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A comparison of equivalent clinical potencies of neuroleptics as used to treat schizophrenia and affective disorders
I. psyclriot. Rcs.. 1976, Vol. 13. pp. 91-9s. Pergamon
Press. Printed in Great Britam.
A COMPARISON OF EQUIVALENT CLINICAL POTENCIES OF NEUROLEPTICS AS USED TO TREAT SCHIZOPHRENIA AND AFFECTIVE DISORDERS RICHARD Laboratory
JED WYATT
and JOAN S. TORGOW
of Clinical Psychopharmacology, Division of Special Mental Health Research, IRP, IZIMH, Saint Elizabeth’s Hospital, Washington, D.C. 20032, U.S.A. (Received 4 December 1975. Reked
3 Jurre 1976)
INTRODUCTiON IN bIORE than
20 yr since the introduction of chlorpromazine (CPZ) for the treatment of schizophrenia, much has been learned about its and the other neuroleptics’ efficacy. However, the mechanism by which the neuroleptics decrease symptomatology in schizophrenic patients is as yet unclear. In this regard it is commonly thought that the neuroleptics have some specificity for schizophrenia. This implies that if their mechanism of action were known, it would say something about the fundamental biochemical deficit of schizophrenia. This review is a preliminary attempt to examine the neuroleptics’ specificity with respect to diagnosis by comparing their use in treating schizophrenia with their use in treating the affective disorders. To make this comparison, the equivalent clinical potencies of drugs found to be of equal efficacy during chronic administration (intradiagnosis comparison) have been compared. Equal efficacy of drugs was determined separately for each disorder on a study-by-study basis and was based on each experimenter’s interpretation of measurements of comparable clinical improvement between drugs. “Equivalent clinical potency” was defined as the daily optimal therapeutic dosage of a given drug expressed as a percentage of the optimal dosage of an equally efficacious clinical standard. METHODOLOGY Nine criteria were used to define the ideal study. Each study was (a) double-blind with (b) randomized samples from (c) either schizophrenic, or depressive and/or manic populations. A comparison of(d) at least two active drugs used in the treatment of schizophrenia or the affective disorders were required; however, (e) combinations of drugs and supplemental drugs (such as sedatives) were precluded. The dosages were (f) flexible and (g) administered orally. (However, studies in which initial doses were administered parenterally and later ones orally were included. Only the data on the oral doses were reviewed.) (h) The drugs reviewed were tested both on schizophrenic and affective disorder patients. (i) Within each study, no difference (p > 0.03) in efficacy was found over time between drugs for each diagnostic group. (Since we reviewed only the drugs’ action on the behavioral disorders and not their overall clinical usefulness, side effects were not taken into account.) 91
92
RICHARD
JED WYATTand JOAS S. TORGOW
These criteria resulted in an unusably small set of studies, so it was necessary to include more loosely controlled studies. At various times criteria (a, b, e, f) and (i) were suspended, with no more than two criteria being inoperative in any one study. The looser criteria gave a sample of 611-61 studies; 461-45 of them researched the sample drugs’ use in schizophrenia, 1733.46-61 studied the drugs in the treatment of the affective disorders. The following informaton was reviewed in each study. The type and subtype of patient population were noted as available (schizophrenics-acute or chronic-and affective disorder patients and characteristics of their disorder). Both the dosage schedule and the actual doses were reviewed. The methods used to evaluate change, including the specific scales and/or subjective global evaluations, were reviewed. If supplemental drugs were used, their type was noted. The dosages were compiled into two lists, one for each disorder, and were standardized to a CPZ = 100 unit scale.* Intermediary studies were employed when no direct comparison between a given drug and CPZ was available.? There was no intermediary available by which to standardize the dosages for five of the drugs as they were used in the affective disorders. The dosages of several tricyclics, however, were found to be equivalent to approx 70% of CPZ’s optimal dosage. Since there is little in the literature to suggest any difference among the equivalent daily doses of the tricyclic antidepressants, it seemed reasonable to set amitriptyline at 70 units to be used as an intermediary. This made possible the comparison of the five additional neuroleptics for the affective disorders.: RESULTS
Eleven drugs were found to be equally efficacious treatments within both schizophrenia and the affective disorders. Their equivalent clinical potencies are shown in Table I. This table also includes data reflecting the drugs classes, the actual doses used, the range of equivalent clinical potencies for each drug, and the number of studies used to compute the equivalent clinical potencies. A Spearman rank-order correlation was performed to compare the ranks of the potencies across-disorder. The coefficient was 0.86 (17 < 0.01). DISCUSSION
In this review several neuroleptic drugs were studied which were about equally efficacious in treating schizophrenia. The drugs’ equivalent clinical potencies were determined.62 (These were found to be comparable to the figures compiled by DAVIS, 1974.)63 The same drugs were also found to be of equal efficacy within the affective disorders. Here, too, equivalent clinical potencies were determined. For the 11 drugs involved there was a high correlation between the rankings (by disorder) of the equivalent clinical potencies. No attempt was made to determine whether or not the neuroleptics were either as useful in treating the *x mg/24 hr Drug A
x 100 = Relative Potency Drug A. y mg/24 hr CPZ ix mg/24 hr Intermediary Drug x a mg/24 hr Drug A x 100 = Rel. Pot. A. b mg/24 hr Int. Drug y mg/24 hr CPZ $x mg/24 hr Drug A x 70 = Rel. Pot. A. y mg/24 hr Amitripytline
.A COMPARISON
TABLE
Drug
1.
i’. COMPARISON (and class)
OF EQUWALE~T
OF EQUIVALE>T
CLINICAL
POTEXIES
CLINICAL
POTE6CIESOFSEUROLEPTICS
AN2
AFFECTIVE
THE
93
NEcRorEPncs AS USED
TO TREAT
SCHIZOPHRES1.A
DISORDERS
Schizophrenia
Equivalent
OF
AEective disorderr
clinical potency* Schizo- Affective phrenia disorders
CPZ (Phenothiazine, 100 Aliphatic) Thioridazine (Pheno108 thiazine, Piperidine) Chlorprothixene 5: (Tbioxanthene) Acetophenazine (Phenothiazine. Piperazine) Haloperidol 24 (Butyrophenone) Pimozide (DiphenylI.2 hutylpiperidine) Mesoridazine (Pbeno45 thiazine, Piperidinc) Oxypenine (Pheayl38 piperazine) Loxapinc (Diben0.2 zoxa*e Perpheoazine (Pheno8.S Piperarine) ~;;;Ix thia@ne, (Thioxan3.2
No. of atudies:
100
-
-28
J’_J
42.5 IO5
Range of Median of Rangcof relative AVerage average potencies daily doses daily doses a;$;; (mg!24 hr) (mgi24 hr)
71-l
16
-
700
200-1800
700
330-958
60-245 (30-55)
,1,1_11
18-55
250
150-450
;I:_,,
12-14
1-1-1
120-152
2
@J-X
0.3-3.5
14
s-32
4
,1,.%
0.7-I-6
15
9-20
70
.$zs_zr
33-90
320
318417
30
-
6IY-3’
1540
120
60-300
-
3,,_,1
7.5-10
120
100-120
-
I5
jI~,S_,,
7.7-10
48
31-182
j-32
1.3-5.4
34
20-67
jll,l2,42_45
75-1500 Range over severalstudies 84-507 Range over severalstudies 135 Max. k Med. 248
-
5
3
.Actual dosei (mg:24 hr)
No. of Range of studies relative potencies across studies
-
Mean
36
Max. 8 Med.
