A control group for psychotherapy research in acute depression: One solution to ethical and methodologic issues

0022-3456/79:0901-0189$02.00/0

J. psychlot. Res.. Vol.15.pp. 189-197.

0 Pergamon PressLtd. 1979. Printedin Great Britain.

A CONTROL

GROUP FOR PSYCHOTHERAPY RESEA’RCH IN ACUTE DEPRESSION : ONE SOLUTION TO ETHICAL AND METHODOLOGIC ISSU’ES ALBERTO DIMASCIO,*

GERALD L. KLERMAN,~**

BRIGITTE A. PRUSOFF,~ CARLOS NEuT/

and

MYRNA

M. WEISSMAN,$

PATRICIA MOORE II

*Department

of Mental Health, Commonwealth of Massachusetts; Tufts University Medical School, Boston, MA (Deceased) tAlcoho1, Drug Abuse and Mental Health Administration (ADAMHA), Rockville, MD. $Departments of Psychiatry and Epidemiology, Yale University School of Medicine; Depression Research Unit, Connecticut Mental Health Center, 904 Howard Avenue, Suite 2A, New Haven, CT 06519. IDepartment of Psychiatry, Yale University School of Medicine; Depression Research Unit, Connecticut Mental Health Center, New Haven, CT BTufts University Medical School, Boston, MA. (Received 26 January 1979; revised 3 July 1979) INTRODUCTION

THE SYSTEMATIC

evaluation of the efficacy of psychotherapy alone, in comparison or in combination with pharmacotherapy requires sophisticated methodology. In psychotherapy research, an appropriate control group is methodologically important and necessary, in order to control for variables other than the treatment which can contribute to patient improvement independent of an active intervention, such as the natural course of the disorder, the non-specific effects of attention, or the effects of patient expectation. A control group must be methodologically sound, acceptable to the patients randomized into it, and ethnically justifiable, particularly when studying the acutely ill patient who may be incapacitated or potentially suicidal. The need for control groups in psychotherapy research has long been recognized, and several types have been employed, including waiting list, 1 2 “rating only” assessment group,1 “nonspecific” treatment,3 low or minimum contact,d-6 or comparisons with untreated patients such as terminators from a treatment program or from an existing nontreated population. Each has its advantages and shortcomings. Although epidemiological studies of community samples demonstrate that many persons meeting the criteria for major depression do not seek treatment, the acutely depressed patient who comes for treatment, and is randomized in clinical trial to a no-treatment group, poses issues in patient acceptance and ethnics.7 The patient must be fully informed of the possibility of assignment to the controlled condition, must not be exposed to undue risk, and must not be deprived of prompt alternate treatment if it is needed. In an earlier maintenance treatment trial study from the Boston-New Haven Collaborative **Presentaddress: Harvard MedicalSchool, MassachusettsGeneral Hospital, Boston, MA. 189

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DIMA~CIOet

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Depression Project, we utilized a “minimum contact” group as a control to assess the efficacy of psychotherapy, given alone or in combination with pharmacotherapy, in maintaining improvement, or in preventing relapse in a sample of recovering depressed patients who had responded markedly to antidepressant treatment during the acute treatment phase.5 In this report, we describe a clinical trial dealing specifically with acutely depressed patients in which we were concerned about the consequences of infrequent, minimum contacts or unavailable clinicians and the possibility of an acutely depressed patient being left without prompt treatment. This paper describes a control group developed and utilized in the treatment of ambulatory acutely depressed patients, involving the collaboration of two clinics.* The treatment study assessed the relative efficacy of psychotherapy alone, pharrnacotherapy alone, or both in combination. This paper will describe our experience with a “non-scheduled treatment control group,” developed to meet simultaneously ethical and scientific concerns. We will describe the safeguards built into the study to protect the safety of acutely ill patients in a clinical trial. STUDY DESIGN

