Amer. I . Orthopsychiat. 46(3), July 1976

METHODOLOGICAL ISSUES IN PSYCHOPHARMACOLOGICAL RESEARCH: Chlorpromazine-A Case in Point David Marholin II, Ph.D., and David Phillips, Ph.D.

Past research on the relative efficacy of powerful psychotropic agents has generally relied on group designs, which may mask critical individual diflerences in drug response. This and other methodological inadequacies raise questions about much of the vast literature in support of the clinical efficacy of chlorpromazine and similar drugs. A research strategy employing withinsubject designs, using a single subject as his own control, is sug,pested as advantageous in assessing individual drug eflects at specific dosage levels.

scrutiny. Moreover, the overwhelming opinion of the medical community is therapeutic efficacy of drugs, and will that CPZ is a valuable, tested, clinically focus on the literature pertaining to one effective drug for a broad spectrum of particular drug, chlorpromazine (CPZ) , populations including, among others, as an example. Because CPZ (trade those labeled as psychotic or schizoname, Thorazine) and its close pheno- phrenic.47 However, despite its widethiazine relatives, used widely since spread use and an extensive literature 1954, have transformed the mental hos- including over 20,000 publications, seripital ward from a panorama of chaotic ous questions remain to be answered. bedlam to an orderly sedate environWhile it is known that changes due to ment,lg it seemed the logical choice for CPZ occur at all levels of the central article will examine the methodThisology employed in evaluating the

Submitted to the Journal in December 1975. Authors are at: Boston University (Marholin), and University of Illinois at Vrbana-Chczmpaign (Phillips).

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nervous system, from the more primitive brain stem to the far reaches of the cortex, the precise physiological mechanisms or effects on anatomical structures are virtually unknown.37 Furthermore, on a purely biological basis, there are many relevant bits of data suggesting a variety of theories of biological effect, including the most accepted hypothesis-that the antipsychotic effects of CPZ are due in some large part to the blocking of dopamine transmitters.26 Unfortunately, the available evidence does not favor one theory of CPZ biological action over another. Current trends in therapeutic practice toward a behavioral or learning theory orientation 27, 08, 6g make it especially important to understand the precise effects of CPZ upon the learning processes and behavior. Research findings with CPZ on animals, normal subjects, and psychiatric patients suggest a trend showing significant decreases in learning on a wide variety of tasks, with a linear decline as dosage levels are in6R More importantly, several studies suggest that transfer of learning acquired during drug states to nondrug states is minimal.g2.93 However, one must be cautioned that these results should be taken as suggestive only, due 40 to serious methodological With data that indicate some disruption of basic learning processes during CPZ or related phenothiazine treatment, many unanswered questions arise as to its utility as a therapeutic tool: 1 ) What is the generalization of responses learned under drug states to nondrug states? 2) What effect does CPZ have on memory? 3) What is the interaction of CPZ and concurrently applied behavior therapy techniques? Finally, 4 ) what are the long-term effects of CPZ on the, as

yet unspecified, precise properties of learning altered by CPZ? If the behaviors that cause one to be labeled schizophrenic or psychotic are considered to be, at least in part, a process of learning O0 the ramifications of or using treatment procedures that reduce learning or transfer become serious.70.89 Another area of question involves a wide variety of side effects ranging from relatively minor ones such as drowsiness, abnormal skin pigmentation, dry mouth, faintness, and nasal stuffiness 37. 72 to an extrapyramidal syndrome called 24 which includes tardive dyskine~ia,~. the following physical manifestations: 1) a parkinsonian syndrome with motor retardation, depression, mask-like faces, tremor at rest, “pill rolling,” rigidity, salivation, and shuffling gait; 2) dystonia and dyskinesia, including torticollis, tics, facial grimacing, abnormal eye movements, and various involuntary muscle movements (a most striking form is the oculogyric); and 3) akathisia, evidenced by motor restlessness, difficulty in sitting still, and a strong urge to move about. In an extensive review, Crane2‘ found that in a mixed population of chronic, hospitalized patients 15% showed tardive dyskinesia, while Faurby et al 32 reported an incidence of 24.7%. Recent literature suggests that the syndrome persists and is peculiarly treat83 The alarmingly high ment-resi~tant.~~. incidence of tardive dyskinesia is compounded by the fact that many chronic patients are concurrently on some kind of anti-parkinson medication that would tend to mask symptoms associated with the syndrome. In summary, clinical use of CPZ seems to be particularly open to methodological scrutiny due to unknown mechanisms of action; possible interference

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with previous learning, present acquisition, and transfer from drug state to nondrug state; an alarmingly high incidence of physical side effects, some of which seem to be permanent and treatment resistant; and its concurrent widespread use. With these questions in mind, this paper will review the available research dealing with the clinical effectiveness of CPZ on the basis of methodology and relevant applied findings. Selected studies will be evaluated with regard to certain minimal research design criteria suggested by Sprague and Werry; 82 these include : 1 ) placebo control, 2 ) random assignment of subjects, 3 ) use of a double-blind technique, 4 ) standardized dosages, 5 ) standardized evaluations, and 6 ) appropriate statistical analyses. CRITERIA FOR THERAPEUTIC CHANGE

