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01-20-josiassen.fmClozapine Augmented With Risperidone
in the Treatment of Schizophrenia:
A Randomized, Double-Blind, Placebo-Controlled Trial
Richard C. Josiassen, Ph.D.
Objective: The authors evaluated the ef-
with clozapine/risperidone treatment than ficacy and safety of augmenting clozapine with clozapine/placebo. The adverse event Ashok Joseph, M.D.
ment was similar to that for clozapine/pla- Eva Kohegyi, M.D.
Method: In a randomized, double-blind,
Sudhir Stokes, M.D.
tients unresponsive or partially responsive Mahmood Dadvand, M.D.
either placebo (N=20) or up to 6 mg/day of risperidone treatment did not induce addi- risperidone (N=20). Patient psychopathol- tional weight gain, agranulocytosis, or sei- Wynn Wynn Paing, M.D.
ogy was assessed at 2-week intervals with the Brief Psychiatric Rating Scale (BPRS) Rita A. Shaughnessy, M.D., Ph.D.
and the Scale for the Assessment of Nega-tive Symptoms (SANS), among other mea- Conclusions: In patients with a subopti-
mal response to clozapine, the addition of with the Simpson-Angus Rating Scale.
Results: From baseline to week 6 and
significantly in both groups, but the reduc- tions were significantly greater with cloza- provide additional clinical benefit for pa- pine/risperidone treatment. Reductions in tients who are nonresponsive or only par- SANS scores were also significantly greater tially responsive to clozapine alone.
(Am J Psychiatry 2005; 162:130–136)
The landmark study by Kane et al. (1) established week randomized crossover phases. Although higher clozapine as the treatment of choice for severely ill pa- clozapine doses were associated with a greater reduction tients with schizophrenia whose psychotic symptoms are in symptom severity, overall efficacy was disappointing: refractory to conventional antipsychotic treatment. In the only five of 50 patients were judged to be responsive. In a Kane study, 30% of patients with refractory symptoms re- meta-analysis, Wahlbeck et al. (5) found that clozapine sponded to treatment with clozapine. That finding led to was superior to conventional antipsychotics in controlling renewed interest in clozapine and an optimistic outlook symptoms in patients with refractory schizophrenia, but regarding improved treatment for severely ill psychotic only one-third of patients met the criteria for a clinically patients. Meltzer (2) reported in an uncontrolled study that meaningful treatment response. According to a review of 6 months of clozapine treatment yielded a good clinical re- data from clozapine clinical trials by Buckley et al. (6), sponse in 50% of patients whose symptoms had previ- about half of patients with symptoms refractory to other antipsychotic agents are also nonresponsive to clozapine.
However, a considerable number of patients treated These authors estimate that some 325,000 patients in the with clozapine are still nonresponsive or only partially re- United States with refractory schizophrenia spectrum dis- sponsive. For example, in a double-blind comparative orders are also nonresponsive to clozapine or would be if study, Rosenheck et al. (3) reported a lower response rate with clozapine than that reported by either Kane et al. (1) There is little evidence to guide the next treatment steps or Meltzer (2) and that the drug was only slightly better for patients who do not respond to clozapine monother- than the conventional antipsychotic haloperidol. A dou- apy at recommended doses. To improve response rates, ble-blind study by Simpson et al. (4) compared three clo- U.S. psychiatrists began to administer clozapine in doses zapine doses (100, 300, and 600 mg/day) in sequential 16- higher than those administered by European psychia- Am J Psychiatry 162:1, January 2005 JOSIASSEN, JOSEPH, KOHEGYI, ET AL.
trists, but higher doses did not appear to improve efficacy sulting from higher overall drug exposure, leading to (7). Others reasoned that the efficacy of clozapine, an greater liability for tardive dyskinesia. Complex drug regi- agent with broad-spectrum receptor activity but relatively mens can also compromise patient compliance with treat- weak dopamine D2-antagonist properties, might be en- ment, and their benefit may not justify their costs. Given hanced by augmentation with an antipsychotic that pro- the substantial public health burden of clozapine-refrac- tory schizophrenia and the prevalent use of augmentation A limited number of published case reports and small strategies, rigorous investigation of these strategies is of studies have reported the effects of clozapine augmenta- utmost importance. To that end, we conducted a 12-week, tion with other antipsychotics. Sulpiride, a relatively selec- randomized, double-blind, placebo-controlled study of tive D2 antagonist, showed promise in a placebo-con- the efficacy and safety of clozapine augmented with ris- trolled clozapine augmentation trial (9). In this study, peridone in a well-defined group of patients with schizo- eight of 16 patients treated with clozapine and sulpiride, phrenia refractory to clozapine monotherapy.