1
Med. (only dose)
75
Fixed. only dose). 176 Mean 68-480 Range 7.4 Mean 4-16 34-37 9
Range in each of 2 studies Mean
*This is the optimal clinical daily dose for each drug expressed as a percentage of the optimal dose for CPZ. (All drugs are equally efficacious at these doses within each disorder.) + Number of studies used to compute relative potent),
affective disorders as the more conventional drugs, or as useful in treating the affective disorders as in treating schizophrenia. If the equivalent clinical potency correlation is taken at face value, it is suggestive of one of two things: either that schizophrenia and the affective disorders are in fact the same illness manifesting itself through different symptom sets, or that the neuroleptic drugs alter a physiological system which is in some way peripheral to the cause of one or both disorders. The first face-value conclusion-that schizophrenia and the affective disorders are the same illness-is so heretical and contrary to genetic and other data, that much new supportive evidence would be needed for it even to be considered. With regard to the second possibility-that the neuroleptics act through a system peripheral to the core abnormality-some consideration should be given. For the sake of discussing this hypothesis, brain dopamine systems, which appear to be affected by the neuroleptics, may be used as one example. Dopamine systems are thought to partially control motoric behavior and seem to exert this control by setting a tone in the striatum-an important site for motor control junctions. Most of the items on behavioral rating scales, as well as many clinical impressions, are determined by alterations in motoric behavior. The neuroleptics might reduce symptoms by altering them as they are expressed through dopamine systems involved in motoric behavior, rather than at the core root of the dirorder. Let’s hypothesize that the explanation for the neuroleptics’ efficacy in treating the affective disorders is that these drugs actually are relieving only symptoms common both to schizophrenia and the affective disorders. Specifically, the symptoms could be the motoric ones of anxiety-agitation. The hypothesis continues by asserting that the symptomatic relief is
94
RICHARD
JED WYATT~CI~
JOAN
S.
TORGOW
sufficient to account for ratings of overall improvement for the affective disorders, in spite of apparent minimal relief of the depressed mood. However, we have found this situation not to be firmly supported: on the one hand, anxiety-agitation is not overwhelmingly decreased, nor, on the other, does depressive mood remain unrelieved in our sample of studies. Table 2 was compiled from the data reported from the rating scales used in the individual investigations. (The BPRS6J was used in eight studies, and the Hamilton rating scale for depression6s was used in six. We did not analyze the remaining scales, the data from which were reported in no more than one study.) From this table, we see that anxiety was decreased statistically more by the neuroleptics than by placebo in one of the three studies available. However, the other two studies report that the neuroleptics decreased anxiety-agitation more than did placebo without reportin, 0 whether or not the difference is statistically significant. No significant difference is apparent in anxiety-agitation between the neuroleptics TABLE 2. NUMBER
OF AFFECTIVE D[SORDER STUDIES IN WHICH AND DEPRESSIVE MOOD PRODUCED
THERE WERE CHANGES By NEUROLEPTICS
Significant Number of difference studies (p < 0.05)
IN AMETY-AGITATION
No significant difference
Significance of difference not indicated but study supports statement
2
Anxiety-agitation Newoleptic decreased symptom more than did placebo Neuroleptic’seffect
353.55.61
1
0
comparable to that of tricyclice 4JY*j7*58-50
0
4
Neuroleptic decreased symptom more than did 353.55.61 placebo Nerlroleptic’s effect comparable to that of tricyclic 44a-s7*58.60
I
0
0
4
Depressive mood*
*This is specifically “depressive mood”, and not overall “depression”
2
(which could include anxiety and!
or agitation symptoms).
and the tricyclics in four studies. The symptom of depressive mood showed a significantly greater decrease when treated by the neuroleptics than by placebo in at least one out of three studies. The neuroleptics and the tricyclics were not different m treating depressive mood in the four studies reported. The hypothesis discussed above, however, is supported by HOLLISTER and OVERALL’s the study of depression subgroupings. They found 66 that anxious depressions-where anxiety-agitation symptoms would be more heavily weighted-were better treated with neuroleptic drugs, and retarded ones with tricyclics-drugs more commonly associated with the treatment of depression. (Hostile depressions responded equally well to both classes of drugs.) Several studies included in this review support this assertion. The data in Table 2, however, are not portrayed to explore this prediction further. Rather, they show the effects of the drugs tested on the specific anxiety-agitation and depressive mood symptoms across all subtypes of the depressive disorder. If the dopaminergic system is thought to control junctions in the motor neural network, it might be considered to have the same functon in controlling or setting a tone for the affective and cognitive neural systems. The limbic striatum, which is rich in dopamine terminals, might be thought of in such a manner. 67 A change in the tone or function of the
A COMPARISONOF EQLNALE~T CLINICAL POTESCES OF NEUROLEPTICS
95
dopaminergic limbic system by the neuroleptics might then account for the improvement of depressed mood in affective disorders as well as similar changes in affect and cognition in schizophrenia. In this scheme the dopaminergic systems themselves might not be directly altered in one or even both of the disorders, yet the neuroleptics could still be a useful treatment in both. Finally, we compared the relative potencies of 11 neuroleptics as used in both the acute and chronic schizophrenic disorders. 62 The Spearman correlation for the relative potencies was O-96 (p < O-001). Since there is some evidence 68 that acute and chronic schizophrenia are not genetically related disorders, we must consider this data as added evidence for the nonspecificity of neuroleptics for correcting the core deficit. So far we have discussed the relative potency correlations with the qualification that they be only taken at face value. We now want to examine at least one possible artifactual origin of the data. We feel that our remarkably high correlation between the rankings of the relative potencies across disorders is a somewhat unlikely occurrence, in light of the following limitations. Probably the major limitations is the lack of uniformity between studies: the same rating scales were not used throughout, and the individual experimenters’ weightings of and variations on them create even more discrepancy. The sizes and compositions of the samples studied vary greatly. What actually was studied-depressive subtypes, age/sex breakdowns, specific population subgroups such as ex-alcoholics, or the relative efficacy of a new drug, for example-is different for each study, which means that, for each, different types of data were being sought. Too, the neuroleptic drugs were compared to many different standards: minor tranquilizers were used in some studies; also used were other neuroleptics and tricyclics. The use of placebo was erratic. The other major limitation here is the particularly small number of studies with which we have to work, especially studies of the effective disorders. The question then becomes why, when such problems are present, do we still find such a high correlation? As a jumping-off point for analysis of possible artifact, we suggest an explanation that is in part related to the root of the term “neuroleptic”: in the case of both schizophrenic and affective disorder patients, the drug dosages are pushed to the point of (possibly, expected) intolerable side effects. These, may well ocur at the same narrow range of doses in either disorder, regardless of what would be the drug’s psychoactivity beyond that point for one disorder or the other. The “neuroleptic” limitation would perhaps explain why such closely parallel rankings of potency were obtained between the disorders. It does not, however, in and of itself, explain the recordings of equal efficacy between drugs. SUMMARY
In a preliminary attempt to examine the neuroleptics’ specificity with respect to diagnosis, a literature review was conducted. The neuroleptics’ use in treating schizophrenia was compared with their use in treating the affective disorders. Equivalent clinical potencies of drugs found to be equally efficacious (intra-diagnosis comparisons) were computed and compared. This correlation across disorders was found to be high and was attributed to the possibility that the drugs effect their treatment through a system peripheral to one or both core abnormalities. The brain dopamine systems were proposed as the affected area.
RICWRD
96
JED WYATT
and JOAN S.
