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Adverse events during a placebo phase for inpatients with chronic schizophrenia
Adverse Events during a Placebo Phase for Inpatients with Chronic Schizophrenia Nicole van de Laar, Ioline Henter, John J. Bartko, and Richard Jed Wyatt Background: This report builds on a previous analysis examining the long-term effects of a placebo period on a group of inpatients with chronic schizophrenia. In the present analysis, outcome was evaluated through the use of the Psychiatric Adverse Events Rating Scale. Methods: This retrospective analysis examined adverse events for 55 patients with chronic schizophrenia who were placed in a double-blind placebo study on the inpatient units of the National Institute of Mental Health Neuropsychiatric Research Hospital. The number and severity of adverse events experienced by these patients during baseline, placebo, and discharge periods were analyzed. Results: The frequency and severity of adverse events for this group of patients were modest. Most patients did not experience a statistically significant increase in adverse events during their placebo phase; however, a subgroup of patients who were hospitalized for less than 2 months after antipsychotic medications were restored did experience a statistical elevation in adverse events, and that frequency remained statistically elevated at discharge. Conclusions: The results confirm the findings from our previous analysis. Regardless of whether outcome is measured by a behavioral rating scale or by an adverse event scale, given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline. Biol Psychiatry 2001; 50:487– 492 © 2001 Society of Biological Psychiatry Key Words: Schizophrenia, adverse events, placebo
Introduction
T
his report builds on a recent publication (Wyatt et al 1999) describing the long-term effects of a placebo phase in a group of relatively treatment-refractory patients with chronic schizophrenia. In recent years, the scientific and ethical justifications for placebo phases in clinical From the University Medical Center, Location AZU, Utrecht, The Netherlands (NvdL); and Neuropsychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (IH, JJB, RJW). Address reprint requests to Richard Jed Wyatt, M.D., Chief, Neuropsychiatry Branch, NIMH-NIH, 5415 W. Cedar Lane, Suite 106B, MSC 2610, Bethesda, MD 20892. Received February 15, 2001; revised June 6, 2001; accepted June 13, 2001.
© 2001 Society of Biological Psychiatry
trials involving patients with psychiatric disorders have been under intense scrutiny by the scientific community, ethicists, lay persons, and the media. Nevertheless, studies have shown that patients enrolled in research studies are no more likely to suffer adverse consequences, or have a worse long-term course, than those treated in normal clinical settings (Cardon et al 1976; Carpenter 1997; Carroll et al 1980; Giller and Strauss 1984; Kalman et al 1982; Kocsis et al 1981; Macklin 1981; McCrae 1982). During the time the original research was conducted, the prevailing view of the scientific community was that the risks of placing patients with chronic schizophrenia on placebo were reasonable and manageable; furthermore, the conclusions drawn from our completed analysis support this view (Wyatt et al 1999). Both the current and previous analyses are retrospective in nature. Nevertheless, the previous analysis mainly focused on the long-term effects of placebo as measured by behavioral ratings. The instrument used in our analysis was the Psychiatric Symptom Assessment Scale (PSAS) (Bigelow and Berthot 1989)—a modified version of the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962). Preplacebo (“baseline”) behavioral ratings were compared with placebo, postplacebo, and discharge ratings. Briefly, our previous analysis found that patients who had a placebo phase had the expected increase in behavioral ratings during the placebo phase, and then returned with varying speed to their baseline ratings by discharge. Although it is an effective rating instrument, the PSAS does not enumerate potentially detrimental events, such as suicide attempts or other acts of violence that might have occurred during the course of the patients’ hospitalization. The present analysis overcomes this deficiency by looking at specific problems encountered during the course of patients’ hospitalizations. Specifically, we examine the adverse events that occurred before, during, and after a placebo phase. By providing adverse event scores, which are not derived from PSAS scores, the analysis tests in a more pragmatic manner our prior conclusions regarding patient risk during placebo studies. Little consensus exists in the literature regarding how to define adverse events during hospitalizations, particularly 0006-3223/01/$20.00 PII S0006-3223(01)01225-2
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during placebo periods, although there is a general sense that adverse events include anything that might endanger the patient or others. Such adverse events could include heightened risk of violence (Buchanan 1999; Rice and Harris 1995), social dangerousness (Shostakovich 1989), increased risk of suicide or suicide attempts (Goldberg 1987; Michels 2000), or increased risk of absconding from the hospital (Bowers et al 1999). Recent studies seem to define adverse events during a placebo phase as anything that exposes individuals to a greater risk of injury, a risk of either transient or irreversible substantive harm, or the risk of greater substantive discomfort compared with individuals who are receiving standard medications (Leber 2000).
Methods and Materials The patient group for this retrospective analysis is a subgroup (n ⫽ 55) of previously described subjects (n ⫽ 127) (Wyatt et al 1999). All patients had received a DSM-III-R (American Psychiatric Association 1987) diagnosis of schizophrenia at the National Institute of Mental Health (NIMH) Neuropsychiatric Research Hospital at Saint Elizabeths between 1986 and 1994. Although our prior analysis included hospitalizations from 1982 to 1994, in 1986, the NIMH Neuropsychiatric Research Hospital became responsible for keeping its own records; before this, patient records were, and are, the responsibility of St. Elizabeths Hospital in Washington, DC. Records from St Elizabeths are no longer readily available, thus truncating the number of charts available for this analysis. Patients were not admitted because of an acute exacerbation of their illness, but rather because they wished to participate in the research program. These patients were almost always referred to the research program because they were relatively refractory to conventional treatments, meaning that they required frequent or lengthy hospitalizations, and were usually unable to live independently. For these patients, participation in the program meant an in-depth assessment of their illness, the opportunity to be a research subject, and the chance to receive new and appropriate medications in a carefully monitored inpatient setting. Before admission, patients were told that their agreement to join the research project meant they would be asked to participate in a placebo phase conducted for both evaluation and research purposes. The program was not a randomized control trial; all patients who had a placebo phase knew that they would have one, but were blind to its timing. It was felt that examining patients at times when they were not taking antipsychotic medications would elucidate whether research findings were intrinsic to the illness or were due to the effects of medication. Placebo periods were also important for conducting protocols designed to study the pathophysiology of schizophrenia, as well as various treatments (e.g., atypical antipsychotic medications in patients who had never received them). All patients, and usually a family member, signed an informed consent form that had been approved by the NIMH Institutional Review Board. The consent process is described in greater detail in the original article (Wyatt et al 1999).