Before embarking on a discussion of the clinical efficacy of CPZ, it is necessary to arrive at an a priori general definition of “therapeutic effect.” Reduction in symptoms provides a necessary but not sufficient condition for an adequate operational definition. It is generally assumed by therapists who subscribe to psychodynamic models that direct modification of symptomatic behavior is likely to result in “symptom substitution.” While behavioral psychologists have claimed that no data confirming such phenomena exist,Q6counterclaims have gone so far as to suggest that commuted forms of symptom substitution may endanger the very life of ill-fated clients.” Behavior therapists have suggested that removing the symptom is to remove the “illness” or psychological problem.4u-Q0 Psychodynamic proponents postulate that man is ana-

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logous to the internal combustion engine; 84 to complete the analogy, it is suggested that when any of the manifest outlets (symptoms) are eliminated without a reduction of energy (dynamic illness), further system breakdown may be expected.38Whether of psychoanalytic or behavioral persuasion, clinicians generally acknowledge that eliminating symptomatic or deviant behaviors alone is insufficient and likely only to produce small, unpredictable, and transient changes in deviant behavior. A treatment plan that fails to alter the controlling conditions of inappropriate or “symptomatic” behavior will most certainly prove ineffecA program designed solely to eliminate maladaptive behavior does not in itself guarantee that adaptive behavior will ensue. This is particularly true when reduction of ina;ppropriate behavior is brought about through withdrawal of its maintaining positive consequences, employing aversive contingencies, or the imposition of external or internal restraints (e.g., drugs). Although inappropriate behavior that may have served as an effective device for coping with environmental stresses and demands may be temporarily suppressed through various punishment techniques, without the strengthening of incompatible appropriate behavior the client will most likely develop another set of deviant responses that are more successful in avoiding detection and subsequent punishment.18 !iuccessive substitution of inappropriate or maladaptive behavior may arise under conditions where responses are either punished or physically restrained without providing alternative, adaptive responses in aversive or threatening Successive substitutions of behavior may

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be viewed by some as symptom substitution. However, from a strict behavioral viewpoint, one is unjustified in attributing a new response to some inner dynamics caused by the elimination of another response. Behaviorally, the new response is viewed simply as the next highest probability response in the individual’s hierarchy of behaviors which will yield maintaining consequences. It is proposed, therefore, that behavior is a function of past and present environmental contingencies, rather than internal structure conditions. In summary, while treatment aimed at reducing deviant or symptomatic behavior may successfully eliminate that particular behavior, a different one may develop. The problem of possible maladaptive response substitution, however, may easily be solved by including in the original treatment program procedures that effectively remove the maintaining conditions for the deviant behavior and concurrently teach the client alternative adaptive behaviors. While inappropriate or symptomatic behaviors lead to the clinical diagnosis of schizophrenia, the behavioral deficits of the client may be a key factor leading to identification and possible institutionalization or preventing return to the community. For example, bizarre verbal behaivior of the labeled schizophrenic patient may be less likely to prevent a particular individual from functioning in the community than would his inability to perform particular tasks necessary to hold a job. In other words, suppressing inappropriate delusional speech may or may not be related to the client’s subsequent ability to attain and maintain a job in the community. On the other hand, a program aimed at both reducing delusional speech and increasing job related be-

haviors (e.g., punctuality, following instructions, exhibiting specific job tasks) will more likely be successful in maintaining the client upon his return to the community. In conclusion, a clinical treatment goal acceptable to most disciplines regardless of philosophical or scientific orientation, might then be stated as “a reduction in deviant or symptomatic behavior while concurrently demonstrating the acquisition of adaptive behaviors necessary to function independently of continued institutional or other one-to-one support.” Clinical improvement might then be defined operationally as “demonstrating any subset of both of these objectives not evidenced at some earlier point in time during treatment.” The behavioral effects of CPZ have been described by Delay and Deniker 2* as follows: Sitting or lying, the patient is motionless in his bed, often pale and with eyelids lowered. He remains silent most of the time. If he is questioned, he answers slowly and deliberately in a monotonous, indifferent voice; he expresses himself in a few words and becomes silent. Without exception the response is fairly appropriate and adaptable, showing that the subject is capable of attention and of thought. But he rarely initiates a question and he does not express his anxieties, desires, or preferences. He is usually aware of the improvement induced by the treatment but does not show euphoria. The apparent indifference or the slowing of responses to external stimuli, the diminution of initiative and of anxiety without a change in the state of waking and consciousness or of intellectual faculties constitute the psychological syndrome attributable to the drug. (p. 274)

Delay and Deniker most certainly imply improvement in the patient they describe. The frequency of “symptoms” in this psychotic patient is clearly functionally decreased. However, it appears

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that the frequencies of a large number of other behaviors are similarly decreased. One would be unable to classify this patient as clinically improved by the author’s criteria of therapeutic improvement. Among over 12,000 clinical reports, there are more than 60 semicontrolled experimental studies comparing CPZ to a placebo on various indices of improvement. In reviewing 61 studies employing some control procedures, Klein and Davis 4 8 reported that 50 studies found CPZ more effective than a placebo, while the remaining eleven found CPZ equal to a placebo. After rating the studies for dose adequacy, ranging from small fixed doses to large flexible dose schedules, they found that the studies finding CPZ ineffective utilized very small doses. Klein and Davis found clearcut therapeutic improvement in almost all studies using moderate or large doses of c e z . Klein and Davis suggested that the majority of the 61 studies reviewed were methodologically inadequate, employing poor controls, inadequate measuring devices, and the like. Of the 61 studies reviewed eleven were found to be . . . methodologically sound using such criteria as double-blind control, random assignment of treatment, adequate dosage, careful quantitative and qualitative assessment of patient change, large patient samples, and adequate statistical analysis of the data.48 (p. 5 5 )