Patient population

Eligible for the study were nonpsychotic, nonbipolar, acutely depressed outpatients of either sex, aged 18-55, who met the diagnostic criteria of major depression. The diagnosis of major depression was made by a psychiatrist using the interview procedure of the Schedule for Affective Disorders and Schizophrenia @ADS)8 and the Research Diagnostic Criteria (RDC)P In addition, the presenting illness had to be at least moderate in severity (a rating of 7 or more on the Raskin Three Area Depression Scale [range 3-15])r2 with a reported onset of at least 2 weeks. Patients with another predominant psychiatric disorder were excluded as were those who had failed to respond to an adequate trial of amitriptyline in the past 3 months or to a minimum of 3 months of weekly individual psychotherapy. Also excluded were patients presenting with organicity, present or past signs of schizophrenia, chronic alcoholism, drug addiction, or medical conditions for which tricyclics were contraindicated. Treatment assignment

After l-week evaluation period, patients who met the inclusion criteria were randomized into one of four treatment conditions. All treatment continued for 16 weeks. Patients were made fully aware of their participation in a treatment research project, and of the implications of random assignment to the various treatment conditions. Participation was only by the informed written consent of the patient. Treatment groups were as follows: Psychotherapy alone. Psychotherapy alone included at least one weekly 50-min session of interpersonal psychotherapy by an experienced psychiatrist. The psychotherapy focused on the patient’s current life situations and interpersonal relationships rather than on an exploration of intrapsychic material or remote past experiences. The goals and techniques of the therapy have been described in a manual.10 *Clinical Research Services Unit, Institute for Research and Rehabilitation, affiliated with Tufts Medical School; Depression Research Unit, Connecticut affiliated with Yale University School of Medicine.

Boston State Hospital and Mental Health Center and

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Pharmacotherapy alone. Patients in the pharmacotherapy alone treatment group were prescribed amitriptyline in an increasing dose (100-200 mg) to an optimum level over a 4-week period. Patients showing response were stabilized to a maintenance level (100 f 25 mg) for the remaining 12 weeks of the study. Combined psychotherapy and pharmacotherapy. Patients in this group received both psychotherapy and pharmacotherapy, as described above. Non-scheduled treatment control. Patients in this group were assigned a psychiatrist but were told that there would be no active treatment initially, although the psychiatrist would see them periodically for research assessment and, if needed, would be available for clinical consultation. It was explained also that if their clinical condition should become rapidly worse and intolerable between the scheduled rating periods or if they felt the need for different treatment, they could arrange an immediate appointment with the psychiatrist for evaluating the initiation of active treatment. Finally, patients in this group were informed that many persons improve spontaneously, especially if they are assured that there is someone to rely on if ever quick intervention is needed. This non-scheduled control group served to document the natural course of the untreated acute depressive episode. At each clinic one psychiatrist was responsible for both the psychotherapy and pharmacotherapy of all patients. It was the psychiatrist’s responsibility to manage the patients clinically in accordance with the research protocol’s requirements and limits. Sufficient time was available so that the psychiatrist could see the patient for extra visits, if required. Thus, this non-scheduled group design allowed the patient easy access to the psychiatrist in the event of worsening of symptoms, crises, or other discomforts. Patients in this group could see the psychiatrist for one extra visit during the month. If more contact was required the patient was considered a research failure. At this point, a full rating of the patient’s clinical and social status was taken and the patient was terminated from the research study and treated by the psychiatrist as deemed clinically appropriate. The patient’s end-point rating at the point of termination and the timing of termination was entered into the efficacy analysis. A record was kept of all contacts with the patient during the course of randomized treatment as well as a record of the alternate treatment received following early termination up to the planned 16 weeks. Clinical safeguards In addition to providing the control group with easy access to the psychiatrist if required, other safeguards were built into the study. These safeguards, described below, were designed to address clinical and ethical issues of patient care and to reduce biased decision making with regard to the patient’s clinical status. Patient inclusion criteria. Patients were excluded from the study if they were considered potentially suicidal or psychotic, or if they required hospitalization. Independent clinical evaluator. In a controlled clinical trial of a pharmacologic agent, a double-blind design and a placebo are used to reduce the introduction of clinician-patient bias and efficacy-expectation. However, psychotherapy cannot be double-blind designed since it would be difficult to determine a “placebo” for psychotherapy. Therefore, as an alternative, we used an independent clinical evaluator to assess the patients’ clinical status. All patients were told that they would be seen periodically by the psychiatrist and by an