TORGO~
REFERENCES I. National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group. Phenothiazine treatment in acute schizophrenia. Archs gen. Psychiat. 10, 246, 1964. 2. HANLON,T. E., MICHAUX, M. H., 0~4, K. Y., SHATFER. J. W. and KARLAND, A. A. The comparative effectiveness of eight phenothiazines. Psychopharmacologia 7, 89, 1965. 3. LASKY,J. J., JSLE~, C. J., CAFFEY, E. M., BENNE~, J. L., ROSEXBL~N, Xl. P. and HOLUSTER, L. E. Drug treatment of schizophrenic patients. A comparative evaluation of chlorpromazine, chlor prothixene, fluphenazine, reserpine, thioridazine, and triflupromazine. Dis. nerv. Syst. 23, 698, 1962. 4. SCHIELE,B. C., VESTRE, M. D. and STEIN, K. E. A comparison of thioridazine, trifluoperazine, chlorpromazine, and placebo: a double-blind controlled study on the treatment of chronic, hospitalized, schizophrenic patients. J. din. exp. Psychopath. 22, 151, 1961. 5. GALBRECHT, C. R. and KLEIT, C. J. Predicting response to phenothiazines: the right drug for the right patient. J. nerv. menf. Dis. 147, 173, 1968. 6. CLARK, M. L., HUBER, W. K., CHARALAWPOUS, K. D., SEIWFETINIDES, E. A., TROUSDALE, W. and COLMORE, J. P. Drug treatment in newly admitted schizophrenic patients. Archs gen. Psychiat. 25, 404.1971. 7. H~NDLEY, J. P., KERIX, M. T. and THOMPSON, M. Comparison of three phenothiazines on chronic psychotic behavior. Dis. nerv. Sysf. 26, 91, 1965. 8. STABENAU, J. R. and GRINOLS, D. R. A double-blind comparison of thioridazine and chlorpromazine. Psychiatric Q. 38, 42, 1964. 9. REMVIG, J. and SOXSE, L. M. Chlorprothixene (Truxal) compared to chlorpromazine. Psychopharmacologia 2,203, 1961. 10. BARTOLUCCI, G., LEHXIANN, H. E., BAN, T. A. and LEE, H. Clinical studies with clopenthixol (Sordinol) on chronic psychiatric patients. Cur. ther. Res. 8, 581, 1966. II. STERLIN, C., BAS, T. A. and JARROLD, L. The place of thiothixene among the thioxanthenes. Clrrr. rher. Res. 14, 205, 1972. 12. GOLDBERG, S. C., FROSCH, W. A., DROSSMAN, A. K., SCHOOLER, M. R. and JOHNSON, G. F. S. Prediction of response to phenothiazines in schizophrenia. A cross-validation study. Archs gen. Psychiat. 26, 367, 1972. 13. OVERALL. J. E.. HOLLISTER. L. E.. HONIGFELD. G. H.. KL~IB.UL. L. H.. JR.. MEYER. F.. BENNETT. J. L. and COFFEY,’ E. M., JR. .Comparison of acetophanazine with perphenazine in schizophrenics: Clin. Pharmac. Ther. 4,200, 1963. 14. HOLLISTER, L. E., OVERALL, J. E., BENNE-IT,J. L., KIMBALL,I. and SHELTON,J. Specific therapeutic
actions of acetophenazine, perphenazine and benzquinamide in newly-admitted schizophrenic patients. Clin. Pharmac. Ther. 8, 249, 1967. 15. Fox, W., GOBBLE,I. F., CLOS, M. and DENISON,E. A clinical comparison of trifluperidol, haloperidol, and chlorpromazine. Gwr. ther. Res. 6,409, 1964. in controlling the symptoms of acute psychoses. Part II: 16. GOLDSTEIN,B. J. and CLYDE, D. J. Haloperidol A double-blind evaluation of haloperidol and trifluoperazine. Clrrr. ther. Res. 8, 236, 1966. of haloperidol, trifluperidol, and chlor17. PRAIT, J. P., BISHOP, M. P. and GALLANT, D. M. Comparison promazine in acute schizophrenic patients. Curr. ther. Res. 6, 562, 1964. and thioridazine in treatment of chronic schizophrenics. 18. PRASAD, L. and TOWNLEY, M. C. Haloperidol Dis. new. Syst. 27,122,
1966.
19. LUCKEY,W. T. and SCHIELE,B. C. A comparison of haloperidol and trifluoperazine (A double-blind controlled study on chronic schizophrenic outpatients). Dis. new. Sysf. 28, 181, 1967. new addition to the drug treatment of 20. LAFAVE, H. G., STEWART, H. and SEGOVIA, G. Haloperidol: schizophrenia. Can. psychiat. Ass. J. 12, 597, 1967. 21. WESTON,M. J., BENTLEY,R., UXWI;U,A., MORRIS,M. and HARPER,M. A. A comparative trial of haloperidol and thioridazine: management of chronic schizophrenia. Amt. N.Z. J. Psychiar. 7, 52, 1973. 22. HOLLISTER,L. E., OVERALL,J. E., CAFFEY,E., BENNETT,J. L., MEYER,F., KLVBUL, I. and HONIGFELD, G. Controlled comparison of haloperidol with thiopropazate in newly admitted schizophrenics. J. new. ment. Dis. 135, 544, 1962. 23. CHOUINARD,G., LEHMAN,H. E. and BAN, T. A. Pimozide in the treatment of chronic schizophrenic patients. Curr. ther. Res. 12, 598, 1970. 24. MORRIS,P. A., MACKENZIE,D. H. and MASHETER,H. C. A comparative double-blind trial of pimozide and fluphenazine in chronic schizophrenia. Br. J. Psychiat. 117, 683, 1970. 25. DOUGLAS,K. W. and HIXDLEY,J. P. A comparison of mesoridazine and chlorpromazine in chronic psychiatric patients. J. din. Pharmacol. 9, 176, 1969.
A CO.~IPAIUONOF EQUX&E&T CLIXICU POTESCIESOF NEUROLEPTICS
97
26. FREE~WN, H. A double-blind comparison of mesoridazine and chlorpromazine in chronic schizophreni&. Dis. nerv. Syst. 3-1,289,-1973. 27. SUGARUN. A. A. Comnarison of TPS-23 and thiridazine in chronic schizouhrenic oatients. Curr. fher. Res. 7, j20, 1965. _ 28. MENA, A., GRAYSOX,H. and COHEN,S. A study of thioridazine and its side chain derivative, mesoridazine, in chronic male hospitalized psychiatric patients. J. new Drugs 6, 345, 1966. 29. CALWELL, W. P. K., JACOBSEN,M. and SKARBEK,A. A comparative study of oxypertine and trifluoperazine in chronic schizophreniaa new application of the Wing Rating Scale. Br. J. Psychiut. 110,520,1964.
30. CLAGHORN,J. Differential drug effects on social and symptomatic behaviors. Cur. fher. Res. 12, 580, 1970. 31. NEAL,C. D., COLLIS,M. D. and I~~LAH,N. W. A comparative trial of oxypertine and chlorpromazine in chronic schizophrenia. Cur. rher. Res. 11, 367. 1969. 32. HOLLISTER,L. E., OVERALL,J. E., KATY, G., HIGGENBOTTOM, W. E. and KIMBALL,I., JR. Oxypertine and thiothixene in newly admitted schizophrenic patients. Clin. Pharmac. Ther. 12, 531, 1971. 33. HUNT, P. V. A comparison of the effects of oxypertine and trifluoperazine in withdrawn schizophrenics. Br. J. Psychiat. 113, 1419, 1967. 34. SKARBEK,A. and JACOBSEN,M. Oxypertine: a review of clinical experience. Br. J. Psychiut. 111, 1173, 1965. 35. SERAFETINIDES, E. A., WILLIS, D. and CL.UK, M. L. The EEG effects of dibenzoxazepines (loxapine succinate) as compared to CPZ: EEG changes as drug side effects. Znf. Pharmacopsychiat. 6,38, 1971.