Of the eleven studies judged methodologically sound by Klein and Davis, eight were available and examined with regard to the therapeutic efficacy of the prototype antipsychotic drug, CPZ. 1 . Schiele, Vestre and Stein 77 presented data on the comparative values of thioridazine, CPZ, and a placebo in the treatment of chronic schizophrenic patients. Eighty male patients with an

48 I

average age of 40.6 years and an average stay in the hospital of 10.0 years were selected on the basis of a diagnosis of schizophrenia without evidence of complicating organic factors. Patients were randomly assigned to one of four drug groups: thioridazine, trifluoperazine, CPZ, or placebo. The ward physician was free to vary the medication to achieve maximum effectiveness, and he was the only person who knew which patient was in each condition. The ward staff knew there was a placebo group. All capsules were identical in appearance. Doses averaged 35 mg,/day for trifluoperazine, 958 mg/day for thioridazine, and 895 mg/day for CPZ. Clinical effectiveness was judged on the basis of ratings from the Manifest Behavior Scales ( MBS ) and scores on thc Minnesota Multiphasic Personality Inventory (MMPI) taken at a pretreatment evaluation and at eight-week and sixteen-week evaluations. The nursing assistants made the behavior ratings. No interobserver reliability was mentioned. At the end of the first eight weeks of treatment, all drugs were significantly better than the placebo in reducing symptoms as derived from a pathology scale of the MBS. No significant change occurred after Week 8. There were no significant changes in the MMPI scores for the 43 patients who were able to cornplete it. A third measure, a global clinical evaluation, at the end of sixteen weeks yielded results compatible with the MBS, with 50% of those in the drug conditions showing only slight improvement. Although the nurses knew the experimental conditions, and the physician who prescribed the medication was the chairman of the sixteen-wee k global clinical evaluation meeting, thle design was said to be strictly double-blind. It

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is clear that the double-blind require- made prior to treatment, after one ments have not been met. The criteria month of treatment, and at the end of for change on the MBS, a reduction in the eight-week period. An analysis of symptoms, does not meet the stated re- variance revealed that CPZ and the other quirements of clinical improvement. four phenothiazines tested were statistiThe authors stress that 60% of the sub- cally more effective than the active jects in the placebo group got worse. placebo, phenobarbital. The clinical scales yielded an overall Given that all subjects were on various phenothiazine treatments immediately index of psychopathology and eleven prior to the study, a group switched to symptom cluster scores. After one a placebo most certainly would be dis- month of treatment, the scores revealed criminable by the nursing staff from that those patients receiving the phenotemporary withdrawal reactions and re- thiazines were less restrictive, belligerduction of side effects alone. It is reason- ent, and disturbed in their thinking than able to assume that the higher frequen- were patients receiving phenobarbital. cies of symptoms in the placebo group These changes were accompanied by a would be interpreted as patient regres- decrease in the amount of physical care sion. These serious methodological flaws required. It is possible that the sedating severely limit the usefulness of this and symptom reduction effects of these drugs were the variables responsible for study. 2. Casey et a1 21 compared the clini- the rated improvements due to a negacal effectiveness of an active placebo, tively reinforcing effect on the ward perphenobarbital, to five phenothiazine sonnel who supplied the ratings of pacompounds, CPZ, mepazine, trifluprom- tient improvement. One must be skeptiazine, prochlorperazine, and perphena- cal of the control procedures when 35 zine. A total of 640 newly admitted different hospitals are involved in the schizophrenic men (average age 34) in sample. There are serious questions 35 VA hospitals were randomly assigned about control and rater reliability, which to one of the six drugs. While the limit the confidence of this study. 3. Casey et a1 2o employed 692 men method section is very unclear, the summary reports a double-blind procedure. with schizophrenic reactions hospitalPatients were started on low equivalent ized in 37 different VA hospitals to study doses of each drug for four weeks. Dur- the relative effectiveness of CPZ, promaing the final eight weeks, each prescrib- zine, phenobarbital, and an inert ing physician adjusted the dose for each placebo. The average patient was 36 patient to evoke optimal therapeutic re- years old and had been hospitalized for sponse, with average doses during the seven years. Chronic subjects outnumfinal eight weeks being: CPZ, 635 mg/ bered acute subjects 81% to 19%. Conday; triflupromazine, 175 mg/day; mep- trols included random assignment of azine, 190 mg/day; prochlorperazine, treatments, reported use of a double90 mg/day; and perphenazine, 50 mgl blind procedure, and appropriate counday. Clinical effectiveness was devised ter-balancing techniques. Both CPZ and from two psychiatric rating scales promazine were given in daily dosages of 400 mg., and phenobarbital was (MSRPP and the CEPS). No reliability measures were reported. Ratings were administered in daily dosages of 200

