Medical Psychiatric Patients Clinic Patients (N=112) (N=95)
NEUROTIC
Depressed Psychiatric Clinic Patients (N=73)
Anxiety Depression
4.44 3.48
4.05 3.08
Irritability Hypochondriasin
4.07
2.57
2.68
2.30
4.64
3.18
306
3.27 4.96
Improved
48
42
9
16
ANXIOUS
Unimproved 22 29 X2=9.60,
p<.OO1
patients is provided by the observation that somatically focused medical clinic patients complained significantly more about the many research forms used. While psychiatric clinic patients evaluated these research forms largely as positive, medical clinic patients evaluated them as negative. One may well expect the less educated, less intelligent patient who is more concrete in his thinking and unable to see the emotionality of his complaints to be more threatened and upset by such research forms, not only because these forms are emotionally oriented but also because the patients’ low I.Q. often does not allow them to understand many of the questions asked.
TWO
Patients
Emotional
X229.1l,
IN
than both, present
anxious anxiety in the
p<.Ol
patients (p<.00l [N=185]), and depression are definitely two patient populations.
3. Hypochondriasis scores are highest in anxious, somatizing, low socio-economic medical clinic patients and lowest in middle to middle-upper class psychiatric private patients ( p < .001 [N = 207] ) Since it is a wellestablished fact that hypochondriasis is hard to influence therapeutically, one may observe another factor which contributes to the poorer clinical improvement rate found in the medical clinic patient group. Also, there may exist evidence for a selective process, that is, patients are either referred or accepted for psychotherapy only if they have none or little somatic or hypochondriacal complaints. It was also of interest to us to find that hypochondriasis is significantly lower in the depressed clinic group as compared with the anxious clinic group (p<.OO1 [N168]) thus throwing doubt on the belief by many that hypochondriasis as well as somatizations can be considered pure depressive equivalents. .
4. Finally, irritability is high in anxious, private patients, belonging to the middle socio-economic class, who also dropped out least and reported lowest incidences of side effects in our studies; irritability is low in patient populations of low socio-economic status (p< .001 [N = 207]), in whom we also observed higher incidences of drop outs and side effects, but less clinical improvement. Earlier we interpreted dropping out of therapy as well as the reporting of side efects, particularly when occurring on placebo, as frequently representing an indirect expression of hostility, to be associated with lower hostility scores on the Buss-Durkee hostility scale, and to occur primarily in patients who could not express direct hostility or, in other words, were unable to tell the physician that he was not helping them and/or that they disliked participating in research.2’3 Volume
VI
THIRD SYMPOSIUM: ANXIETY AND DEPRESSION TABLE V. CLINICAL IMPROVEMENT PRODUCED BY TYBAMATE AND PLACEBO AS RELATED TO INITIAL SYMPTOM LEVEL
Initial Symptom Level
Difference Seor.. pre-pool 2 weeb)
DruR
Hilth
-2.92"
Low N
-0.50
:-.;
Global Improvement
(~
Anxiety Placebo
-1.12 29 +0.17 12
p'
DruR
.01
-1.75
n.s.
-1.25
Irritability Placebo
+0.40 14 -0.67 17
p
DruR
.05
0
n.s.
-1.35
Depression Placebo
+0.20 13 0 32
(post 2 weeb) Placebo
p
Drult
n.s.
-0.78
.02
-0.90
+0.67 18 -0.78 18
*p values derived by Student's t-tests, or chi square where Studrnt's t-test not appropriate because of excessive drnotes improvement.
p
.02 n.s.
skewin~.