Patients with a history of violence, or for whom a placebo phase was considered inadvisable, were hospitalized concomitantly but did not have a placebo phase; they are not included in this analysis. Six patients were excluded from this analysis because data in their charts were not available for the entirety of the three time periods being studied.
Statistical Methods The major statistical methods used in this analysis are repeated measure analysis of variance (ANOVA) with Greenhouse-Geisser epsilon probability levels reported. Post hoc testing of statistically significant ANOVA results was done via the Bonferroni t, using appropriately pooled mean square ANOVA error terms. Analyses were conducted using NCSS 2000 (NCSS 2000 Statistical System for Windows, Number Cruncher Statistical Systems, Kaysville, UT).
Phases Three phases were retrospectively studied: baseline, placebo, and discharge. To have a more comprehensive picture of patient risk, the baseline, placebo, and discharge phases in this analysis were longer than in the previous analysis that studied the PSAS. The timing of the baseline and discharge phases was chosen on the assumption that they would best reflect a patient’s optimal level of functioning; during these two periods patients would be least likely to participate in research protocols and would most likely be receiving an optimal dose of medication. Phase length was also important, because phases needed to be long enough to reliably observe a variety of potential adverse events. The baseline phase lasted 4 weeks. During this phase, patients scheduled to have a placebo phase were placed on standardized coded medication (usually haloperidol), at a dose deemed optimal based on past history and current medication response. The phase ended about 1 week before the placebo phase began, about the time it took to switch a patient from active medication to placebo. During the hospitalizations, use of coded medication ensured that patients and staff were blind to the timing of the placebo phase, although the ward physician was aware of the timing. The length of the placebo phase was highly variable: 7 to 225 days (mean ⫽ 64 days), but patients generally remained in the placebo phase for 6 or more weeks. The placebo phase ended for a variety of reasons, including a worsening of patient symptoms, at the request of the patient or his family, or at the request of various observers on the research unit, including members of the clergy. For patients who continued to do well when medication free, the placebo phase was extended longer than 6 weeks. At the end of their placebo phase, patients were switched to active coded medication (usually haloperidol), which was kept at a constant dose for at least 6 weeks. For patients who did not remain in the study more than 6 weeks following the placebo phase, this period included their discharge phase; otherwise the patients’ medication was optimized on an individual basis before discharge, usually at the end of the 6-week post-placebo period. Like the baseline phase, the discharge phase lasted 4 weeks and ended 1 week before the actual discharge date. The final week was not
Adverse Events for Placebo Patients
included because impending discharge might have been unusually stressful for patients and thus affected both ratings and behavior.
Measurement of Adverse Events Charts were reviewed by a psychiatrist (Dr. van de Laar) blind to the timing of the placebo phase. An adverse events rating scale, the Psychiatric Adverse Events Rating Scale (PAERS), was developed after careful review of both patient charts and relevant literature. Information about adverse events was obtained by reading data collected in the patients’ charts during the baseline, placebo, and discharge phases. These charts contained daily nurse notes, psychiatrist’s notes, and monthly progress notes made by representatives of several disciplines (e.g., physicians, clinical social workers, occupational therapists, recreational therapists, etc.). After an initial review of several charts, it was decided that an adverse event would be defined as an incident that required the psychiatrist to see the patient (see Table 1). Adverse events were assessed in two ways. First, the number of events per period of interest was noted, and second, each event was rated for severity. Increased symptoms, whether or not they were related to an event, were not included, because these had previously been rated using the PSAS. Because of the wide range in their severity, each event was “scored” by rating the consequences of the events as “prescribed” by the ward psychiatrist (see Table 1). Severity was assessed through three categories: restriction status, observation status, and medication status. Scoring of an event was cumulative. For example, if a patient threw an ashtray through a window after a dispute with a nurse, he might be restricted to the ward, checked every 30 min, and given a sedative. As Table 1 explains, the PAERS takes into account each consequence of the event—the ward restriction, the 30-min checks, and the need to prescribe a sedative—and incorporates it into the adverse event score.