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“independent clinical evaluator” (who was either a psychiatrist or a psychologist) for an assessment of their clinical status. The patients were told that the independent clinical evaluator purposely had not been apprised of the specific treatment each patient was receiving and they were instructed not to reveal this information or even hint at it-for instance, by discussing drug side effects. Patients were told that the role of the independent clinical evaluator was to periodically assess their mental and emotional status and to make an independent judgment of their progress, or lack of it. Patients also were told that the clinical evaluator, based on what he observed and on what the patient told him, could tell the psychiatrist that the patient’s clinical status required “more of whatever treatment was given” or a different treatment. The psychiatrist could then encourage more frequent therapy sessions, increase the dosage as allowed by the study protocol, do both, or depending on the circumstances (i.e. severity of the clinical status or non-scheduled assignment), could terminate the patient from the study and treat as required. The patient was told that he/she could request more or different treatment if he/she felt it was necessary. The independent clinical evaluator utilized a battery of standard clinical scales to rate the patients at each rating period. These ratings eventually served as treatment outcome measures. The psychiatrist also rated the patients on these scales but the fact that the clinical evaluator was blind to the treatment, served to mitigate against biases that might have resulted from knowledge of treatment cell assignment. Agreement between psychiatrist and clinical evaluator was examined at the end of the study and were found to be excellent. The agreement on the Raskin Depression Scale, expressed as weighted Kappa, was O-62(p ~0.001) at randomization and 088 (p ~0.001) at termination.11 These “unbiased” rating judgments and observations by the clinical evaluator were used to gauge when a patient’s symptoms or depressed feelings were becoming worse or when the patient could no longer tolerate his/her unchanged status. A uniform judgment of need or distress, independent of treatment received, was thus applied. At this point, the patient could be terminated from the research treatment phase of the study but would still continue to receive treatment at the clinic. Regular research assessments. All patients were seen after 1, 4, 8, 12 and 16 weeks for research assessments of their clinical status. Both an independent clinical evaluatorand the treating psychiatrist rated the patients independently, using the Raskin 3-Area Depression Scale,12 the Hamilton Depression Scale,*3 and the Global Illness Scale. Operationally defined criteria and time requirement for clinical improvement. To further ethically justify the non-scheduled treatment cell (and, in fact, our whole random assignment procedure), the study design specified that at the 8 week ratings, by which time it was expected that active treatment should have resulted in considerable clinical improvement, close scrutiny of treatment requirements be made by the clinical evaluator of all patients who had not shown sufficient improvement. It was our belief that regardless of the study condition to which they had been assigned, active or alternate treatment for any non-improving patients ethically could no longer be delayed. Patients were considered symptomatic failures and terminated from randomized treatment if, after 8 weeks of randomized treatment, they were rated as 9 or more on the Raskin Depression Scale by the clinical evaluator. Included were patients who had previously

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responded and then worsened, as well as those who had never shown a significant clinical improvement over the 8 weeks. In addition, patients were considered symptomatic failures if the clinical evaluator or psychiatrist noted risk of suicide, rapid worsening of symptoms such that hospitalization, ECT or any alternative active interventions were indicated. Alternate treatment. Any patient who was terminated from the randomized treatment cell was offered alternate treatment at the clinic or elsewhere if the treatment required was not available at the clinic, e.g. hospitalization, ECT. If treatment elsewhere was required, the patient was seen at the research clinic until another treatment could be arranged. RESULTS