**~tinus si~
The differential level of observed irritability in Table IV confirms these interpretations. The more irritable, less somatizing, private patient expresses discontent and anger more easily and directly and does not have to resort to dropping out or reporting of side reactions, while the low socio-economic, more somatizing and less irritable medical or psychiatric clinic patient cannot do so. Unable to show dissatisfaction, anger, or hostility directly, he must resort to such indirect hostility expressions as side effects and/or dropping out. Consequently, drop out rates for example, differ significantly between anxious clinic and anxious private patients (X 2 = 6.12, p<.02, N=207). The above findings make it appear obvious that clinical improvement observed in controlled studies can well be influenced significantly by existing patterns and degree of psychopathology; particularly if drug and placebo exert differential effects on different symptom clusters or patterns of psychopathology. Earlier we reported on such influence of different symptom focus on study outcome; we found that Deprol (meprobamate, 400 mgm., and benactyzine, 1 mgm., produced most and Tofranil (imipramine) least improvement in mildly to moderately depressed medical clinic patients, while the reverse was observed for more affectively oriented depressed, psychiatric clinic patients. tO Data collected in a controlled study of tybamate (Solacen, 2000 mgm./d) and placebo may serve as an illustration as to how levels of pre-study psychopathology as well as of several symptom clusters may affect drug study outcome.H Results found with the "dizzy" factor of the September-October, 1965
Clyde Mood Scale,t2 a factor being heavily loaded by such items as dizzy, sick to the stomach, jittery, and shaky, is presented in Graph 3, and demonstrates that homogeneity of regression does not exist here and that the slopes of tybamate and placebo scores differ significantly from each other. Since only tybamate but not placebo responses were affected by initial level, and since tybamate produced largest improvement in patients with high pre-scores on this "dizzy" factor, one can easily understand why significant drug-placebo differences occur only in this "high symptom" patient group. Similar results, related to differences in the slopes of regression lines, were found in several other symptom clusters, rated by the physician on seven point scales. Dividing the
CHANGE IN ··DIZZY·· FACTOR OF THE CLYDE MOOD SCALE OVER A 2 WEEK PERIOD (Dizzy, Sick to ~tomoch, Jittery, Shaky) (N = 51)
/
Placebo
/
70
/
/ /
Tybomote
/
6S
/ /
/ IIJ
"/
F 0 8.10
/ 55
IIJ
6S
70
Pre - Score
Graph. No.3. 307
PSYCHOSOMATICS
total study population into patients with high and low ratings of anxiety, depression, and irritability, it can be observed in Table V that only tybamate patients with high, but not with low initial levels of anxiety and irritability improved significantly more than placebo patients. It can also be observed in the same table that, in contrast to the anxiety and irritability clusters, tybamate produced significantly more improvement over placebo in the low depression cluster, but not in the high depression cluster. Since most patients were only mildly depressed in this study, a significant dmg-placebo difference in this cluster could however also be observed for the total population (p<.05). Table V also demonstrates that dmg patients improved significantly less in the high depressed groups as compared with the low depressed groups (t = 2.46, p. < .05), and significantly more in the high anxious groups as compared with the low anxious groups (t=3.18, p.<.OI). Finally, Table V furthermore gives global improvement data, using the physicians' global judgement of clinical change, executed after two weeks on a +3 to -3 scale, for patients who were high and patients who were low on a 64 Item Neurotic Symptom Check List at study onset. Again, significant drug-placebo differences were observed in high psychopathology patients but not in low psychopathology patients. This fact appears to be related primarily to the high improvement rate observed in placebo patients with low initial levels of psychopathology (improvement: high vs. low psychopathology placebo patients t = 2.54, p<.05). Comparing clinical overall improvement (physicians' global improvement scale) produced by tybamate and placebo for the total study population, no significant differences between dmg and placebo can be observed at the two-week level (XZ = 1.66), but this difference becomes significant at the four-week level (xz=5.57, p.<.02).1I These data were further supported by the finding that for the total study population and over a two-week period, tybamate, as compared to placeho. decreased significantly the total scores of the 64 Item Patient Checklist 308
(dmg-placebo difference = 4.37, p<.OI) and decreased almost significantly the scores on the "sleepy" (p<.IO) and "unhappy" (p <.10) factors of the Clyde Mood Scale. SUMMARY
It could be demonstrated, based on data collected in controlled clinical studies, that several non-dmg variables, such as sex, age, and intelligence, as well as the patient's symptom focus, i.e., whether his neurosis is primarily somatically or emotionally expressed, can indeed affect dmg treatment outcome in general and controlled dmg study outcome in particular. Finally, using data collected in a double-blind study of tybamate ( Solacen) and placebo as an illustration, it could be demonstrated that Initial Levels of total psychopathology as well as of several subclusters, e.g., dizzy, anxiety, irritability, and depression, may influence dmg study outcome. In this particular study, patients with high neurotic overall psychopathology, high anxiety, high irritability, and high scores on the "dizzy" factor, improved most with tybamate when compared with placebo. It was also of interest to find that mildly depressed patients improved significantly. Disregarding initial levels, at least in this tybamate study, decreases the significance of dmgplacebo difference in improvement rate. This influence of initial level on improvement is particularly strong during the first two weeks, so that for the total population only one of many measures shows a significant (p<.05), and only two measures an almost significant (p <.10) dmg-placebo difference for this period. At four weeks, however, most comparisons between dmg and placebo become significant. One therefore can come to the tentative conclusion that tybamate is effective clinically in anxious, irritable, neurotic patients who also suffer from mild elements of depression, that tybamate may produce best results in the "sicker" neurotic patients, and that the dmg may be used successfully in patients presenting a mixed neurotic symptomatology. Data presented today may help to explain some of the divergent findings reported in the literature, and awareness of the possible importance that such factors as age, sex, intelliVolume VI
THIRD SYMPOSIUM: ANXIETY AND DEPRESSION
gence, symptom focus, and level of pathology may have for observed clinical results, may lead to an increased sophistication in psychiatric drug research, and hopefully in drug treatment. REFERE~CES