Results Part One: Events Across Phases The average number and severity of the events per period are listed in Table 2. As Table 2 shows, 91 events occurred in all. Roughly 35% of the patients (n ⫽ 19) had no adverse events during any of the three periods of interest. Two thirds of the total number of events took place during the placebo phase. Unauthorized leave was the most common event in all time periods, representing almost one third of the total number of events (29 events, 22 patients). The second most frequent event was physical aggression (14 events, 12 patients), followed by destructive behavior (13 events, 10 patients). Suicidal ideation was rare, and there was only one episode of homicidal ideation. Neither suicidal behavior nor homicidal behavior occurred. Thirteen of the events comprised two event categories. Table 2 also summarizes the mean severity per event, per phase. Event scores could range from 1 to 12. Scores
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Table 1. Psychiatric Adverse Events Rating Scale (PAERS) Event categories A. Unauthorized leave: Every time a patient left without permission and the ward psychiatrist was called. Depending on the restriction status of the patient, unauthorized leave could vary between leaving the ward for a few minutes to leaving the hospital for days. B. Physical aggression: Actual physical hostility directed at other persons (other patients or staff members). This could vary between a slap and a severe blow. C. Verbal aggression: Screaming or shouting, often with verbal threats (which could sometimes include homicidal threats). D. Destructive behavior: Physical aggression directed at objects, whether or not actual damage was inflicted (e.g., kicking a door). E. Self-inflicted injuries: When a patient injured him/herself. These could be intentional, such as self-mutilation, or non-intentional, such as an injury that resulted from destructive behavior. F. Suicidal ideation: Thoughts of killing oneself, as defined by the ward psychiatrist. G. Homicidal ideation: Thoughts of killing others, as defined by the ward psychiatrist. H. Substance abuse: Use of alcohol or drugs. This was either reported by the patient or detected by “tox-screen.” I. Shoplifting J. Inappropriate sexual behavior: This could vary from “exposing oneself” to intercourse. Event scores, by Treatment Category 1. Restriction level a. No restrictions (1) b. Restricted to grounds (2) c. Restricted to building (3) d. Restricted to unit (4) e. Seclusion with open door (5) f. Seclusion with locked door (6) 2. Frequency of observation a. 30 min checks (⫹1) b. 15 min checks (⫹2) c. Constant observation (⫹3) 3. Use of medication a. Sedative (⫹1) b. Medication change (⫹2) (During baseline or discharge phases, this could mean a change in dose or a change in kind of medication; during the placebo phase this meant the end of the placebo phase.) c. Involuntary medication (⫹3) Example: Patient left the ward while restricted to unit. She was very frightened and agitated and walked into a nurses’ meeting on another floor. As a consequence of her behavior the patient was placed into seclusion with the door open, under constant observation, and was given a sedative. This event was noted as: A.1e.2c.3a and scored as 5 ⫹ 3 ⫹ 1 ⫽ 9.
ranged from 1 to 6 during the baseline phase, from 1 to 11 during the placebo phase, and from 1 to 9 during the discharge phase. For the total patient group, the events were generally least severe during the baseline phase, the mean severity increased during the placebo phase, and the severity eventually decreased during the discharge phase, although it did not return to baseline levels. Information about types of treatment, which was used to calculate severity, is summarized in Table 3. Restriction to
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Table 2. Number (and Average Severity) of Events in Baseline, Placebo, and Discharge Phases Events Unauthorized leave Physical aggression Verbal aggression Destructive behavior Self-inflicted injuries Suicidal ideation Homicidal ideation Substance abuse Shoplifting Inappropriate sexual behavior
Baseline
Discharge
7 (2.85) 17 (4.11) 3 (2) 7 (5.85) 2 (4.5) 9 (4.55) 1 (1) 2 (7.5) 8 (6.875)
5 (5.2) 4 (5.75) 1 (7) 4 (4.25)
1 (4) 1 (4)
2 (1) 3 (2)
Unauthorized leave and inappropriate sexual behavior Physical and verbal aggression Physical aggression and destructive behavior Verbal aggression and destructive behavior Verbal aggression and self-inflicted injuries Destructive behavior and self-inflicted injuries Suicidal and homicidal ideation Total
Placebo
Table 4. Points per Events per 100 Days
1 (1)
1 (1)
2 (5.5)
1 (3)
1 (7) 1 (7) 1 (6) 18 (4.38)
unit was the most common restriction measure for all phases. For 19 of the 91 events, no restriction measures were taken. Few of the events required observation. Even fewer events required a change in medication status. Treatment of events with medications occurred most often in the placebo phase. Finally, it should be noted that none of the events were associated with physical injuries (e.g., cuts, broken bones, etc.). Table 3. Number of Events (and Number of Patients) in Treatment Categories Treatment category 1. Restriction level a. No restrictions b. Restricted to grounds c. Restricted to building d. Restricted to unit e. Seclusion with door open f. Seclusion with door locked 2. Frequency of observation a. 30 min checks b. 15 min checks c. constant observation 3. Use of medication a. Sedative b. Medication change c. Involuntary medication
Placebo
Discharge
55 1542 13 11 (20%) 45 (80%) 1/119 2.69
55 3542 60 33 (60%) 22 (40%) 1/59 5.11
55 1514 18 14 (25.45%) 42 (74.55%) 1/84 4.38
2.5 2.14 1.14 1.75
25.58 5.28 4.34 8.54
12.87 4.28 0.42 4.09
a Statistically significant differences existed between all three phases within Group 1. No phase differences existed within either Groups 2 or 3. b The group by response interaction was F(4,104) ⫽ 6.79, p ⬍ .001.
5 (6.2) 1 (7)
13 (2.69) 60 (5.11)
Patients Days Events Patients with events (%) Patients without events (%) Event/days Severity of events Points/event/100 days Group 1a (n ⫽ 10) Group 2 (n ⫽ 20) Group 3 (n ⫽ 25) Total sampleb (n ⫽ 55)
Baseline
Baseline
Placebo
Discharge
5 (5) 1 (1)
9 (8)
5 (4) 1 (1)
7 (5)
32 (22) 5 (5) 14 (7)
6 (6) 5 (3)
4 (4) 6 (4) 8 (6)
2 (2) 1 (1) 1 (1)
7 (5) 4 (4) 1 (1)
1 (1) 3 (2) 1 (1)
Part Two: Another View of the Longer Term Our prior analysis found that, by discharge, patients’ PSAS ratings had returned to baseline. Nevertheless, we also found that the speed with which patients recover after a placebo phase is highly variable, with some patients taking weeks to recover and others only a few days. The main finding of our previous analysis was that, given a sufficiently lengthy recovery period, patients going through a placebo phase returned to baseline. In the present sample, significant variation existed in the number of days between the end of the placebo phase and the beginning of the discharge phase. Therefore, we divided our total patient group into three subgroups. The patients in Group 1 (n ⫽ 10) were discharged less than 2 months after the placebo phase ended (minimum 21 days; mean 42 days). Group 2 (n ⫽ 20) remained in the hospital more than 2 months but less than a year between the end of the placebo phase and their discharge date (mean: 227 days). Group 3 (n ⫽ 25) was in the hospital for more than a year (mean: 779 days) after the placebo phase ended. Event scores per period were the initial response variable of interest; however, because of the varying number of days and varying number of events per days, the reformulated response variable was defined as points per events per 100 days. This definition indexed the response variable, allowing it to be interpreted across varying time points. Basic statistical results are summarized in Table 4. A two-way repeated measures ANOVA, where the response variable is points per events per 100 days, was run with the three groups as the between-subjects factors and the three time periods— baseline, placebo, and discharge—as the repeated measure within-subjects factor. The group-bytime period interaction was statistically significant [F(4,104) ⫽ 6.79, p ⬍ .001]. Figure 1 highlights this interaction.