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mg. A crossover design was used in which, following twelve weeks of treatment, subjects were changed to one of the other three conditions. Clinical changes in patients were measured by two psychiatric rating devices, the MSRPP and the CEPS, at three-week intervals. No interobserver reliabilities were reported. Results indicated that CPZ was statistically better than any of the other three agents, while promazine was more effective than either placebo. As with the previously summarized study by Casey et al,*l these results must be taken as merely suggestive, given dubious consistent control procedures with 37 different hospitals, no reported reliability or validity measures, a possible side effect confound, and inappropriate criteria for clinical improvement. 4. Hollister, Erickson and Motzenhecker 4 4 compared the therapeutic effects of CPZ, triflupromazine, and phenobarbital in a double-blind study employing a crossover design. The subjects were 60 male hospitalized chronic schizophrenics. Their median age was 36, and two-thirds of the subjects had been continually hospitalized for more than five years (median length of seven years). All subjects had been treated with CPZ for at least six months prior to the study. Exact dosages are reported for phenobarbital only (32 mg/day) . A psychiatrist’s opinion and an abbreviated version of the Hospital Adjustment Scale were employed as criteria measures of improvement. No reliabilities were reported. The subjects were equally divided among triflupromazine, continued CPZ, and phenobarbital for four months. Results indicated statistically significant better results for CPZ and triflupromazine as compared to pheno-

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barbital. There was a notable lack of reported method and control procedures. This study was particularly deficient methodologically and the results must be viewed skeptically. 5 . Kurland et a1 4 0 assigned 238 newly admited male and female acutely disturbed patients randomly to six weeks of treatment with one of the following: perphenazine, prochlorperazine, triflupromazine, mepazine, CPZ, promazine, phenobarbital (active placebo) and an inert placebo. The drugs were reportedly given on a double-blind basis. After admission the patients were evaluated for 48 hours prior to any treatment. At the conclusion of the 48 hours, minimum daily dosages (i.e., as stated by the drug companies) were administered parenterally. From Day 3 of drug therapy, medication was given orally. Although not knowing which drug they were giving, physicians were allowed to increase dosages until they felt they had achieved optimum therapeutic results. The physician could terminate the treatment at any time he felt the patient was not improving sufficiently. Average dosages per day were as follows: perphenazine, 30.8 mg/day; prochlorperazine, 45.38 mg/day; triflupromazine, 1 10.45 mg/day; mepazine, 135.64 mg/day; CPZ 401.35 mg/day; promazine, 438.92 mg/day; phenobarbital, 183.64 mglday; and placebo, three capsules. Criterion measures included the total morbidity score on the Multidimensional Scale for Psychiatric Patients (MSRPP) and the adapability score on the Psychiatric Scale of Target Symptoms ( PSTS) . Rater reliability from prestudy data indicated a reliability of .69 for items on the MSRPP ward oljservation battery and .75 for a one-hour in-

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Withdrawal and Paranoid Belligerence were among the few behaviorally specific, operationalized criteria (i.e., behavior checklist items). That a sedating drug would reduce high magnitude observable behavior, such as verbal Paranoid Belligerence, while not initiating high frequency social behavior in the withdrawn patient is not inconsistent with an overall-sedating-effect hypothe. . . the ability of the individual to meet ensis. The factors that contributed heavily vironmental demands without disintegrating to a positive difference in favor of CPZ inner stress.49 (p. 9 ) . and four of its derivatives were ConThis evaluation was made by the ward ceptual Disorganization, Perceptual Dispsychiatrist. The method does not speorganization, and Thinking Disorder. cify whether or not it was the same perThese criteria measures were derived son who was prescribing the drugs. Pafrom the psychiatric interview with dutients were tested weekly on the PSTS bious reliability. It is suggested that imand bi-weekly with the MSRPP. Results provements in these areas would likely indicated significantly reduced MSRPP be inferred from a sedated individual total morbidity for all conditions with who is engaging overall in significantly the e x c e p t i o n of mepazine, inert less verbal behavior than prior to mediplacebo, and phenobarbital. Results cation. were similar with PSTS ratings. 7. National Institute of Mental As in several of the other studies reHealth carried out a collaborative viewed, the improvement criteria, while study in nine separate hospitals in which not strictly operationalized, represented the effects of fluphenazine, thioridazine, a decrease in frequency of inappropriate and CPZ were compared with those of a behavior. However, there are no data placebo. The population of the study showing any concurrent increase in totaled 344 male and female newly functional behavior. The apparent im- admitted schizophrenics with an average provement of the phenothiazine groups age of 28.2 years. The design of the could very easily be confounded with an study was similar to the others examoverall decrease in all behavior. There ined here in that subjects were randomly is some evidence to support this hypoth- assigned to treatment groups, and flexiesis in data from a follow-up factor ble dosage schedules were used in a analysis 50 of this initial study.49 double-blind fashion. The average dos6. Kurland et a1 50 found in their age for each treatment was CPZ, 654.8 follow-up that neither the inert placebo mglday; fluphenazine, 6.4 mg/day; and nor phenobarbital differed significantly thioridazine, 700 mg/day. Clinical asfrom any of the five phenothiazines for sessment techniques included a weekly the psychological construct, Withdrawal. global assessment of degree of illness There was significant difference from by the ward physician, the Inpatient placebo to phenothiazine treatment for Multidimensional Psychiatric Scale, a second factor, Paranoid Belligerence. and the Burdock Ward Behavior Rating terview by a psychologist (i.e., second part of MSRPP). Reliability scores for the PSTS were not reported, although it is implied that they were low enough to require redefinitions. Items on the MSRPP dealt with thinking disorders, paranoid belligerence, and agitated depression. The Adaptability score from the PSTS might be stated as