1. Green, D. \1.: Side effects-quantification. Fed. Pmc., :21: 179, 196:2.
2. Hickels, K.: Psychopharmacologic agents: A clinical psychiatrist's individualistic point of \'iew: patient and doctor variables. ]. Nerv. .\ lCllt. Dis., 136:540 (June) 1963. 3. Downing, R. and Rickels, K.: Self report of hostilitv and the incidence of side reactions in neurotic out-paticnts treated with tranquilizing drugs amI placebo. Submitted. 4. Rickels, K. and Snow, L.: Meprobamate and phenoharhital sodium in anxious neurotic psychiatric and medical clinic out-patients: A controlled study. PSIjc1lOplwrmacologill, 5:339, 1964. 5. Jenner. F. A.. Kerry, R. J. and Parkin, D.: A controllcd trial of methaminodiazepoxide (ChlorI wish to thank all my co-workers, Drs. Downing and Raah in particular, for helping in the research reportcd hcr~n.
6. 7. 8. 9.
10. 11.
l"
diazepoxide, "Libriurn") in the treatment of anxiety in neurotic patients. ]. Ment. Sci., 107 :575 (May) 1961. Rickels, K., Raab, E., DiSilverio, R. and Mock, J.: Double-blind evaluation of protriptyline ( MK-240) and placebo. In preparation. Rickels, K. and Downing, R.: In preparation. Miner, J. B.: Intelligence in the United States. New York: Springer, 1958. Rickels, K. and Anderson, F. L.: Attrited and completed lower socio-economic class outpatients in psychiatric drug treatment. Submitted. Rickels, K., Ward, C. and Schut, L.: Different populations, different drug responses. Am. ] . Med. Sci., 247:328 (March) 1964. Raab, E., Rickels, K. and Moore, E.: A douhleblind evaluation of tybamate in anxious neurotic medical clinic patients. Am. ]. Psyc1liat., 120: 1005 (April) 1964. Clyde, D. J.: Manual for Clyde Mood Scale, Biometric Laboratory, University of Miami, Coral Gables, Florida, 1963.
Dcpartment of PSljclliatTlj 203 Piersol Building Universitlj Hospital 3600 Spruce Street Philodelphia 4, Pennsljlvania
Current Antidepressant Therapy EDWI:-<
DUNLOP, M.D.
INTRODUCTION
METHODS AND MATERIALS
• The subtitle of the Third Symposium on Anxiety and Depression although not appearing on the program, but on yesterday's luncheon tickets, "What's New In Psychophannacology," will limit the presentation of this data to the newer psychopharmaceutical agents used for the treatment of depression. Between December, 1964, and January, 1965, three new antidepressant agents were made avaliable for prescription. These are the first since the new Federal Drug Administration regulations went into effect and are of significance to those interested in the treatment of depression by psychophannacology. The drugs are as follows:
Norpramin and Pertofrane are demethylated metabolites of imipramine, and in extensive clinical trials in this country and abroad appear to be more active antidepressants than the parent substance. The clinical types of depression which have shown the best therapeutic response are endogenous depression, psychotic depressive reaction, involutional depressive reactions, and reactive depressions. Those depressions associated with schizophrenia or schizophrenics going through a depressive response appear to respond less favorably. Since 1961, more than 100 depressed patients have been treated with Desipramine. These include both hospitalized and outpatient cases and represent all varieties of depression ranging from the most severe, some frequently resistant to other antidepressant agents and electro-shock, to those of a mild nature and ambulatory status. Today, many patients are treated in the community by non-
1. desipramine (Pertofrane) (Geigy) 2. desipramine (Norpramin) (Lakeside) 3. nortriptyline (Aventyl) (Lilly) Doctor Dunlop is Director of Research, Fuller Memorial Sanitarium, South Attleboro, \Iassachusetts. September-October, 1965
309