Adverse Events for Placebo Patients
Figure 1. Points per events per 100 days for Groups 1, 2, and 3, with SE.
The Bonferroni t post hoc test of the interaction components also revealed several significant findings. At baseline, there were no differences among the three subgroups for the response variable (points per events per 100 days). The major contributing factor to the significant interaction is the time pattern within Group 1. With the interaction post hoc test, all pairwise time periods within Group 1 were statistically significant (p ⬍ .05); however, within both Groups 2 and 3 there were no pairwise time differences (see Figure 1 for pattern illustrations).
Discussion Overall, the analysis generated two main findings. First, the frequency and severity of adverse events for this group of patients were modest. Second, most patients did not experience a statistically significant increase in adverse events during their placebo phase; however, a subgroup of patients who were hospitalized for less than 2 months after antipsychotic medications were restored did experience a statistically elevated increase in adverse events, and that frequency remained statistically elevated at discharge. Our initial finding was that the frequency and severity of adverse events experienced during hospitalization by a group of inpatients with chronic schizophrenia who had a placebo phase were modest. Only 36 of 55 (65%) patients experienced an adverse event in any of the three phases. Expressed differently, in more than 18 patient years, only 91 events occurred. Unauthorized leave, the most common event for each phase, was in most cases managed relatively easily through simple restriction measures. No suicide attempts or homicidal behavior occurred. Suicidal ideation occurred rarely but was always controllable through the use of precaution measures, such as restriction to unit and increased observation. These findings support our prior analysis (Wyatt et al 1999) and other reviews (Carpenter and Conley 1999; Carpenter 1997; Carpenter et al 1997; Gilbert et al 1995) suggesting that the risks
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associated with placebo periods are reasonable and manageable for most inpatients with chronic schizophrenia. The second intriguing finding, and one that supports conclusions from our previous analysis, came from comparing the frequency and severity of events. This was done first for the total patient group across the three phases of interest, and second between patient subgroups divided on the basis of length of hospitalization after the placebo phase ended. Most patients did not have an increase in adverse events during the placebo phase compared with their baseline phase. One subgroup, however—patients who were discharged from the hospital less than 2 months after resuming medications— had a significant increase in adverse events during the placebo phase, and this increase remained statistically elevated at discharge. The data suggest an association between the patients discharged earliest, at a time when recovery from placebo was underway but still highly variable, and those with the greatest increase in event scores. Indeed, this subgroup was responsible for the increased event scores during the placebo phase for the total sample. The significant increase in adverse events for this subgroup of patients suggests the importance of identifying such patients in advance (for instance, before beginning a study or during baseline), so that decisions regarding whether or not to enter a placebo phase can be carefully weighed. Unfortunately, in our analysis there were no distinguishing differences—including PSAS scores, medication dose in chlorpromazine equivalents, or education level— between the three groups at baseline (analysis not shown). The hospital’s screening procedures had prevented a number of patients with a past history of violence or history of poor response to placebo periods from participating in the placebo phase, and those who demonstrated during the baseline phase that a placebo phase was ill advised also did not participate. Nevertheless, a subgroup of patients in the analysis had a significant increase in the frequency and severity of adverse events during the placebo phase. Because of the retrospective nature of our data and our analysis, we are unable to speculate further on the characteristics of this at-risk subgroup; identifying such patients will have to be the subject of future research endeavors. Results from our previous (Wyatt et al 1999) and other (Gilbert et al 1995; Glovinsky et al 1992; Keck et al 1989; Nedopil and Ruther 1981; Sautter et al 1993; Stern et al 1993) studies found that patient response to the restoration of antipsychotic medications is mixed with regard to time, and that, given a sufficiently lengthy recovery period, patients of the nature studied here will return to baseline functioning. Conclusions drawn from the present analysis support these observations and suggest that longer, and
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perhaps more closely monitored, post-placebo periods will be necessary for this still undefined subgroup of patients. Currently, the use of placebo phases for research purposes is increasingly being called into question, and it seems likely that it will become increasingly difficult to dismiss concerns about such phases without appropriate data (Leber 2000). Studies such as this one, which addresses the issue of whether specific types of harm occur more frequently during placebo phases, therefore become increasingly valuable.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders-IIIR, 3rd edition, revised. Washington, DC: The American Psychiatric Association. Bigelow LB, Berthot BD (1989): The Psychiatric Symptom Assessment Scale (PSAS). Psychopharmacol Bull 25:168 – 179. Bowers L, Jarrett M, Clark N, Kiyimba F, McFarlane L (1999): Absconding: Outcome and risk. J Psychiatr Ment Health Nurs 6:213–218. Buchanan A (1999): Risk and dangerousness. Psychol Med 29:465– 473. Cardon P, Dommel F, Trumble R (1976): Injuries to research subjects. A survey of investigators. N Engl J Med 295:650 – 654. Carpenter WT, Conley RR (1999): Sense and nonsense: An essay on schizophrenia research ethics. Schizophr Res 35:219 –225. Carpenter WTJ (1997): The risk of medication-free research. Schizophr Bull 23:11–18. Carpenter WTJ, Schooler NR, Kane JM (1997): The rationale and ethics of medication-free research in schizophrenia. Arch Gen Psychiatry 54:401– 407. Carroll R, Miller A, Ross B, Simpson G (1980): Research as an impetus to improved treatment. Arch Gen Psychiatry 37:377– 380. Gilbert PL, Harris MJ, McAdams LA, Jeste DV (1995): Neuroleptic withdrawal in schizophrenic patients. A review of the literature. Arch Gen Psychiatry 52:173–188.