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Scale. No reliabilities were reported. Significant differences were found in favor of the three drug conditions over the placebo although no statistics were reported. A noteworthy account of side effects was included in the discussion section as a basis for comparison of side effects of the three psychoactive drugs. Drowsiness was present as a side effect in 53.4% of the CPZ group, 36.3% of the fluphenazine group, 51.6% of the thioridazine group, and only 9.5% of the placebo group. In addition to drowsiness there are several other side effects (e.g., dryness of mouth, constipation) that occur from three to five times as frequently in the three phenothiazine groups as in the placebo group. Herein lies a major confounding factor, making the conclusions dubious at best. 8. Adelson and Epstein evaluated four phenothiazine derivatives-cpz, perphenazine, prochlorperazine, and tritluoperazine-under double-blind conditions with 288 male (average age 38.6) and female (average age 39.7) chronically ill schizophrenic patients over an eight-month period. Half of the 288 subjects had been hospitalized from two to five years, and half from six to ten years. An active placebo made up from a combination of scopolamine and chlorprophenpyridamine, used for the stated purpose of simulating side effects, and an inactive lactose placebo completed the six possible treatment conditions. Identically coded capsules were supplied to the ward psychiatrist in units of one and two (unit mg. determined by previous limits for each drug). He was allowed to increase dosage by one unit per day for the first ten days, after which drug dosage could be further increased by two units per day up

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to what was considered an optimal clinical dosage with a ceiling of 30 units per day. The average daily dosages in each condition were: CPZ, 1800 mg.; perphenazine, 18 1.84 mg.; prochlorperazine, 338.10 mg.; trifluoperazirie, 621.25 mg.; and active placebo, 30 mg. Patients remained on their drug or placebo for three months, at which point they were slowly withdrawn from drugs over a two-week period and held completely off treatment for one month. At the end of this period, maintenance dnig treatment was instituted if necessary. The MSRPP and a psychiatric opinion constituted the evaluative instruments. During the course of treatment, evaluations were carried out four times: immediately prior to the beginning of drug treatment, after four months, after five and one-half months (drug had been withheld for one month), and at the end of eight months. With each of the four phenothiazines there was a decrease in the mean morbidity Emcoreon the MSRPP over the eight-month period, while the placebo groups remained essentially unchanged. The psychiatrist’s estimates of improvement were in agreement with the MSRPP.Both criteria differences were highly statistically significant. The results of this study are similar to many studies. The inappropriateness of the evaluation criteria and lack of reported interobserver reliabilities make the result of drug-induced therapeutic gain equally as questionable as in other reported studies. Of the original target population, 75 patients were discharged to the community. Of the 75, five came from the placebo-treated patients and the remaining 70 came from the phenothiazine-treated patients. Although this seems impressive in favor of the pheno-

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thiazine group, to make any definitive statements it would be necessary to have clear behavioral criteria for discharge as well as some indication of how the subjects were functioning on the outside. Side effects were carefully recorded throughout the study. It is clear from subsequent totals that both placebos had fewer side effects than the four psychoactive compounds (i.e., active placebo, 187; inactive placebo, 161; CPZ, 538). Side effects are clearly confounded with treatment effects and a strict double-blind procedure. SUMMARY OF CLINICAL STUDIES

A consistent set of methodological flaws is found in each of the eight studies reviewed. The criteria-for-change measures were clearly insufficient, the measures for the most part being a list of symptoms, and patient improvement becoming a reduction in these symptoms. Keeping in mind the a priori definition of treatment success or improvement, it should be clear that symptom reduction is not necessarily correlated with an increase in functionally appropriate or adaptive behavior. It is not surprising that patients under heavy dosages of a tranquilizing drug such as CPZ will be seen as portraying less symptomatic behavior. It would, however, be interesting to have concurrent behavioral measures of other behaviors to test for a generalizing decrease in total patient behavior. It seems highly likely that this concurrent decrease in behavior would be overlooked in a large institutional setting. Reduction in patient symptomatic behavior, a set of stimuli highly aversive to the nurses and doctors on the wards, represents a potent negative reinforcer to the ward agents. The same nurses and doctors on the wards are

likely to interpret this gross reduction in symptomatic behavior as patient improvement. Although a reduction in bizarre or symptomatic behavior may be the result of CPZ, employing such a “therapeutic” technique alone might be classically defined as a “punishment” procedure.s0 Because punishment may be functionally defined as the presentation of any stimulus which reduces the frequency of the behaviors preceding its presentation,80 there is no denying that CPZ acts, in part at least, as a punisher. As with any punishment technique, CPZ “therapy” has its side effects. Two have already been discussed-1 ) the physical damage the drug causes, and 2) the unfortunate fact that desirable as well as undesirable behaviors are suppressed. Finally, one side effect CPZ has in common with other punishment techniques (e.g., withdrawal of privileges, infliction of pain) is that it causes resentment and escape behaviors on the part of the patient.63 This response has been noted in patients who commonly avoid the actual injection of their medication and occasionally protest being “drugged up.” As when considering the use of any punishment technique, its potential utility must be carefully weighed against its possible undesirable side effects.s More sophisticated behavioral assessment devices are necessary to discriminate reduction in symptom-specific behavior from reduction in all behavior. The reliability measures for the clinical assessment tools employed, although infrequently reported, are so low as to suggest that the improvement criteria are merely based on a global nonspecific personal rating. Such a nonscientific method renders suspect the results of even the supposed methodologically