36. SHOPSIN,B., PEAR~OS,E., GERSHON,S. and COLLINS,P. A controlled double-blind comparison between loxapine succinate and chlorpromazine in acute newly hospitalized schizophrenic patients. Curr. ther. Res. 14,739, 1972. 37. BISHOP,M. P. and GALLANT,D. M. Loxapine: Cut-r. ther. Res.12, 594, 1970.
a controlled evaluation in chronic schizophrenic
patients.
38. CASEY,J. E., LASKY,J. J., KLE~, C. J. and HOLLISTER,L. E. Treatment of schizophrenic reactions with phenothiazine derivatives. A comparative study of chlorpromazine, triflupromazine, mepazine, prochlorperazne, perphenazine, and phenobarbital. Am. J. Psychiat. 117, 97, 1960. 39. KURLAND,A. A., MICH.~UX,M. H., HANLON,T. E., OTA, K. Y. and SIMPOULOS,A. M. The comparative effectiveness of six phenothiazine compounds, phenobarbital and inert placebo in the treatment of acutely ill patients: personality dimensions. J. net-v. ment. Dis. 134, 48, 1962. 40. KLJRLAND,A. A., HANLON,T. E., TATOII, M. H., OTA, K. Y. and SIMPOPOULOS, A. M. The comparative effectiveness of six phenothiazine compounds, phenobarbital and inert placebo in the treatment of acutely ill patients: global measures of severity of illness. J. nerv. ment. Dis. 133, 1, 1961. 41. ADELSON,D. and EPSTEIN,L. J. A study of phenothiazines with male and female chronically ill schizophrenic patients. J. nerv. menr. Dis. 134, 543, 1962. 42. BISHOP, &I. P., FULMER,T. E. and GALLAS~, D. M. Thiothixene vs trifluoperazine in newly-admitted schizophenic patients. Cut-r. ther. Res. 8,509, 1966. 43. GALLANT, D. M., BISHOP, M. P., T~htbio~s, E. and GOULD, A. R. Thiothixene (P-4657B): controlled evaluation in chronic schizophrenic patients. Cut-r. ther. Res. 8, 153, 1966. 44. WOLPERT,A., SHEPPARD,C. and MERLES,S. Thiothixene, thioridazine, and placebo in male chronic schizophrenic patients. Clin. Pharmac. Ther. 9, 456, 1968. 45. DENBER,H. C. B. and TURNS, D. Double-blind comparison of thiothixene and trifluoperazine in acute schizophrenia. Psychosomntics 13, 100, 1972. 46. AZIMA,H., D~ROST, H. and ARTHURS,D. The effect of thioridazine (Mellaril) or mental syndromes. Comparison with chlorpromazine and promazine. Can. med. Ass. J. 81, 549, 1959. 47. General Practitioner Clinical Trials. Thioridazine as an anti-deoressant. Pracfifioner 209., 95.I 1972. 48. OVERALL,J. E., HOLLISTER,L. E., MEYER,F., KIMBALL,I. and SHELTON,J. Imipramine and thioridazine in depressed and schizophrenic uatients. JAMA 189. 605. 1964. 49. ROSE~AL, s. H. and BOWDEN,C. I,. A double blind comp&ison of thioridazine (Mellaril) vs diazepam (Valium) in patients with chronic mixed anxiety and depressive symptoms. Curr. res. Ther. 15, 261, 1973. 50. LODGEPATCH,I. C., PITT, B. M. and YEO, Y. M. The direct comparison of antidepressants: imipramine and chlorprothixene. J. phychiat. Res. 5, 273, 1967. 51. HOLLISTER,L. E., OVERALL,J. E., POKORZ~Y, A. D. and SHELTON,J. Acetophenazine and diazepam in anxious depressions. Archs gen. Psychiat. 24, 273, 1971.
98
RICH-
JED WYATT
and JOAN S. TORGOW
52. SHOPSLU,B., GERSHON,S., THOMPSON,H. and COLLINS,P. Psychoactive drugs in mania: a controlled comparison of lithium carbonate, chlorpromazine and haloperidol. Archs gen. Psychiut. 32, 34, 1975.
53. REYNTJENS,A. M. and VAN MIERLO, F. P. A comparative double-blind trial of pimozide in stressinduced psychic and functional disorders. Curr. m&. Res. Opin. 1, 116, 1972. 54. OVERALL,J. E., BROW, D., WILLIAMS,J. D. and NEILL, L. T. Drug treatment of anxiety and depression in deto.xitied alcoholic patients. Archs gen. Psychiut. 29, 218, 1973. 55. BRAUZER.B., GOLD~TEN,B. J., STEINBOOK, R. M. and JACOBSON,A. F. The treatment of mixed anxiety and depression with loxapme: a controlled comparative study. J. din. Pharmacol. 14, 455, 1974. 56. General Practitioner Clinical Trials. Antidenressant effects of tranouillizers. Prucfifioner 206, 146, 1971. 57. HOLLI~TER,L. E., OVERALL,J. E., SHELTON,J., PEP*~NGTON,V.,‘KIMBALL, I. and JOHNSON,M. Drug therapy of depression: Amitriptyline, perphenazine and their combination in different syndromes. Archs gen. Psychiat. 17,486, 1967. 58. SIMPSOII,G. M., A.MIN,M., ANGUS, J. W. S., EDWARDS, J. G., Go, S. H., and LEE, J. H. Role of antidepressants and neuroleptics in the treatment of depression. Archs gen. Psychiar. 27, 337, 1972.
59. HARE. H. P. Comnarison
of diazenam. chlorpromazine _. -
and a placebo in psychiatric practice. /. new
Drugs 3,233, 1663. 60. PAYKEL, E. S., PRICE, J. S., GILUN, R. V., PALMAI,G. and CHESSER,E. S. A comparative pramine and chlorpromazine in depressed patients. &-. J. Psychiat. 114, 1281, 1968.
trial of imi-
61. RAXIN, A., SCHULTERBRANDT, J. G., REATIG, N. and MCKEON, J. J. Differential response to chlorpromazine, imipramine, and placebo. Archs gen. Psychiut. 23, 164, 1970. 62. WYATT. R. J. Biochemistry and schizophrenia-IV. The neuroleptics-their mechanism of action: a review of the biochemical literature. P‘sychopharmacol. Bull. 12, 5‘, 1976. 63. DAVIS, J. M. Dose equivalence of the anti-psychotic drugs. J. Psychiut. Res. 11,65, 1974. 64. OVERALL.J. E. and GORHAM.D. R. The brief psychiatric rating scale. Psycho/. Rep. 10, 799, 1962. 65. HAMILTON,IM. A rating scale-for depression. J. Neural. Neurosirg. Psychiat. 23,56, 1960. 66. HOLLISTER,L. E. and OVERALL,J. E. Reflections on the specificity of action ofantidepressants. Psychosomatics 6, 361, 1965. 67. STEVENS, J. R. An anatomy of schizophrenia? Archs gen. Psychiat. 29, 177, 1973. 68. KETY. S. S.. ROSENTHAL.D.. WENDER.P. H. and SCHULSINGER, F. Mental illness in the biological and adbptive’families of adopted schizophrenics. Am. J. Psychiat. 128, 302, 1971.