compared with only one of 12 patients given clozapineand placebo, demonstrated a score reduction of 20% or more on the Brief Psychiatric Rating Scale (BPRS). How-ever, in a controlled trial conducted in China, clozapine Patients
augmentation with chlorpromazine was not superior to Inpatients or outpatients who continued to experience signifi- clozapine monotherapy (10). Case reports and a small pa- cant psychotic symptoms despite adequate treatment with cloza-pine were eligible to participate in this trial. Study participants tient series have suggested promise for clozapine aug- were recruited from a large population of state hospital inpatients mentation with loxapine (11), pimozide (12), and olanzap- and recently discharged patients living in highly structured com- ine (13), but rigorous trials of these agents have not been munity settings. Thorough records of psychiatric history and prior antipsychotic drug therapy were available for all patients.
Risperidone is, to date, the most extensively docu- Patients were included if they 1) had a DSM-IV diagnosis ofschizophrenia or schizoaffective disorder; 2) were 20–65 years of mented clozapine augmentation agent. Compared with age; 3) had, before treatment with clozapine, documented treat- clozapine, risperidone has greater affinity for D2 and sero- ment failure after two antipsychotics approved by the U.S. Food tonin 5-HT2 receptors. Multiple case reports (14–18) have and Drug Administration were administered for an adequate du- described a benefit from clozapine augmentation with ris- ration in a sufficient dose (6 or more weeks of 1000 mg/day of peridone, but several others (reviewed by Chong and chlorpromazine equivalents); 4) demonstrated a documentedfailure to show a satisfactory clinical response to an adequate trial Remington ) have reported negative results. Of greater of clozapine (3 or more months of at least 600 mg/day of oral cloz- interest are three uncontrolled prospective treatment apine or a plasma drug level of 350 ng/ml or higher); and 5) had studies in larger series of patients. In the first study (20), 12 persistent psychotic symptoms, as evidenced by either a total patients with psychotic symptoms previously refractory to score of at least 45 on the BPRS (on which each of 18 items is clozapine monotherapy received open-label clozapine scored from 1 to 7) or a rating of moderately ill (4 or more) on atleast two of the four BPRS positive symptom items (hallucinatory augmented with risperidone for 4 weeks. By the end of the behavior, conceptual disorganization, unusual thought content, trial, 10 of the patients exhibited a 20% or greater reduc- tion in BPRS total scores. In the second study (21), a 12- Study Procedures
week trial, seven of 13 patients with symptoms refractoryto clozapine demonstrated a 20% or greater reduction in All patients were fully informed about the benefits, risks, and potential adverse effects involved in participating in this study total scores on the Positive and Negative Syndrome Scale, and signed an informed consent document. They continued to be and four were rated as “much improved” on the Clinical treated by their primary psychiatrist, who also signed the in- Global Impression (CGI) improvement scale. In contrast, formed consent. Patients remained in their current living ar- the results of the third trial showed that none of the 12 pa- rangements without any study-related modifications to their tients whose symptoms were refractory to clozapine ex- daily routines beyond regularly scheduled clinical rating sessions.
hibited a response (20% reduction in the Positive and Neg- A 4-week baseline evaluation and clozapine run-in phase was followed by 12 weeks of placebo-controlled augmentation with ative Syndrome Scale total score) after they had received 4 risperidone. To initiate the baseline observation period, all pa- weeks of combined treatment with clozapine and risperi- tients had to have remained on a stable dose of clozapine for at least 4 weeks. Baseline doses of clozapine were established by Although augmentation strategies are poorly docu- treating psychiatrists and remained stable throughout the study.
After the run-in period, patients were randomly assigned in a 1:1 mented, they are fairly common in clinical practice, with ratio to augmentation with risperidone or matching placebo. Ris- perhaps one-sixth of patients with psychosis in the United peridone was started at 1 mg/day, with planned increases to 1 or States receiving more than one antipsychotic drug (23, 24).