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sound studies that have been reviewed. All of the studies specifically reviewed purported to employ a double-blind control procedure. The double-blind procedure refers to the knowledge of the observer and the patient as to which of at least two treatment conditions are in effect.34 None of the studies were, in fact, double-blind. Any drug treatment causing significant and typical side effects in a reasonable proportion of the patients receiving an adequate clinical dose will enable many observers to discriminate patients on the drug from those on placebo.73 Even those studies employing an active placebo are subject to this criticism, in that it is never possible to match physiological side effects precisely. Several of the studies reviewed, which report differential frequencies of side effects across conditions, provide evidence of this obvious and serious problem in treatment evaluation. Cole,23 Sprague and Werry,82 and others ll. 04. 70. O4 have questioned the feasibility of ever achieving a perfect double-blind design, in light of this inescapable problem; it thus becomes of greater importance to develop relevant, valid, and reliable behavioral measures of change due to treatment.52* 86 Most of the studies reviewed allowed flexible dosage schedules to permit maximum therapeutic effects. While consistent with the principles of psychopharmacological medicine, the flexible dosage schedules represent a major limitation on attempts to compare one phenothiazine treatment to another.7e* In addition to problems of within-study comparisons, it is not possible to make consistent across-study conclusions due to vast dosage differences among similar drugs in different studies. Few studies report attempts to con53v

trol for treatment milieu. In some investigations, psychotherapy is terminated for all patients, while in others it continues. While ECT and other psychotropic drugs are “generally” reported as being discontinued, there is no control for daily environmental conditions across experimental treatment phases. It is highly likely that those patients under drug conditions, being more sedate, are more likely to be selected for participation in extra-drug therapy than those more active and deviant placebo patients. If this is indeed the cast:, milieu and the drug treatment factor would be directly confounded.l”* 71 A variety of other less than adequate methodological considerations include: 1) poor or nonexistent definitions of clinical populations, 2 ) violations of statistical principles, 3) concurrent medications given for side effects, 4) excluding subjects from the final analysis who were discontinued due either to severe side effects or to deterioration in psychiatric condition,51 and 5 ) not clearly reporting the experimental method so as to allow independent replication. The methodological iriadequacies of the studies reviewed raise the general issue of whether or not CPZ treatment is, in fact, beneficial. If it is not, the administration of CPZ and its closely related phenothiazine agents merely creates an “illusion of treatment,” with the deadly effect of‘ making other therapeutic practices seem unnece~sary.’~ It becomes apparent, upon critical methodological scrutiny, that many of the studies widely cited in support of the clinical use of CPZ are inadequate, and their results may be seriously questioned. Continued reliance upon equivocal studies to support the use of any

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procedure or drug does not advance the state of knowledge; one has merely to look at the paucity of clearly understood and predictable effects of CPZ to question the overall contribution of such research. Methodologies that meet critical research criteria can alleviate these shortcomings. Several widely acceptable research methods are available, but each has certain requirements that must be met to assure confidence in their results. The studies reviewed in this paper all utilized a group-statistical research design employing a variety of indirect dependent measures. Many of the ratingscale categories are less than precise, and, in the absence of reported reliability coefficients, the results must be suspect. A return to a more basic unit of analysis, namely, observable behavior which can be objectively defined and reliably measured over time, is suggested. In addition to eliminating some of the more generally agreed upon serious methodological flaws in clinical studies attempting to evaluate the therapeutic ~ * ~should ~ efficacy of c ~ z ,an~ attempt be made to clearly define and reliably observe, record, and report specific behavioral changes in individual patients before, during, and after drug treatment. The initial step in monitoring individualsubject behavioral change would require specific operational definitions of classes of behavior related to one's concept of therapeutic gain, whether they be social, self-help, academic, cognitive, or emotional behaviors.l2, l 3 The main requirement in defining change-related behaviors is preparing criteria so unequivocal that two or more observers will be in almost total agreement at all times. Following the acquisition of precise behavioral definitions, some method for the