Press. Printed in Great Britam.
A COMPARISON OF EQUIVALENT CLINICAL POTENCIES OF NEUROLEPTICS AS USED TO TREAT SCHIZOPHRENIA AND AFFECTIVE DISORDERS RICHARD Laboratory
JED WYATT
and JOAN S. TORGOW
of Clinical Psychopharmacology, Division of Special Mental Health Research, IRP, IZIMH, Saint Elizabeth’s Hospital, Washington, D.C. 20032, U.S.A. (Received 4 December 1975. Reked
3 Jurre 1976)
INTRODUCTiON IN bIORE than
20 yr since the introduction of chlorpromazine (CPZ) for the treatment of schizophrenia, much has been learned about its and the other neuroleptics’ efficacy. However, the mechanism by which the neuroleptics decrease symptomatology in schizophrenic patients is as yet unclear. In this regard it is commonly thought that the neuroleptics have some specificity for schizophrenia. This implies that if their mechanism of action were known, it would say something about the fundamental biochemical deficit of schizophrenia. This review is a preliminary attempt to examine the neuroleptics’ specificity with respect to diagnosis by comparing their use in treating schizophrenia with their use in treating the affective disorders. To make this comparison, the equivalent clinical potencies of drugs found to be of equal efficacy during chronic administration (intradiagnosis comparison) have been compared. Equal efficacy of drugs was determined separately for each disorder on a study-by-study basis and was based on each experimenter’s interpretation of measurements of comparable clinical improvement between drugs. “Equivalent clinical potency” was defined as the daily optimal therapeutic dosage of a given drug expressed as a percentage of the optimal dosage of an equally efficacious clinical standard. METHODOLOGY Nine criteria were used to define the ideal study. Each study was (a) double-blind with (b) randomized samples from (c) either schizophrenic, or depressive and/or manic populations. A comparison of(d) at least two active drugs used in the treatment of schizophrenia or the affective disorders were required; however, (e) combinations of drugs and supplemental drugs (such as sedatives) were precluded. The dosages were (f) flexible and (g) administered orally. (However, studies in which initial doses were administered parenterally and later ones orally were included. Only the data on the oral doses were reviewed.) (h) The drugs reviewed were tested both on schizophrenic and affective disorder patients. (i) Within each study, no difference (p > 0.03) in efficacy was found over time between drugs for each diagnostic group. (Since we reviewed only the drugs’ action on the behavioral disorders and not their overall clinical usefulness, side effects were not taken into account.) 91
92
RICHARD
JED WYATTand JOAS S. TORGOW
These criteria resulted in an unusably small set of studies, so it was necessary to include more loosely controlled studies. At various times criteria (a, b, e, f) and (i) were suspended, with no more than two criteria being inoperative in any one study. The looser criteria gave a sample of 611-61 studies; 461-45 of them researched the sample drugs’ use in schizophrenia, 1733.46-61 studied the drugs in the treatment of the affective disorders. The following informaton was reviewed in each study. The type and subtype of patient population were noted as available (schizophrenics-acute or chronic-and affective disorder patients and characteristics of their disorder). Both the dosage schedule and the actual doses were reviewed. The methods used to evaluate change, including the specific scales and/or subjective global evaluations, were reviewed. If supplemental drugs were used, their type was noted. The dosages were compiled into two lists, one for each disorder, and were standardized to a CPZ = 100 unit scale.* Intermediary studies were employed when no direct comparison between a given drug and CPZ was available.? There was no intermediary available by which to standardize the dosages for five of the drugs as they were used in the affective disorders. The dosages of several tricyclics, however, were found to be equivalent to approx 70% of CPZ’s optimal dosage. Since there is little in the literature to suggest any difference among the equivalent daily doses of the tricyclic antidepressants, it seemed reasonable to set amitriptyline at 70 units to be used as an intermediary. This made possible the comparison of the five additional neuroleptics for the affective disorders.: RESULTS
Eleven drugs were found to be equally efficacious treatments within both schizophrenia and the affective disorders. Their equivalent clinical potencies are shown in Table I. This table also includes data reflecting the drugs classes, the actual doses used, the range of equivalent clinical potencies for each drug, and the number of studies used to compute the equivalent clinical potencies. A Spearman rank-order correlation was performed to compare the ranks of the potencies across-disorder. The coefficient was 0.86 (17 < 0.01). DISCUSSION
In this review several neuroleptic drugs were studied which were about equally efficacious in treating schizophrenia. The drugs’ equivalent clinical potencies were determined.62 (These were found to be comparable to the figures compiled by DAVIS, 1974.)63 The same drugs were also found to be of equal efficacy within the affective disorders. Here, too, equivalent clinical potencies were determined. For the 11 drugs involved there was a high correlation between the rankings (by disorder) of the equivalent clinical potencies. No attempt was made to determine whether or not the neuroleptics were either as useful in treating the *x mg/24 hr Drug A
x 100 = Relative Potency Drug A. y mg/24 hr CPZ ix mg/24 hr Intermediary Drug x a mg/24 hr Drug A x 100 = Rel. Pot. A. b mg/24 hr Int. Drug y mg/24 hr CPZ $x mg/24 hr Drug A x 70 = Rel. Pot. A. y mg/24 hr Amitripytline
.A COMPARISON
TABLE
Drug
1.
i’. COMPARISON (and class)
OF EQUWALE~T
OF EQUIVALE>T
CLINICAL
POTEXIES
CLINICAL
POTE6CIESOFSEUROLEPTICS
AN2
AFFECTIVE
THE
93
NEcRorEPncs AS USED
TO TREAT
SCHIZOPHRES1.A
DISORDERS
Schizophrenia
Equivalent
OF
AEective disorderr
clinical potency* Schizo- Affective phrenia disorders
CPZ (Phenothiazine, 100 Aliphatic) Thioridazine (Pheno108 thiazine, Piperidine) Chlorprothixene 5: (Tbioxanthene) Acetophenazine (Phenothiazine. Piperazine) Haloperidol 24 (Butyrophenone) Pimozide (DiphenylI.2 hutylpiperidine) Mesoridazine (Pbeno45 thiazine, Piperidinc) Oxypenine (Pheayl38 piperazine) Loxapinc (Diben0.2 zoxa*e Perpheoazine (Pheno8.S Piperarine) ~;;;Ix thia@ne, (Thioxan3.2
No. of atudies:
100
-
-28
J’_J
42.5 IO5
Range of Median of Rangcof relative AVerage average potencies daily doses daily doses a;$;; (mg!24 hr) (mgi24 hr)
71-l
16
-
700
200-1800
700
330-958
60-245 (30-55)
,1,1_11
18-55
250
150-450
;I:_,,
12-14
1-1-1
120-152
2
@J-X
0.3-3.5
14
s-32
4
,1,.%
0.7-I-6
15
9-20
70
.$zs_zr
33-90
320
318417
30
-
6IY-3’
1540
120
60-300
-
3,,_,1
7.5-10
120
100-120
-
I5
jI~,S_,,
7.7-10
48
31-182
j-32
1.3-5.4
34
20-67
jll,l2,42_45
75-1500 Range over severalstudies 84-507 Range over severalstudies 135 Max. k Med. 248
-
5
3
.Actual dosei (mg:24 hr)
No. of Range of studies relative potencies across studies
-
Mean
36
Max. 8 Med.