Initial patient acceptance of the non-scheduled treatment

The patients’ initial acceptance of randomization to a non-scheduled treatment group was excellent. When informed of their assignment to the non-scheduled treatment group, 91% of the patients accepted it (Table 1). In fact, the acceptance rate for the non-scheduled treatment group was better than for psychotherapy (68%) or for pharmacotherapy alone (83 %). TABLE 1. INITL~L PATIENTACCEPTANCEOF ASSIGNMENT TO RANDOMIZED TREATMENT Treatment groups Patients’ acceptance of treatment assignment at point of randomization

Psychotherapy and pharmacotherapy N %

Assignment rejected Assignment accepted All patients

Psychotherapy N %

Pharmacotherapy N %

Non-scheduled treatment N %

1 23

4 96

8 17

32 68

4 20

17 83

2 21

9 91

-i;i

loo

23

loo

24

100

23

loo

~2 = 8.3. (3 d.f.).

p < 0.05. Clinical course and termination

There were no serious negative outcomes in the non-scheduled treatment. There were no suicides, no suicide attempts, and no hospitalizations in that group. However, termination before the prescribed 16 weeks of treatment was high. Only 33 % of patients assigned to the non-scheduled treatment control group completed the 16 weeks in their assigned treatment group; 14 % of the patients requested alternative treatment; and the remaining 53 % of the patients in the non-scheduled treatment group were determined by the clinical evaluator to be symptomatic failures (Table 2). The completion rates in the other treatment groups were higher. These results have been described in full detail elsewhere.i4,15 As stated previously, the protocol required that patients receive alternative treatment if they were rated as 9 or more on the Raskin Depression Scale after 8 weeks of randomized treatment. Subsequent treatment

Those patients who terminated early were treated promptly by the clinic. Most received combination treatment or pharmacotherapy and only 7% received no further treatment (Table 3).16

ALBERTO DIMASCIO et al.

194 TABLE 2. COMPLETIONAND

EARLY

TERMINATION

FROM

RANDOMIZEDTREATMENT(N =

Randomized treatment Psychotherapy and Pharmacotherapy Psychotherapy Pharmacotherapy

81)

Non-scheduled treatment

Reasons for termination

N

%

N

%

Completed 16 weeks Early termination Symptomatic failures Non-symptomatic withdrawal* Total

16

70

12

71

8

40

7

33

1 6 23

4 26 100

3 2 17

17 12 100

5 7 20

25 35 loo

11 3 21

53 14 loo

N

%

N

%

~2 = 18.1. (6 d.f.).

p < 0.01. *Non-symptomatic effects.

withdrawals included refusals, missed appointments,

failure to take medication, side

TABLE 3. TREATMENTRECEIVEDAFTEREARLY TERMF NATION BY PATIENTS INITIALLY RANDOMIZED INTO NON-SCHEDULEDTREATMENT (N = 14) Subsequent non-randomized treatment Psychotherapy and pharmacotherapy Psychotherapy Pharmacotherapy No further treatment

% 43 7 43 7

Clinical status of patients completing 16 weeks of non-scheduled treatment

While most patients assigned to the non-scheduled control group terminated before 16 weeks, the 7 out of the 21 patients who completed the full 16-week course in this group did quite well. There were no significant differences in clinical status between treatment groups for patients completing the 16 weeks (Table 4). DISCUSSION

These results demonstrate that the non-scheduled treatment control group in a clinical trial involving acutely depressed ambulatory patients is methodologically sound, acceptable to patients, and ethical. However, it also has limitations. Hospitalized, psychotic, bipolar, and suicidal depressed patients were excluded and the results cannot be generalized to these groups. Moreover, it must be emphasized that the non-scheduled group was not a notreatment group. The patients had the security of knowing a physician was available if they wished. Some patients in the non-scheduled group may have been inadvertently reassured that their problem was not so serious as to require immediate treatment. The non-scheduled sessions provided non-specific support which could have reduced treatment differences in a clinical trial testing psychotherapy. The non-scheduled group was, however, methodologically sound. Patients remained available for periodic assessments of their clinical status so that the effects of natural remission, patient expectation, and, to a lesser extent, the non-specific effects of attention could be documented. It was also acceptable to patients. Few patients refused this treatment assignment and, therefore, the bias of initial patient attrition was reduced. Moreover, it was

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TABLE4. CLINICALSTATUSOF PATIENTSCOMPLETING 16 weeks OF TREATMENT*?