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Giller E, Strauss J (1984): Clinical research: A key to clinical training. Am J Psychiatry 141:1075–1077. Glovinsky D, Kirch DG, Wyatt RJ, (1992): Early antipsychotic response to resumption of neuroleptics in drug-free chronic schizophrenic patients. Biol Psychiatry 31:968 –970. Goldberg RJ (1987): The assessment of suicide risk in the general hospital. Gen Hosp Psychiatry 9:446 – 452. Kalman T, Talon N, Frances A, Kocsis J (1982): A controlled study of satisfaction among psychobiology research patients. Am J Psychiatry 139:344 –347. Keck PE, Cohen BM, Baldessarini RJ, McElroy SL (1989): Time course of antipsychotic effects of neuroleptic drugs. Am J Psychiatry 146:1289 –1292. Kocsis J, Francis A, Kalman T, Shear M (1981): The effect of psychobiological research on treatment outcome. A controlled study. Arch Gen Psychiatry 38:511–515. Leber P (2000): Placebo controls: No news is good news. Arch Gen Psychiatry 57:319 –320. Macklin R (1981): ‘Due’ and ‘undue’ inducements: On paying money to research subjects. IRB 31:1. McCrae R (1982): Are stress questionnaires stressful? IRB 4:1. Michels KB (2000) The placebo problem remains. Arch Gen Psychiatry 57:321–322. Nedopil N, Ruther E (1981): Initial improvement as predictor of outcome of neuroleptic treatment. Pharmacopsychiatria 14: 205–207. Overall JE, Gorham DR (1962): The Brief Psychiatric Rating Scale. Psychol Res 25:168 –179. Rice ME, Harris GT (1995): Violent recidivism: Assessing predictive value. J Consult Clin Psychol 63:737–748. Sautter F, McDermott B, Garver D (1993): Familial differences between rapid neuroleptic response psychosis and delayed neuroleptic response psychosis. Biol Psychiatry 33:15–21. Shostakovich BV (1989): On social dangerousness of mental patients. Schizophr Bull 15:555–538. Stern RG, Kahn RS, Harvey PD, Amin F, Apter SH, Hirschowitz J (1993): Early response to haloperidol treatment in chronic schizophrenia. Schizophr Res 10:165–171. Wyatt RJ, Henter ID, Bartko JJ (1999): The long-term effects of placebo in patients with chronic schizophrenia. Biol Psychiatry 46:1092–1105.
Introduction
T
his report builds on a recent publication (Wyatt et al 1999) describing the long-term effects of a placebo phase in a group of relatively treatment-refractory patients with chronic schizophrenia. In recent years, the scientific and ethical justifications for placebo phases in clinical From the University Medical Center, Location AZU, Utrecht, The Netherlands (NvdL); and Neuropsychiatry Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (IH, JJB, RJW). Address reprint requests to Richard Jed Wyatt, M.D., Chief, Neuropsychiatry Branch, NIMH-NIH, 5415 W. Cedar Lane, Suite 106B, MSC 2610, Bethesda, MD 20892. Received February 15, 2001; revised June 6, 2001; accepted June 13, 2001.
© 2001 Society of Biological Psychiatry
trials involving patients with psychiatric disorders have been under intense scrutiny by the scientific community, ethicists, lay persons, and the media. Nevertheless, studies have shown that patients enrolled in research studies are no more likely to suffer adverse consequences, or have a worse long-term course, than those treated in normal clinical settings (Cardon et al 1976; Carpenter 1997; Carroll et al 1980; Giller and Strauss 1984; Kalman et al 1982; Kocsis et al 1981; Macklin 1981; McCrae 1982). During the time the original research was conducted, the prevailing view of the scientific community was that the risks of placing patients with chronic schizophrenia on placebo were reasonable and manageable; furthermore, the conclusions drawn from our completed analysis support this view (Wyatt et al 1999). Both the current and previous analyses are retrospective in nature. Nevertheless, the previous analysis mainly focused on the long-term effects of placebo as measured by behavioral ratings. The instrument used in our analysis was the Psychiatric Symptom Assessment Scale (PSAS) (Bigelow and Berthot 1989)—a modified version of the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962). Preplacebo (“baseline”) behavioral ratings were compared with placebo, postplacebo, and discharge ratings. Briefly, our previous analysis found that patients who had a placebo phase had the expected increase in behavioral ratings during the placebo phase, and then returned with varying speed to their baseline ratings by discharge. Although it is an effective rating instrument, the PSAS does not enumerate potentially detrimental events, such as suicide attempts or other acts of violence that might have occurred during the course of the patients’ hospitalization. The present analysis overcomes this deficiency by looking at specific problems encountered during the course of patients’ hospitalizations. Specifically, we examine the adverse events that occurred before, during, and after a placebo phase. By providing adverse event scores, which are not derived from PSAS scores, the analysis tests in a more pragmatic manner our prior conclusions regarding patient risk during placebo studies. Little consensus exists in the literature regarding how to define adverse events during hospitalizations, particularly 0006-3223/01/$20.00 PII S0006-3223(01)01225-2
488
N. van de Laar et al
BIOL PSYCHIATRY 2001;50:487– 492
during placebo periods, although there is a general sense that adverse events include anything that might endanger the patient or others. Such adverse events could include heightened risk of violence (Buchanan 1999; Rice and Harris 1995), social dangerousness (Shostakovich 1989), increased risk of suicide or suicide attempts (Goldberg 1987; Michels 2000), or increased risk of absconding from the hospital (Bowers et al 1999). Recent studies seem to define adverse events during a placebo phase as anything that exposes individuals to a greater risk of injury, a risk of either transient or irreversible substantive harm, or the risk of greater substantive discomfort compared with individuals who are receiving standard medications (Leber 2000).