2 mg/day on day 4, to 2 or 3 mg/day on day 8, to 4 mg/day on day Understandably, this situation has caused some concern 21, and to 6 mg/day on day 22. Each patient’s study medication (25–28). In addition to their poorly documented efficacy, dose was managed by a nonblinded research fellow not involvedin any aspect of patient care who acted as intermediary between polypharmacy regimens pose certain risks, including the study investigators, treating psychiatrist, and pharmacy. The pharmacokinetic interactions, increased risk of adverse raters, treating psychiatrist, and patient remained blinded events, and, at least theoretically, loss of “atypicality” re- throughout the study. At each weekly clinic visit, the treating psy- Am J Psychiatry 162:1, January 2005 RISPERIDONE AUGMENTATION OF CLOZAPINE THERAPY
TABLE 1. Demographic and Clinical Characteristics of 40
with placebo and clozapine with risperidone. The a priori P a ti en ts Wi th Re fra cto r y Sc hi z o p hre ni a R a nd o m l y
planned comparisons used between-group repeated measures Assigned to 12 Weeks of Double-Blind Treatment With
analysis of variance (ANOVA) (SPSS 9.0 for Windows, general lin- Clozapine Augmented With Either Risperidone or Placebo
ear model, SPSS, Inc., Chicago) with group (the two treatment groups) and time (baseline, week 6, and week 12) as main effects.
The ANOVA model also included a group-by-time interaction term. The specific two-group efficacy comparisons across time were BPRS total score, BPRS positive symptom score (sum of BPRS hallucinatory behavior, conceptual disorganization, un- usual thought content, and suspiciousness), and negative symp- tom score (sum of global SANS ratings).
Between-group differences on the safety evaluation were de- termined by using a repeated-measures ANOVA model when ap- propriate; otherwise, the unmatched t test and chi-square com-parisons were performed. Exploratory analyses were performed by using an analysis of covariance model on the efficacy and safety endpoints to examine the influence of age, duration of ill- ness, and dose and duration of clozapine therapy used through- All significance tests were performed by using two-tailed prob- abilities with an alpha level of 0.05.
Forty patients with persistent psychotic symptoms en- tered the trial and were randomly assigned in equal num- bers to receive clozapine combined with either risperi- done or placebo. Background characteristics of the two groups were similar (Table 1). The initial clozapine dose a Significant between-group difference (χ2 =23.4, df=1, p<0.005).
was significantly higher and the initial SANS score some- b Significant between-group difference (t=2.79 df=38, p<0.005).
what lower, although not reaching significance, in the clo-zapine/risperidone group than the clozapine/placebo chiatrist could instruct the research fellow to either continue or group. In general, all patients had severe refractory symp- increase the current dose of blinded study medication. Patients toms that had affected their lives for an average of more judged by their treating psychiatrist to be unable to tolerate the than 20 years. They had not responded to at least two and dose escalation schedule because of adverse effects (other thanclinical symptoms of schizophrenia) were maintained at their in some cases six or more different antipsychotic drugs.
maximum tolerated dose for the remainder of the study.
Nine had not responded to a trial of risperidone. More-over, as required for study entry, they had continued to Patient Assessments
manifest substantial psychotic symptoms despite having Biweekly systematic evaluations of psychopathology and ad- received optimal treatment with clozapine as monother- verse events were initiated during the 4-week baseline observa- apy, and their BPRS, CGI, and SANS scores indicated con- tion period and continued throughout the 12-week randomizedtreatment phase. These assessments were performed primarily siderable psychopathology. The duration of prior clozap- by two senior research fellows, blinded to treatment assignment ine treatment ranged from 30 to 584 weeks (mean=396.9, and not directly involved in patient care. Raters evaluated the SD=174.4), and two patients had received doses as high as same patients throughout the study period; however, a third “back-up” rater was available for times of planned vacations andillness. All three raters took part in regularly scheduled (at least All patients completed 12 weeks of treatment in their monthly) practice ratings with other patients or videotaped inter- randomly assigned group. Mean doses of risperidone were views to maintain consistency and to identify any “idiosyncratic” 4.1 mg/day (SD=1.4) at week 6 and 4.43 mg/day (SD=1.5) approaches that developed over time.
at week 12. Only eight patients received the maximum 6 Efficacy evaluations included the BPRS (29), CGI (30), and mg/day dose of risperidone. Of those, two experienced Scale for the Assessment of Negative Symptoms (SANS) (31).
acute akathisia and required dose reduction.