Week

Raskin total

Hamilton total

Global illness

0 1 4 8 12 16 0 1 4 8 12 16 0 1 4 8 12 16

Psychotherapy and pharmacotherapy N= 16 a-38 7.68 6.56 5.54 4.83 4.38 16.19 12.81 10.35 7.37 6.55 4.99 3.69 3.46 2.83 2.58 2-19 1.82

Psychotherapy N= 12 8.67 6.64 6.16 5.02 5-39 4.99 15.83 12.48 10.02 9.00 7.42 6.67 3.75 2.90 3.01 2.32 2.50 1.83

Pharmacotherapy N-8 8-63 7.60 6.93 5.95 560 4.74 17.50 12.62 9.94 I.22 7.80 5.61 3.88 3.53 2.93 2.68 2.62 l-97

Non-scheduled treatment N=l 8.29 7.50 6.96 5.79 5.37 4.73 14.57 13.25 11.80 9.21 7.69 8.63 3.57 3.24 3.07 2.35 2.01 2.03

*Analyses were run as a one-way analysis of covariance with treatment as a factor. The means are adjusted for initial pretreatment levels. tNo statistically significant differences among treatments were found at any rating period.

ethically justifiable. There were no clinically serious outcomes such as suicides or hospitalization. The patients were not exposed to undue risks. Their clinical needs were met promptly and they received alternate treatment if necessary. The possible bias of the research team in determining when to withdraw a patient was removed by having the patient’s clinical status evaluated by someone independent of and blind to the treatment. In spite of the fact that more patients did not respond in the control group, it remains ethically justifiable to include such a group in a clinical study for the following reasons. A substantial minority of patients did not require alternative treatment and were spared the cost of psychotherapy and/or possible side effects of medication. Any patient who did not respond received an alternative treatment promptly. Larger patient samples are required to determine which patient characteristics predict the efficacy of a non-scheduled treatment intervention. The non-scheduled treatment control group should be considered in relationship to other types of commonly-used control groups. Waiting list. With this method, patients are randomized on to a waiting list and receive no treatment while on the waiting list. The advantage of this method is that patients who remain under this condition do not receive any treatment and, therefore, do not have the non-specific effects of support in knowing a physician is available to treat them, if they wish. This type of control group would tend to maximize differences between treatment groups. However, the disadvantage is that acutely ill patients may not receive treatment promptly if their condition worsens and does not improve, or they may go elsewhere for treatment and be lost to follow-up, so that no documentation of clinical course is available.

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Low or minimal contact. With this method, patients receive psychotherapy but at a reduced rate, e.g. monthly rather than weekly. Low or minimal contact may be insufficient for meeting the clinical needs of acutely ill patients promptly, although it is suitable in a maintenance trial where the patients are recovered. Attention. With this method, patients are seen regularly and complete research assessments, carry on conversations with a person not trained in psychotherapy, or attend a coffee klatch, but they are not offered specific psychotherapy. This method controls for the non-specific effects of attention but may not be sufficient to promptly meet the clinical needs of acutely ill patients. Again, however, it is suitable in maintenance trials of recovered depressed patients. All control groups have advantages and shortcomings. While the waiting list group is the most efficient in cost and in maximizing treatment differences, the limited availability of help might result in patient attrition or lack of necessary treatment in the event of a worsening of symptoms. The low contact or attention-only control, as with the non-scheduled control, may minimize treatment differences but does keep the acutely ill patient under surveillance in the event of a change in clinical status. The non-scheduled control is explicit, however, in encouraging the patient to request further or different help from the research clinic, as needed. The explicit contact plus the added safeguards, as described, assure that patients will receive treatment promptly and will remain with the research clinic for evaluation through the course of the study. SUMMARY