Methods and Materials The patient group for this retrospective analysis is a subgroup (n ⫽ 55) of previously described subjects (n ⫽ 127) (Wyatt et al 1999). All patients had received a DSM-III-R (American Psychiatric Association 1987) diagnosis of schizophrenia at the National Institute of Mental Health (NIMH) Neuropsychiatric Research Hospital at Saint Elizabeths between 1986 and 1994. Although our prior analysis included hospitalizations from 1982 to 1994, in 1986, the NIMH Neuropsychiatric Research Hospital became responsible for keeping its own records; before this, patient records were, and are, the responsibility of St. Elizabeths Hospital in Washington, DC. Records from St Elizabeths are no longer readily available, thus truncating the number of charts available for this analysis. Patients were not admitted because of an acute exacerbation of their illness, but rather because they wished to participate in the research program. These patients were almost always referred to the research program because they were relatively refractory to conventional treatments, meaning that they required frequent or lengthy hospitalizations, and were usually unable to live independently. For these patients, participation in the program meant an in-depth assessment of their illness, the opportunity to be a research subject, and the chance to receive new and appropriate medications in a carefully monitored inpatient setting. Before admission, patients were told that their agreement to join the research project meant they would be asked to participate in a placebo phase conducted for both evaluation and research purposes. The program was not a randomized control trial; all patients who had a placebo phase knew that they would have one, but were blind to its timing. It was felt that examining patients at times when they were not taking antipsychotic medications would elucidate whether research findings were intrinsic to the illness or were due to the effects of medication. Placebo periods were also important for conducting protocols designed to study the pathophysiology of schizophrenia, as well as various treatments (e.g., atypical antipsychotic medications in patients who had never received them). All patients, and usually a family member, signed an informed consent form that had been approved by the NIMH Institutional Review Board. The consent process is described in greater detail in the original article (Wyatt et al 1999).
Patients with a history of violence, or for whom a placebo phase was considered inadvisable, were hospitalized concomitantly but did not have a placebo phase; they are not included in this analysis. Six patients were excluded from this analysis because data in their charts were not available for the entirety of the three time periods being studied.
Statistical Methods The major statistical methods used in this analysis are repeated measure analysis of variance (ANOVA) with Greenhouse-Geisser epsilon probability levels reported. Post hoc testing of statistically significant ANOVA results was done via the Bonferroni t, using appropriately pooled mean square ANOVA error terms. Analyses were conducted using NCSS 2000 (NCSS 2000 Statistical System for Windows, Number Cruncher Statistical Systems, Kaysville, UT).
Phases Three phases were retrospectively studied: baseline, placebo, and discharge. To have a more comprehensive picture of patient risk, the baseline, placebo, and discharge phases in this analysis were longer than in the previous analysis that studied the PSAS. The timing of the baseline and discharge phases was chosen on the assumption that they would best reflect a patient’s optimal level of functioning; during these two periods patients would be least likely to participate in research protocols and would most likely be receiving an optimal dose of medication. Phase length was also important, because phases needed to be long enough to reliably observe a variety of potential adverse events. The baseline phase lasted 4 weeks. During this phase, patients scheduled to have a placebo phase were placed on standardized coded medication (usually haloperidol), at a dose deemed optimal based on past history and current medication response. The phase ended about 1 week before the placebo phase began, about the time it took to switch a patient from active medication to placebo. During the hospitalizations, use of coded medication ensured that patients and staff were blind to the timing of the placebo phase, although the ward physician was aware of the timing. The length of the placebo phase was highly variable: 7 to 225 days (mean ⫽ 64 days), but patients generally remained in the placebo phase for 6 or more weeks. The placebo phase ended for a variety of reasons, including a worsening of patient symptoms, at the request of the patient or his family, or at the request of various observers on the research unit, including members of the clergy. For patients who continued to do well when medication free, the placebo phase was extended longer than 6 weeks. At the end of their placebo phase, patients were switched to active coded medication (usually haloperidol), which was kept at a constant dose for at least 6 weeks. For patients who did not remain in the study more than 6 weeks following the placebo phase, this period included their discharge phase; otherwise the patients’ medication was optimized on an individual basis before discharge, usually at the end of the 6-week post-placebo period. Like the baseline phase, the discharge phase lasted 4 weeks and ended 1 week before the actual discharge date. The final week was not
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included because impending discharge might have been unusually stressful for patients and thus affected both ratings and behavior.
Measurement of Adverse Events Charts were reviewed by a psychiatrist (Dr. van de Laar) blind to the timing of the placebo phase. An adverse events rating scale, the Psychiatric Adverse Events Rating Scale (PAERS), was developed after careful review of both patient charts and relevant literature. Information about adverse events was obtained by reading data collected in the patients’ charts during the baseline, placebo, and discharge phases. These charts contained daily nurse notes, psychiatrist’s notes, and monthly progress notes made by representatives of several disciplines (e.g., physicians, clinical social workers, occupational therapists, recreational therapists, etc.). After an initial review of several charts, it was decided that an adverse event would be defined as an incident that required the psychiatrist to see the patient (see Table 1). Adverse events were assessed in two ways. First, the number of events per period of interest was noted, and second, each event was rated for severity. Increased symptoms, whether or not they were related to an event, were not included, because these had previously been rated using the PSAS. Because of the wide range in their severity, each event was “scored” by rating the consequences of the events as “prescribed” by the ward psychiatrist (see Table 1). Severity was assessed through three categories: restriction status, observation status, and medication status. Scoring of an event was cumulative. For example, if a patient threw an ashtray through a window after a dispute with a nurse, he might be restricted to the ward, checked every 30 min, and given a sedative. As Table 1 explains, the PAERS takes into account each consequence of the event—the ward restriction, the 30-min checks, and the need to prescribe a sedative—and incorporates it into the adverse event score.