direct observation and recording of frequencies of occurrence of the class or classes of criterion behavior is necessary. The final step involves devising an objective and practical recording procedure to be carried out by direct service staff (e.g., time sampling) so as to be able to register the frequencies of occurrences and nonoccurrences within a specified time inter~al.'~. 58 Hall 39 has outlined a set of practical techniques for measuring discretely defined behaviors without the use of expensive automatic recording devices. Moreover, Alevizos et a1 have provided guidelines for deciding on the kind of observation and recording method to use with various target behaviors. The aforementioned procedures have been successfully used in monitoring rehabilitation programs,e1 psych~therapy,~~ academic achievement,I5 parent-child relationship^,^' and adaptive social, self-help, and vocational behaviors of chronic schizophrenics.4, 5, 0 With a set of operationally defined behaviors specifically related to therapeutic gain and a method to reliably record their relative frequency of occurrence or nonoccurrence during any specified time period, it would be possible to assess clearly the effects of any particular drug treatment such as CPZ through single-subject experimental designs.RRPrior to drug treatment, a baseline of criterion behaviors could be acquired to which the treatment condition might be compared. Furthermore, either an ABA reversal type individual-subject design or a multiple baseline technique used with a group of patients '. 79 would allow for an evaluation of the effectiveness of CPZ treatment, with the absence of drug treatment representing baseline conditions ( A ) and the presence of drug

MARHOLIN AND PHILLIPS treatment representing the experimental condition ( B ) . Since the mid- 1950s, behavioral pharmacology has developed a methodology that is widely accepted for the scientific study of specific drug effects on behavior.22, 29. 30, 5 0 , S i , ** Prior to the development of a behavioral individual analysis approach, psychopharmacology had frequently employed sophisticated group-statistical research designs to study the effects of various drug conditions on human performance. It might be emphasized at this point that there are appropriate uses for both groupstatistical and individual functional analysis methodologies, with each resting on certain assumptions and criteria of adequacy. Group-statistical research methodology usually involves the administration of drugs to one of two or more groups of otherwise “identically” treated subjects. The resulting differences on some dependent measure, such as a checklist, direct observation of behavior, or test performance, is then evaluated statistically as to the probability of the differences resulting from “chance.” Sprague and WerryE2have stated that the most frequent inadequacy found in drug research employing group designs is methodological in nature. Typically, little information is provided concerning many possibly relevant subject variables, dosage levels, schedules of reinforcement, medication history, and the actual task involved in the study.s7 When employing group designs in drug investigations, there are certain requirements for a valid scientific study. The following six criteria, suggested by Sprague and Werry,R2 are not intended to be exhaustive. Meeting these six criteria obviously will not insure a valid, replicable study, but,

489

clearly, without their observance little progress will be made. 1. Placebo control. One should control for the possible effect of administering any drug. The administratron procedure may in itself affect behavior. I n addition, one needs to estimate the magnitude of placebo effects on certain variables by using a no-drug condii.ion. 2 . Random assignment of Jubjects. Random assignment to groups must be used to avoid biased samples in the groups. Hunches or idiosyncratic procedures of assignment may seriously bias the samples. This is true of matchedpair designs and crossover sequence of treatments, and is necessary in order to meet the unusual assumptions of the statistical tests. 3 . Double-blind. Neither the subject nor the person evaluating the subject’s behavior can be aware of which is the placebo, drug, or no-drug conditions. This attempts to avoid the investigator’s expectations from influencing his assessment. 4 . Standardized dosages. Dosage must be standardized in some way for some period of time. Use of mg/kg procedure is desirable in the absence of other empirical information on dose effect variability. 5 . Standardized evaluations. The measurement device, if it is soma instrument such as a scale or test, must be empirically validated and its reliability established. 6 . Appropriate statistical unalysis. Statistical analysis of the data using tests of which the assumptions are mei: is critical. The inappropriate use of a statistical technique provides uninterpretable information. For many purposes, group designs meeting these and other criteria can pro-

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vide useful information. One of the major strengths of a group-statistical design is in program evaluation. That is, with a large number of potential recipients of a treatment method, one may evaluate overall average benefits. However, such traditional group data functions are likely to obscure characteristics of individual performance; Estes,31 Hayes,42and Sidman 78 have empirically shown that the average curve of a group does not necessarily have the same form as those of individual members of a heterogeneous group.Oi Precisely how one individual is affected over time as a function of systematic changes in treatment is perhaps the most important factor to consider in attempting to establish experimentally functional relationships between the administration of a drug and its subsequent effects. Employing a group-statistical approach, where the data for all of the subjects within a group are averaged, may lead to highly misleading conclusions. For example, while half the patients in a particular treatment condition might show very large positive or therapeutic effects as a function of a specific drug, the other half might demonstrate large negative effects. Hence, in the final analysis one would conclude that there were no significant differences due to the drug treatment condition. However, it is obvious that in this case very important data could be obscured. An individual subject analysis, on the other hand, would allow for the experimental examination of each subject in an attempt to establish clearly the functional relationships between drug parameters associated with the particular drug treatment condition and the ensuant individual's behavior. When a single-subject analysis approach is used, certain evaluative cri-