1
Med. (only dose)
75
Fixed. only dose). 176 Mean 68-480 Range 7.4 Mean 4-16 34-37 9
Range in each of 2 studies Mean
*This is the optimal clinical daily dose for each drug expressed as a percentage of the optimal dose for CPZ. (All drugs are equally efficacious at these doses within each disorder.) + Number of studies used to compute relative potent),
affective disorders as the more conventional drugs, or as useful in treating the affective disorders as in treating schizophrenia. If the equivalent clinical potency correlation is taken at face value, it is suggestive of one of two things: either that schizophrenia and the affective disorders are in fact the same illness manifesting itself through different symptom sets, or that the neuroleptic drugs alter a physiological system which is in some way peripheral to the cause of one or both disorders. The first face-value conclusion-that schizophrenia and the affective disorders are the same illness-is so heretical and contrary to genetic and other data, that much new supportive evidence would be needed for it even to be considered. With regard to the second possibility-that the neuroleptics act through a system peripheral to the core abnormality-some consideration should be given. For the sake of discussing this hypothesis, brain dopamine systems, which appear to be affected by the neuroleptics, may be used as one example. Dopamine systems are thought to partially control motoric behavior and seem to exert this control by setting a tone in the striatum-an important site for motor control junctions. Most of the items on behavioral rating scales, as well as many clinical impressions, are determined by alterations in motoric behavior. The neuroleptics might reduce symptoms by altering them as they are expressed through dopamine systems involved in motoric behavior, rather than at the core root of the dirorder. Let’s hypothesize that the explanation for the neuroleptics’ efficacy in treating the affective disorders is that these drugs actually are relieving only symptoms common both to schizophrenia and the affective disorders. Specifically, the symptoms could be the motoric ones of anxiety-agitation. The hypothesis continues by asserting that the symptomatic relief is
94
RICHARD
JED WYATT~CI~
JOAN
S.
TORGOW
sufficient to account for ratings of overall improvement for the affective disorders, in spite of apparent minimal relief of the depressed mood. However, we have found this situation not to be firmly supported: on the one hand, anxiety-agitation is not overwhelmingly decreased, nor, on the other, does depressive mood remain unrelieved in our sample of studies. Table 2 was compiled from the data reported from the rating scales used in the individual investigations. (The BPRS6J was used in eight studies, and the Hamilton rating scale for depression6s was used in six. We did not analyze the remaining scales, the data from which were reported in no more than one study.) From this table, we see that anxiety was decreased statistically more by the neuroleptics than by placebo in one of the three studies available. However, the other two studies report that the neuroleptics decreased anxiety-agitation more than did placebo without reportin, 0 whether or not the difference is statistically significant. No significant difference is apparent in anxiety-agitation between the neuroleptics TABLE 2. NUMBER
OF AFFECTIVE D[SORDER STUDIES IN WHICH AND DEPRESSIVE MOOD PRODUCED
THERE WERE CHANGES By NEUROLEPTICS
Significant Number of difference studies (p < 0.05)
IN AMETY-AGITATION
No significant difference
Significance of difference not indicated but study supports statement
2
Anxiety-agitation Newoleptic decreased symptom more than did placebo Neuroleptic’seffect
353.55.61
1
0
comparable to that of tricyclice 4JY*j7*58-50
0
4
Neuroleptic decreased symptom more than did 353.55.61 placebo Nerlroleptic’s effect comparable to that of tricyclic 44a-s7*58.60
I
0
0
4
Depressive mood*
*This is specifically “depressive mood”, and not overall “depression”
2
(which could include anxiety and!
or agitation symptoms).
and the tricyclics in four studies. The symptom of depressive mood showed a significantly greater decrease when treated by the neuroleptics than by placebo in at least one out of three studies. The neuroleptics and the tricyclics were not different m treating depressive mood in the four studies reported. The hypothesis discussed above, however, is supported by HOLLISTER and OVERALL’s the study of depression subgroupings. They found 66 that anxious depressions-where anxiety-agitation symptoms would be more heavily weighted-were better treated with neuroleptic drugs, and retarded ones with tricyclics-drugs more commonly associated with the treatment of depression. (Hostile depressions responded equally well to both classes of drugs.) Several studies included in this review support this assertion. The data in Table 2, however, are not portrayed to explore this prediction further. Rather, they show the effects of the drugs tested on the specific anxiety-agitation and depressive mood symptoms across all subtypes of the depressive disorder. If the dopaminergic system is thought to control junctions in the motor neural network, it might be considered to have the same functon in controlling or setting a tone for the affective and cognitive neural systems. The limbic striatum, which is rich in dopamine terminals, might be thought of in such a manner. 67 A change in the tone or function of the
A COMPARISONOF EQLNALE~T CLINICAL POTESCES OF NEUROLEPTICS
95
dopaminergic limbic system by the neuroleptics might then account for the improvement of depressed mood in affective disorders as well as similar changes in affect and cognition in schizophrenia. In this scheme the dopaminergic systems themselves might not be directly altered in one or even both of the disorders, yet the neuroleptics could still be a useful treatment in both. Finally, we compared the relative potencies of 11 neuroleptics as used in both the acute and chronic schizophrenic disorders. 62 The Spearman correlation for the relative potencies was O-96 (p < O-001). Since there is some evidence 68 that acute and chronic schizophrenia are not genetically related disorders, we must consider this data as added evidence for the nonspecificity of neuroleptics for correcting the core deficit. So far we have discussed the relative potency correlations with the qualification that they be only taken at face value. We now want to examine at least one possible artifactual origin of the data. We feel that our remarkably high correlation between the rankings of the relative potencies across disorders is a somewhat unlikely occurrence, in light of the following limitations. Probably the major limitations is the lack of uniformity between studies: the same rating scales were not used throughout, and the individual experimenters’ weightings of and variations on them create even more discrepancy. The sizes and compositions of the samples studied vary greatly. What actually was studied-depressive subtypes, age/sex breakdowns, specific population subgroups such as ex-alcoholics, or the relative efficacy of a new drug, for example-is different for each study, which means that, for each, different types of data were being sought. Too, the neuroleptic drugs were compared to many different standards: minor tranquilizers were used in some studies; also used were other neuroleptics and tricyclics. The use of placebo was erratic. The other major limitation here is the particularly small number of studies with which we have to work, especially studies of the effective disorders. The question then becomes why, when such problems are present, do we still find such a high correlation? As a jumping-off point for analysis of possible artifact, we suggest an explanation that is in part related to the root of the term “neuroleptic”: in the case of both schizophrenic and affective disorder patients, the drug dosages are pushed to the point of (possibly, expected) intolerable side effects. These, may well ocur at the same narrow range of doses in either disorder, regardless of what would be the drug’s psychoactivity beyond that point for one disorder or the other. The “neuroleptic” limitation would perhaps explain why such closely parallel rankings of potency were obtained between the disorders. It does not, however, in and of itself, explain the recordings of equal efficacy between drugs. SUMMARY
In a preliminary attempt to examine the neuroleptics’ specificity with respect to diagnosis, a literature review was conducted. The neuroleptics’ use in treating schizophrenia was compared with their use in treating the affective disorders. Equivalent clinical potencies of drugs found to be equally efficacious (intra-diagnosis comparisons) were computed and compared. This correlation across disorders was found to be high and was attributed to the possibility that the drugs effect their treatment through a system peripheral to one or both core abnormalities. The brain dopamine systems were proposed as the affected area.
RICWRD
96
JED WYATT
and JOAN S.