Results Part One: Events Across Phases The average number and severity of the events per period are listed in Table 2. As Table 2 shows, 91 events occurred in all. Roughly 35% of the patients (n ⫽ 19) had no adverse events during any of the three periods of interest. Two thirds of the total number of events took place during the placebo phase. Unauthorized leave was the most common event in all time periods, representing almost one third of the total number of events (29 events, 22 patients). The second most frequent event was physical aggression (14 events, 12 patients), followed by destructive behavior (13 events, 10 patients). Suicidal ideation was rare, and there was only one episode of homicidal ideation. Neither suicidal behavior nor homicidal behavior occurred. Thirteen of the events comprised two event categories. Table 2 also summarizes the mean severity per event, per phase. Event scores could range from 1 to 12. Scores
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Table 1. Psychiatric Adverse Events Rating Scale (PAERS) Event categories A. Unauthorized leave: Every time a patient left without permission and the ward psychiatrist was called. Depending on the restriction status of the patient, unauthorized leave could vary between leaving the ward for a few minutes to leaving the hospital for days. B. Physical aggression: Actual physical hostility directed at other persons (other patients or staff members). This could vary between a slap and a severe blow. C. Verbal aggression: Screaming or shouting, often with verbal threats (which could sometimes include homicidal threats). D. Destructive behavior: Physical aggression directed at objects, whether or not actual damage was inflicted (e.g., kicking a door). E. Self-inflicted injuries: When a patient injured him/herself. These could be intentional, such as self-mutilation, or non-intentional, such as an injury that resulted from destructive behavior. F. Suicidal ideation: Thoughts of killing oneself, as defined by the ward psychiatrist. G. Homicidal ideation: Thoughts of killing others, as defined by the ward psychiatrist. H. Substance abuse: Use of alcohol or drugs. This was either reported by the patient or detected by “tox-screen.” I. Shoplifting J. Inappropriate sexual behavior: This could vary from “exposing oneself” to intercourse. Event scores, by Treatment Category 1. Restriction level a. No restrictions (1) b. Restricted to grounds (2) c. Restricted to building (3) d. Restricted to unit (4) e. Seclusion with open door (5) f. Seclusion with locked door (6) 2. Frequency of observation a. 30 min checks (⫹1) b. 15 min checks (⫹2) c. Constant observation (⫹3) 3. Use of medication a. Sedative (⫹1) b. Medication change (⫹2) (During baseline or discharge phases, this could mean a change in dose or a change in kind of medication; during the placebo phase this meant the end of the placebo phase.) c. Involuntary medication (⫹3) Example: Patient left the ward while restricted to unit. She was very frightened and agitated and walked into a nurses’ meeting on another floor. As a consequence of her behavior the patient was placed into seclusion with the door open, under constant observation, and was given a sedative. This event was noted as: A.1e.2c.3a and scored as 5 ⫹ 3 ⫹ 1 ⫽ 9.
ranged from 1 to 6 during the baseline phase, from 1 to 11 during the placebo phase, and from 1 to 9 during the discharge phase. For the total patient group, the events were generally least severe during the baseline phase, the mean severity increased during the placebo phase, and the severity eventually decreased during the discharge phase, although it did not return to baseline levels. Information about types of treatment, which was used to calculate severity, is summarized in Table 3. Restriction to
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Table 2. Number (and Average Severity) of Events in Baseline, Placebo, and Discharge Phases Events Unauthorized leave Physical aggression Verbal aggression Destructive behavior Self-inflicted injuries Suicidal ideation Homicidal ideation Substance abuse Shoplifting Inappropriate sexual behavior
Baseline
Discharge
7 (2.85) 17 (4.11) 3 (2) 7 (5.85) 2 (4.5) 9 (4.55) 1 (1) 2 (7.5) 8 (6.875)
5 (5.2) 4 (5.75) 1 (7) 4 (4.25)
1 (4) 1 (4)
2 (1) 3 (2)
Unauthorized leave and inappropriate sexual behavior Physical and verbal aggression Physical aggression and destructive behavior Verbal aggression and destructive behavior Verbal aggression and self-inflicted injuries Destructive behavior and self-inflicted injuries Suicidal and homicidal ideation Total
Placebo
Table 4. Points per Events per 100 Days
1 (1)
1 (1)
2 (5.5)
1 (3)
1 (7) 1 (7) 1 (6) 18 (4.38)
unit was the most common restriction measure for all phases. For 19 of the 91 events, no restriction measures were taken. Few of the events required observation. Even fewer events required a change in medication status. Treatment of events with medications occurred most often in the placebo phase. Finally, it should be noted that none of the events were associated with physical injuries (e.g., cuts, broken bones, etc.). Table 3. Number of Events (and Number of Patients) in Treatment Categories Treatment category 1. Restriction level a. No restrictions b. Restricted to grounds c. Restricted to building d. Restricted to unit e. Seclusion with door open f. Seclusion with door locked 2. Frequency of observation a. 30 min checks b. 15 min checks c. constant observation 3. Use of medication a. Sedative b. Medication change c. Involuntary medication
Placebo
Discharge
55 1542 13 11 (20%) 45 (80%) 1/119 2.69
55 3542 60 33 (60%) 22 (40%) 1/59 5.11
55 1514 18 14 (25.45%) 42 (74.55%) 1/84 4.38
2.5 2.14 1.14 1.75
25.58 5.28 4.34 8.54
12.87 4.28 0.42 4.09
a Statistically significant differences existed between all three phases within Group 1. No phase differences existed within either Groups 2 or 3. b The group by response interaction was F(4,104) ⫽ 6.79, p ⬍ .001.