teria are n e c e ~ s a r yFirst, . ~ ~ the behavior of interest must be adequately defined, so that anyone assessing the same behavior would agree as to its occurrence or nonoccurrence. Secondly, reliable techniques of recording the behavior must be employed and an account of the reliability coefficient included in the report. Pretreatment baseline rates of the target behavior must be established as a basis for comparison. Introduction of treatment must not be confounded with other relevant variables. Single-subject designs have several distinct advantages over group-statistical procedures; lo*65 they allow the researcher to 1 ) evaluate effects of drugs on specific, clinically relevant problem behaviors; 2 ) determine individual differences in effect due to differing dosage levels; 3) evaluate specific drug effects on a range of clinically relevant behaviors for each individual; 4 ) assess systematically the interaction' between drugs and other therapeutic endeavors; 5 ) carry out the design relatively inexpensively in any clinical setting; 6) evaluate systematically drug dosage curves, latencies, duration of effects, and peak effectiveness dosages; and 7) avoid the ethical problems inherent in withholding treatment from control groups. Among other recent examples of psychopharmacological research making good use of single-subject methodologies, 4 9 , Q8 Liberman et al 54 presented three cases in which the effects of phenothiazines were observed on clinically relevant behaviors of highly disturbed, psychotic individuals. For didactic purposes, one of their three single-subject studies will be summarized; it is offered as a practical guide to an analyticexperimental methodology for experi85v

49 I

MARHOLIN AND PHILLIPS Figure I AVERAGE NUMBER OF REFUSALS TO ENGAGE IN BRIEF CONVERSATION NO DRUG

PLACEBO

STELAZINE

PLACEBO STELAZlNE

SLSSIONS

mental-clinical investigation of drug effects on single organisms. John was a 2 1 -year-old high school graduate admitted to the clinical research unit of Cararillo State Hospital because of “social withdrawal from peers and a high rate of describing somatic delusions and hypochondriacal preoccupations” (p. 317). He complained that his “head was like a piece of wood” and that he felt that “his body was a hollow tube filled with a vacuum.” At the time of admission, John was receiving maintenance trifluperazine (Stelazine), 20 mg/day. He had been hospitalized twice over a previous three-year period. Two operationally defined measures were recorded by the staff of the clinical research unit during eighteen randomly, timesampled conversations held six days/week. The first measure, compliance with social interaction, was defined as whether John followed through with a conversation prompted by a member nf the nursing staff who systematically approached him and asked him to join in an informal chat. Compliance with this social interaction was defined as a “social response,” while noncompliance was defined as an “asocial response.” A semistandard verbal format was used by the nursing staff to prompt his verbal participation. The second measure was the presence or absence of delu-

sional or hypochondriacal verbal content in these time-sampled chats. When John did engage in conversation with a staff member, any expression of “sick talk” was noted for that 30-second interval. Interrater reliability for these two behavioral measures was reported to exceed 90%. An A-AI-B-AI-B within-subject design was employed to assess the effect of Stelazine on John’s social withdrawal and contcnt of his conversations (i.e., “sick” or “healthy”). During the first fourteen days of the study, John was taken off all medication ( A ) . After this baseline period he was placed on a placebo for eight days ( ~ 1 ) . The drug treatment phase lasted twelve days ( B ) , during which John was given 60 mg/day of Stelazine in a single dose. A return to the placebo condition lasted eight days ( A ~ ) ,and finally the drug treatment phase was reinstated (B). The effect of Stelazine on social participation is clearly shown in FIGURE l.* During the nodrug condition ( A ) John was extremely withdrawn, refusing two-thirds of his chats with nursing staff by the end of the baseline period. The placebo condition (A’) resulted in a temporary but transitory increase in socialization. However, the drug condition (B) resulted in a rapid and stable decrease in social withdrawal, with John participating in all eighteen of the prompted chats during the final four days of the treatment period. A return to the placebo condition ( A ~ ) led to an increase in social withdrawal, with the final reinstitution of the Stelazine drug treatment condition (B) again producing an increase in “social responses.” On the contrary, the presence or absence of drug treatment was not shown to be correlated with the frequency of “sick” (i.e., delusional or hypochondriacal) or “healthy” (i.e., rational) talk.

Hence, the methodology employed allowed the investigators to conclude that the drug under systematic study affected two operationally defined classes of behavior differentially. REFERENCES 1. ADELSON, D. AND EPSTEIN, L. 1962. A study

*FIGURE1 is reprinted, with permission, from Journal of Nervous and Mental Disease 0 1973 The Williams & Wilkins Co., Baltimore.

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MARHOLIN AND PHILLIPS thiazines and phenobarbital on verbal conditioning of schizophrenics. Psychol. Rep. 17 1 289-290. VESTRE. RE. N. 1966. The effects of phenothiazine drugs on verbal conditioning of schizophrenics. J. Psychol. 64:257-264. 94. WING, L. 1956. The use of reserpine in chronic psychotic patients: a controlled trial. J. Ment. Sci. 102:530-541. 95. WOLF, M., R I S L E Y , T. AND M E E S , H. 1964. Application of operant conditioning procedures to the behavior problems of an

495 autistic child. Behav. Res. Thcr. 1 :305312. 96. YATES, A . 1958. Symptoms and symptom substitution. Psychol. Rev. 65:37 1-374. W.ZEAMAN, D. AND HOUSE, B. 1963. The role of attention in retardate discrimination learning. / t i Handbook of Mental Deficiency, N . Ellis, ed. McGraw-Hill, New York. 98. ZIKE, K. 1972. Drugs in maladapive school behavior. Unpublished manuscript. (Available from author at Harbor General Hospital, Los Angeles.)

For reprints: Dr. David Marholin 11, Department of Special Education, Boston University, 765 Commonwealth Ave., Boston, Mass. 02215