We have demonstrated that a non-scheduled treatment control group together with an available therapist as needed, an independent evaluator of the patients’ clinical status, specified and predetermined improvement criteria, and alternative treatment if needed, is a feasible and ethically sound control for psychotherapy in a clinical trial of acutely depressed patients. It allows for a comparison group for psychotherapy within the bounds of acceptable clinical practice. Patients will accept and tolerate this assignment. Those who require additional or alternative treatment receive it as indicated clinically. In fact, in clinical practice most acutely depressed patients are treated on a “call me as needed,” non-scheduled basis by general physicians. Acknowledgements-This collaborative work was supported by US PHS Grants Nos. MH26467-Tufts University School of Medicine, and MH 26466-Yale University School of Medicine, from the Clinical Research Branch, National Institute of Mental Health; Alcohol, Drug Abuse and Mental Health Administration (ADAMHA). ROBERTAHERCEG-BARON,M. A., carried out the statistical analyses. REFERENCES 1. SHAW, B. Comparison of cognitive therapy and behavior therapy in Consult. clin. PsychoI. 45, 543, 1977. 2. REHM,L. P. Studies in self control treatment of depression. Paper Assessment of Treatment of Depression. American Psychological 1976. 3. FUCHS, C. S. and REHM,L. R. A self-control behavior therapy program Psychol. 45,206, 1977. 4. FRIEDMAN,A. S. Interaction of drug therapy with marital therapy in Psychiat. 32, 619, 1975.

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DEPRESSION

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5. KLERMAN,G. L., DIMASCIO, A., WEISSMAN,M. M., PRUSOFF,B. A. and PAYKEL,E. S. Treatment of depression by drugs and psychotherapy. Am. J. Psychiut. 131,186.1974. 6. Covr, L., LIPMAN, R. and DEROGATIS,L. Drugs and group psychotherapy in neurotic depression. Am. J. Psychiat. 131, 191, 1974. 7. WEISSMAN,M. M. and MYERS, J. K. Psychiatric disorders in a U.S. community: the application of research diagnostic criteria to a resurveyed community sample. Submitted for publication. 8. ENDICO~~, J. and SPITZER, R. L. A diagnostic interview: the schedule for affective disorders and schizophrenia. Archs gen. Psychiat. 35, 837, 1978. 9. SPITZER,R. L., ENDICOIT, J. and ROBINS,E. Research diagnostic criteria: rationale and reliability. Archs gen. Psychiatry 35, 773, 1978. 10. KLERMAN,G. L. and NEU, C. Short-term interpersonal psychotherapy. Boston-New Haven Collaborative Study Psychotherapy Manual. (Unpublished manual) 1977. 11. CICCHEITI, E. V., CHINYU, L., FONTANA,A. F. and Downs, B. N. A computer program for assessing specific category rater agreement for qualitative data. Educ. Psycholog. Measurement 38, 805, 1978. 12. RASKIN,A., SCHULTERBRANDT, J. and REATIG,N. Replication of factors of psychopathology in interview, ward behavior and self-reuort ratings of hospitalized depressives. J. nerv. ment. Dis. 148, 87, 1969. 13. HAMILTON,M. A rating scale for depression. J.-Neurol. Nekrosurg. Psychiat. 23,56, 1960. 14. WEISSMAN.M. M.. PRUSOFF.B. A.. DIMASCIO. A., NEU, C.. GOKLANEY.M. and KLERMAN.G. L. The efficacy’of drugs and psychotherapy in the treatment.of acute depressive episodes. Am. j. Psychiat. 136,555,1979. 15. DIM-O, A., WEISSMAN,M. M., PRUSOFF,B. A., NEU, C., ZWILLING,M. and KLERMAN,G. L. Differential symptom reduction by drugs and psychotherapy in acute depression. Archs gen. Psychiat., in press. 16. HERCEG-BARON,R., PRUSOFF,B. A., WEISSMAN,M. M., DIMASCIO, A., NEU, C. and KLERMAN,G. L. Pharmacotherapy and psychotherapy in acutely depressed patients: a study of attrition patterns in a clinical trial. Comp. Psychiat. 20, 315, 1979.