TORGO~
REFERENCES I. National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group. Phenothiazine treatment in acute schizophrenia. Archs gen. Psychiat. 10, 246, 1964. 2. HANLON,T. E., MICHAUX, M. H., 0~4, K. Y., SHATFER. J. W. and KARLAND, A. A. The comparative effectiveness of eight phenothiazines. Psychopharmacologia 7, 89, 1965. 3. LASKY,J. J., JSLE~, C. J., CAFFEY, E. M., BENNE~, J. L., ROSEXBL~N, Xl. P. and HOLUSTER, L. E. Drug treatment of schizophrenic patients. A comparative evaluation of chlorpromazine, chlor prothixene, fluphenazine, reserpine, thioridazine, and triflupromazine. Dis. nerv. Syst. 23, 698, 1962. 4. SCHIELE,B. C., VESTRE, M. D. and STEIN, K. E. A comparison of thioridazine, trifluoperazine, chlorpromazine, and placebo: a double-blind controlled study on the treatment of chronic, hospitalized, schizophrenic patients. J. din. exp. Psychopath. 22, 151, 1961. 5. GALBRECHT, C. R. and KLEIT, C. J. Predicting response to phenothiazines: the right drug for the right patient. J. nerv. menf. Dis. 147, 173, 1968. 6. CLARK, M. L., HUBER, W. K., CHARALAWPOUS, K. D., SEIWFETINIDES, E. A., TROUSDALE, W. and COLMORE, J. P. Drug treatment in newly admitted schizophrenic patients. Archs gen. Psychiat. 25, 404.1971. 7. H~NDLEY, J. P., KERIX, M. T. and THOMPSON, M. Comparison of three phenothiazines on chronic psychotic behavior. Dis. nerv. Sysf. 26, 91, 1965. 8. STABENAU, J. R. and GRINOLS, D. R. A double-blind comparison of thioridazine and chlorpromazine. Psychiatric Q. 38, 42, 1964. 9. REMVIG, J. and SOXSE, L. M. Chlorprothixene (Truxal) compared to chlorpromazine. Psychopharmacologia 2,203, 1961. 10. BARTOLUCCI, G., LEHXIANN, H. E., BAN, T. A. and LEE, H. Clinical studies with clopenthixol (Sordinol) on chronic psychiatric patients. Cur. ther. Res. 8, 581, 1966. II. STERLIN, C., BAS, T. A. and JARROLD, L. The place of thiothixene among the thioxanthenes. Clrrr. rher. Res. 14, 205, 1972. 12. GOLDBERG, S. C., FROSCH, W. A., DROSSMAN, A. K., SCHOOLER, M. R. and JOHNSON, G. F. S. Prediction of response to phenothiazines in schizophrenia. A cross-validation study. Archs gen. Psychiat. 26, 367, 1972. 13. OVERALL. J. E.. HOLLISTER. L. E.. HONIGFELD. G. H.. KL~IB.UL. L. H.. JR.. MEYER. F.. BENNETT. J. L. and COFFEY,’ E. M., JR. .Comparison of acetophanazine with perphenazine in schizophrenics: Clin. Pharmac. Ther. 4,200, 1963. 14. HOLLISTER, L. E., OVERALL, J. E., BENNE-IT,J. L., KIMBALL,I. and SHELTON,J. Specific therapeutic
actions of acetophenazine, perphenazine and benzquinamide in newly-admitted schizophrenic patients. Clin. Pharmac. Ther. 8, 249, 1967. 15. Fox, W., GOBBLE,I. F., CLOS, M. and DENISON,E. A clinical comparison of trifluperidol, haloperidol, and chlorpromazine. Gwr. ther. Res. 6,409, 1964. in controlling the symptoms of acute psychoses. Part II: 16. GOLDSTEIN,B. J. and CLYDE, D. J. Haloperidol A double-blind evaluation of haloperidol and trifluoperazine. Clrrr. ther. Res. 8, 236, 1966. of haloperidol, trifluperidol, and chlor17. PRAIT, J. P., BISHOP, M. P. and GALLANT, D. M. Comparison promazine in acute schizophrenic patients. Curr. ther. Res. 6, 562, 1964. and thioridazine in treatment of chronic schizophrenics. 18. PRASAD, L. and TOWNLEY, M. C. Haloperidol Dis. new. Syst. 27,122,
1966.
19. LUCKEY,W. T. and SCHIELE,B. C. A comparison of haloperidol and trifluoperazine (A double-blind controlled study on chronic schizophrenic outpatients). Dis. new. Sysf. 28, 181, 1967. new addition to the drug treatment of 20. LAFAVE, H. G., STEWART, H. and SEGOVIA, G. Haloperidol: schizophrenia. Can. psychiat. Ass. J. 12, 597, 1967. 21. WESTON,M. J., BENTLEY,R., UXWI;U,A., MORRIS,M. and HARPER,M. A. A comparative trial of haloperidol and thioridazine: management of chronic schizophrenia. Amt. N.Z. J. Psychiar. 7, 52, 1973. 22. HOLLISTER,L. E., OVERALL,J. E., CAFFEY,E., BENNETT,J. L., MEYER,F., KLVBUL, I. and HONIGFELD, G. Controlled comparison of haloperidol with thiopropazate in newly admitted schizophrenics. J. new. ment. Dis. 135, 544, 1962. 23. CHOUINARD,G., LEHMAN,H. E. and BAN, T. A. Pimozide in the treatment of chronic schizophrenic patients. Curr. ther. Res. 12, 598, 1970. 24. MORRIS,P. A., MACKENZIE,D. H. and MASHETER,H. C. A comparative double-blind trial of pimozide and fluphenazine in chronic schizophrenia. Br. J. Psychiat. 117, 683, 1970. 25. DOUGLAS,K. W. and HIXDLEY,J. P. A comparison of mesoridazine and chlorpromazine in chronic psychiatric patients. J. din. Pharmacol. 9, 176, 1969.
A CO.~IPAIUONOF EQUX&E&T CLIXICU POTESCIESOF NEUROLEPTICS
97
26. FREE~WN, H. A double-blind comparison of mesoridazine and chlorpromazine in chronic schizophreni&. Dis. nerv. Syst. 3-1,289,-1973. 27. SUGARUN. A. A. Comnarison of TPS-23 and thiridazine in chronic schizouhrenic oatients. Curr. fher. Res. 7, j20, 1965. _ 28. MENA, A., GRAYSOX,H. and COHEN,S. A study of thioridazine and its side chain derivative, mesoridazine, in chronic male hospitalized psychiatric patients. J. new Drugs 6, 345, 1966. 29. CALWELL, W. P. K., JACOBSEN,M. and SKARBEK,A. A comparative study of oxypertine and trifluoperazine in chronic schizophreniaa new application of the Wing Rating Scale. Br. J. Psychiut. 110,520,1964.
30. CLAGHORN,J. Differential drug effects on social and symptomatic behaviors. Cur. fher. Res. 12, 580, 1970. 31. NEAL,C. D., COLLIS,M. D. and I~~LAH,N. W. A comparative trial of oxypertine and chlorpromazine in chronic schizophrenia. Cur. rher. Res. 11, 367. 1969. 32. HOLLISTER,L. E., OVERALL,J. E., KATY, G., HIGGENBOTTOM, W. E. and KIMBALL,I., JR. Oxypertine and thiothixene in newly admitted schizophrenic patients. Clin. Pharmac. Ther. 12, 531, 1971. 33. HUNT, P. V. A comparison of the effects of oxypertine and trifluoperazine in withdrawn schizophrenics. Br. J. Psychiat. 113, 1419, 1967. 34. SKARBEK,A. and JACOBSEN,M. Oxypertine: a review of clinical experience. Br. J. Psychiut. 111, 1173, 1965. 35. SERAFETINIDES, E. A., WILLIS, D. and CL.UK, M. L. The EEG effects of dibenzoxazepines (loxapine succinate) as compared to CPZ: EEG changes as drug side effects. Znf. Pharmacopsychiat. 6,38, 1971.