5 (6.2) 1 (7)
13 (2.69) 60 (5.11)
Patients Days Events Patients with events (%) Patients without events (%) Event/days Severity of events Points/event/100 days Group 1a (n ⫽ 10) Group 2 (n ⫽ 20) Group 3 (n ⫽ 25) Total sampleb (n ⫽ 55)
Baseline
Baseline
Placebo
Discharge
5 (5) 1 (1)
9 (8)
5 (4) 1 (1)
7 (5)
32 (22) 5 (5) 14 (7)
6 (6) 5 (3)
4 (4) 6 (4) 8 (6)
2 (2) 1 (1) 1 (1)
7 (5) 4 (4) 1 (1)
1 (1) 3 (2) 1 (1)
Part Two: Another View of the Longer Term Our prior analysis found that, by discharge, patients’ PSAS ratings had returned to baseline. Nevertheless, we also found that the speed with which patients recover after a placebo phase is highly variable, with some patients taking weeks to recover and others only a few days. The main finding of our previous analysis was that, given a sufficiently lengthy recovery period, patients going through a placebo phase returned to baseline. In the present sample, significant variation existed in the number of days between the end of the placebo phase and the beginning of the discharge phase. Therefore, we divided our total patient group into three subgroups. The patients in Group 1 (n ⫽ 10) were discharged less than 2 months after the placebo phase ended (minimum 21 days; mean 42 days). Group 2 (n ⫽ 20) remained in the hospital more than 2 months but less than a year between the end of the placebo phase and their discharge date (mean: 227 days). Group 3 (n ⫽ 25) was in the hospital for more than a year (mean: 779 days) after the placebo phase ended. Event scores per period were the initial response variable of interest; however, because of the varying number of days and varying number of events per days, the reformulated response variable was defined as points per events per 100 days. This definition indexed the response variable, allowing it to be interpreted across varying time points. Basic statistical results are summarized in Table 4. A two-way repeated measures ANOVA, where the response variable is points per events per 100 days, was run with the three groups as the between-subjects factors and the three time periods— baseline, placebo, and discharge—as the repeated measure within-subjects factor. The group-bytime period interaction was statistically significant [F(4,104) ⫽ 6.79, p ⬍ .001]. Figure 1 highlights this interaction.
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Figure 1. Points per events per 100 days for Groups 1, 2, and 3, with SE.
The Bonferroni t post hoc test of the interaction components also revealed several significant findings. At baseline, there were no differences among the three subgroups for the response variable (points per events per 100 days). The major contributing factor to the significant interaction is the time pattern within Group 1. With the interaction post hoc test, all pairwise time periods within Group 1 were statistically significant (p ⬍ .05); however, within both Groups 2 and 3 there were no pairwise time differences (see Figure 1 for pattern illustrations).
Discussion Overall, the analysis generated two main findings. First, the frequency and severity of adverse events for this group of patients were modest. Second, most patients did not experience a statistically significant increase in adverse events during their placebo phase; however, a subgroup of patients who were hospitalized for less than 2 months after antipsychotic medications were restored did experience a statistically elevated increase in adverse events, and that frequency remained statistically elevated at discharge. Our initial finding was that the frequency and severity of adverse events experienced during hospitalization by a group of inpatients with chronic schizophrenia who had a placebo phase were modest. Only 36 of 55 (65%) patients experienced an adverse event in any of the three phases. Expressed differently, in more than 18 patient years, only 91 events occurred. Unauthorized leave, the most common event for each phase, was in most cases managed relatively easily through simple restriction measures. No suicide attempts or homicidal behavior occurred. Suicidal ideation occurred rarely but was always controllable through the use of precaution measures, such as restriction to unit and increased observation. These findings support our prior analysis (Wyatt et al 1999) and other reviews (Carpenter and Conley 1999; Carpenter 1997; Carpenter et al 1997; Gilbert et al 1995) suggesting that the risks
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associated with placebo periods are reasonable and manageable for most inpatients with chronic schizophrenia. The second intriguing finding, and one that supports conclusions from our previous analysis, came from comparing the frequency and severity of events. This was done first for the total patient group across the three phases of interest, and second between patient subgroups divided on the basis of length of hospitalization after the placebo phase ended. Most patients did not have an increase in adverse events during the placebo phase compared with their baseline phase. One subgroup, however—patients who were discharged from the hospital less than 2 months after resuming medications— had a significant increase in adverse events during the placebo phase, and this increase remained statistically elevated at discharge. The data suggest an association between the patients discharged earliest, at a time when recovery from placebo was underway but still highly variable, and those with the greatest increase in event scores. Indeed, this subgroup was responsible for the increased event scores during the placebo phase for the total sample. The significant increase in adverse events for this subgroup of patients suggests the importance of identifying such patients in advance (for instance, before beginning a study or during baseline), so that decisions regarding whether or not to enter a placebo phase can be carefully weighed. Unfortunately, in our analysis there were no distinguishing differences—including PSAS scores, medication dose in chlorpromazine equivalents, or education level— between the three groups at baseline (analysis not shown). The hospital’s screening procedures had prevented a number of patients with a past history of violence or history of poor response to placebo periods from participating in the placebo phase, and those who demonstrated during the baseline phase that a placebo phase was ill advised also did not participate. Nevertheless, a subgroup of patients in the analysis had a significant increase in the frequency and severity of adverse events during the placebo phase. Because of the retrospective nature of our data and our analysis, we are unable to speculate further on the characteristics of this at-risk subgroup; identifying such patients will have to be the subject of future research endeavors. Results from our previous (Wyatt et al 1999) and other (Gilbert et al 1995; Glovinsky et al 1992; Keck et al 1989; Nedopil and Ruther 1981; Sautter et al 1993; Stern et al 1993) studies found that patient response to the restoration of antipsychotic medications is mixed with regard to time, and that, given a sufficiently lengthy recovery period, patients of the nature studied here will return to baseline functioning. Conclusions drawn from the present analysis support these observations and suggest that longer, and
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perhaps more closely monitored, post-placebo periods will be necessary for this still undefined subgroup of patients. Currently, the use of placebo phases for research purposes is increasingly being called into question, and it seems likely that it will become increasingly difficult to dismiss concerns about such phases without appropriate data (Leber 2000). Studies such as this one, which addresses the issue of whether specific types of harm occur more frequently during placebo phases, therefore become increasingly valuable.
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