36. SHOPSIN,B., PEAR~OS,E., GERSHON,S. and COLLINS,P. A controlled double-blind comparison between loxapine succinate and chlorpromazine in acute newly hospitalized schizophrenic patients. Curr. ther. Res. 14,739, 1972. 37. BISHOP,M. P. and GALLANT,D. M. Loxapine: Cut-r. ther. Res.12, 594, 1970.
a controlled evaluation in chronic schizophrenic
patients.
38. CASEY,J. E., LASKY,J. J., KLE~, C. J. and HOLLISTER,L. E. Treatment of schizophrenic reactions with phenothiazine derivatives. A comparative study of chlorpromazine, triflupromazine, mepazine, prochlorperazne, perphenazine, and phenobarbital. Am. J. Psychiat. 117, 97, 1960. 39. KURLAND,A. A., MICH.~UX,M. H., HANLON,T. E., OTA, K. Y. and SIMPOULOS,A. M. The comparative effectiveness of six phenothiazine compounds, phenobarbital and inert placebo in the treatment of acutely ill patients: personality dimensions. J. net-v. ment. Dis. 134, 48, 1962. 40. KLJRLAND,A. A., HANLON,T. E., TATOII, M. H., OTA, K. Y. and SIMPOPOULOS, A. M. The comparative effectiveness of six phenothiazine compounds, phenobarbital and inert placebo in the treatment of acutely ill patients: global measures of severity of illness. J. nerv. ment. Dis. 133, 1, 1961. 41. ADELSON,D. and EPSTEIN,L. J. A study of phenothiazines with male and female chronically ill schizophrenic patients. J. nerv. menr. Dis. 134, 543, 1962. 42. BISHOP, &I. P., FULMER,T. E. and GALLAS~, D. M. Thiothixene vs trifluoperazine in newly-admitted schizophenic patients. Cut-r. ther. Res. 8,509, 1966. 43. GALLANT, D. M., BISHOP, M. P., T~htbio~s, E. and GOULD, A. R. Thiothixene (P-4657B): controlled evaluation in chronic schizophrenic patients. Cut-r. ther. Res. 8, 153, 1966. 44. WOLPERT,A., SHEPPARD,C. and MERLES,S. Thiothixene, thioridazine, and placebo in male chronic schizophrenic patients. Clin. Pharmac. Ther. 9, 456, 1968. 45. DENBER,H. C. B. and TURNS, D. Double-blind comparison of thiothixene and trifluoperazine in acute schizophrenia. Psychosomntics 13, 100, 1972. 46. AZIMA,H., D~ROST, H. and ARTHURS,D. The effect of thioridazine (Mellaril) or mental syndromes. Comparison with chlorpromazine and promazine. Can. med. Ass. J. 81, 549, 1959. 47. General Practitioner Clinical Trials. Thioridazine as an anti-deoressant. Pracfifioner 209., 95.I 1972. 48. OVERALL,J. E., HOLLISTER,L. E., MEYER,F., KIMBALL,I. and SHELTON,J. Imipramine and thioridazine in depressed and schizophrenic uatients. JAMA 189. 605. 1964. 49. ROSE~AL, s. H. and BOWDEN,C. I,. A double blind comp&ison of thioridazine (Mellaril) vs diazepam (Valium) in patients with chronic mixed anxiety and depressive symptoms. Curr. res. Ther. 15, 261, 1973. 50. LODGEPATCH,I. C., PITT, B. M. and YEO, Y. M. The direct comparison of antidepressants: imipramine and chlorprothixene. J. phychiat. Res. 5, 273, 1967. 51. HOLLISTER,L. E., OVERALL,J. E., POKORZ~Y, A. D. and SHELTON,J. Acetophenazine and diazepam in anxious depressions. Archs gen. Psychiat. 24, 273, 1971.
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RICH-
JED WYATT
and JOAN S. TORGOW
52. SHOPSLU,B., GERSHON,S., THOMPSON,H. and COLLINS,P. Psychoactive drugs in mania: a controlled comparison of lithium carbonate, chlorpromazine and haloperidol. Archs gen. Psychiut. 32, 34, 1975.
53. REYNTJENS,A. M. and VAN MIERLO, F. P. A comparative double-blind trial of pimozide in stressinduced psychic and functional disorders. Curr. m&. Res. Opin. 1, 116, 1972. 54. OVERALL,J. E., BROW, D., WILLIAMS,J. D. and NEILL, L. T. Drug treatment of anxiety and depression in deto.xitied alcoholic patients. Archs gen. Psychiut. 29, 218, 1973. 55. BRAUZER.B., GOLD~TEN,B. J., STEINBOOK, R. M. and JACOBSON,A. F. The treatment of mixed anxiety and depression with loxapme: a controlled comparative study. J. din. Pharmacol. 14, 455, 1974. 56. General Practitioner Clinical Trials. Antidenressant effects of tranouillizers. Prucfifioner 206, 146, 1971. 57. HOLLI~TER,L. E., OVERALL,J. E., SHELTON,J., PEP*~NGTON,V.,‘KIMBALL, I. and JOHNSON,M. Drug therapy of depression: Amitriptyline, perphenazine and their combination in different syndromes. Archs gen. Psychiat. 17,486, 1967. 58. SIMPSOII,G. M., A.MIN,M., ANGUS, J. W. S., EDWARDS, J. G., Go, S. H., and LEE, J. H. Role of antidepressants and neuroleptics in the treatment of depression. Archs gen. Psychiar. 27, 337, 1972.
59. HARE. H. P. Comnarison
of diazenam. chlorpromazine _. -
and a placebo in psychiatric practice. /. new
Drugs 3,233, 1663. 60. PAYKEL, E. S., PRICE, J. S., GILUN, R. V., PALMAI,G. and CHESSER,E. S. A comparative pramine and chlorpromazine in depressed patients. &-. J. Psychiat. 114, 1281, 1968.
trial of imi-
61. RAXIN, A., SCHULTERBRANDT, J. G., REATIG, N. and MCKEON, J. J. Differential response to chlorpromazine, imipramine, and placebo. Archs gen. Psychiut. 23, 164, 1970. 62. WYATT. R. J. Biochemistry and schizophrenia-IV. The neuroleptics-their mechanism of action: a review of the biochemical literature. P‘sychopharmacol. Bull. 12, 5‘, 1976. 63. DAVIS, J. M. Dose equivalence of the anti-psychotic drugs. J. Psychiut. Res. 11,65, 1974. 64. OVERALL.J. E. and GORHAM.D. R. The brief psychiatric rating scale. Psycho/. Rep. 10, 799, 1962. 65. HAMILTON,IM. A rating scale-for depression. J. Neural. Neurosirg. Psychiat. 23,56, 1960. 66. HOLLISTER,L. E. and OVERALL,J. E. Reflections on the specificity of action ofantidepressants. Psychosomatics 6, 361, 1965. 67. STEVENS, J. R. An anatomy of schizophrenia? Archs gen. Psychiat. 29, 177, 1973. 68. KETY. S. S.. ROSENTHAL.D.. WENDER.P. H. and SCHULSINGER, F. Mental illness in the biological and adbptive’families of adopted schizophrenics. Am. J. Psychiat. 128, 302, 1971.