Movement disorders were assessed at 2-week intervals with theSimpson-Angus Rating Scale (32). A full biochemistry test panel, Efficacy
urinalysis, and hematologic studies were obtained before ran-domization and at the end of the study. Weekly safety and tolera- By the end of the 12-week treatment period, a treatment bility evaluations included white blood cell counts, temperature, response (20% or greater reduction in BPRS total score) blood pressure, heart rate, and respiration as well as subjective was achieved by seven (35%) of the 20 patients in the cloz- apine/risperidone group and by two (10%) of the 20 pa- Statistical Analysis
tients in the clozapine/placebo group (χ2=25, df=1, The primary objective was to test the hypothesis of differential p<0.01). As seen in Figure 1, the BPRS total scores de- clinical efficacy between the two treatment groups: clozapine creased significantly from baseline to week 12 in both Am J Psychiatry 162:1, January 2005 JOSIASSEN, JOSEPH, KOHEGYI, ET AL.
FIGURE 1. BPRS Total Scores Over the Study Period for 40
FIGURE 2. BPRS Positive Symptom Subscale Scores Over
P a ti en ts Wi th Re fra cto r y Sc hi z o p hre ni a R a nd o m l y
the Study Period for 40 Patients With Refractory Schizo-
Assigned to 12 Weeks of Double-Blind Treatment With
phrenia Randomly Assigned to 12 Weeks of Double-Blind
Clozapine Augmented With Either Risperidone or Placebo
Treatment With Clozapine Augmented With Either Risperi-
done or Placebo
e Symptoms Subscale
e on BPRS P
Time From Baseline (weeks)
Time From Baseline (weeks)
a Significantly different from the score at 12 weeks for clozapine/pla- cebo treatment per ANCOVA with baseline BPRS total score as the a Significantly greater score reduction at 6 and 12 weeks relative to covariate (F=3.15, df=2, 74, p<0.05). clozapine/placebo treatment per ANOVA (group-by-time interac-tion: F=3.18, df=2, 76, p<0.05). treatment groups (main effect for time: F=7.8, df=2, 76,p<0.0001), with a significant group-by-time interaction re- Simpson-Angus Rating Scale scores below 1.0, indicating flecting a greater score reduction with clozapine/risperi- minimal severity of movement disorders. The Simpson- done treatment (F=3.73, df=2, 76, p<0.04). Score reductions Angus Rating Scale scores were lower with clozapine/ from baseline to week 6 were similar in the two groups but risperidone treatment throughout the trial, although they were greater with clozapine/risperidone treatment from increased to approach those of clozapine/placebo treat- week 6 to week 12. To determine whether the initial base- ment by week 12 (Figure 4). The frequency of other adverse line differences contributed to the between-group differ- events such as weight gain, agranulocytosis, and seizures ence, an analysis of covariance was performed using the baseline BPRS total score as the covariate. With the effects Plasma clozapine levels did not increase significantly of the baseline differences removed (main covariate be- during augmentation treatment, and no changes were ob- tween patients effect: F=258.8, df=1, 37, p<0.0001), the served in white blood cell counts. Absolute neutrophil main effect of time was no longer significant (F=0.338, df= counts were comparable in the two groups at baseline butsignificantly higher with clozapine/risperidone treatment 2, 74, p>0.05). However, the between-group difference at endpoint remained significant (Figure 1).
As seen in Figure 2, scores on the BPRS positive symp- Discussion
tom subscale decreased significantly from baseline to week12 in both groups (main effect for time: F=8.3, df=2, 76, The efficacy of clozapine augmented with risperidone p<0.001), but the group-by-time interaction reflected a sig- was superior to that of clozapine combined with placebo nificantly greater score reduction with clozapine/risperi- in this randomized, double-blind trial in 40 patients with done treatment than with clozapine/placebo (Figure 2).
schizophrenia unresponsive to clozapine monotherapy.
Negative symptoms (SANS scores) decreased significantly The beneficial effect of clozapine/risperidone treatment from baseline to week 12 with clozapine/risperidone treat- was observed in the mean BPRS total scores and even ment (main effect for time: F=4.46, df=2, 76, p<0.04), and more prominently in the BPRS positive symptom subscale the between-group difference was significant (Figure 3).
scores. In addition, negative symptom scores on the SANSimproved significantly with clozapine/risperidone treat- Safety and Tolerability
ment relative to clozapine/placebo treatment. Except for In general, double-blind augmentation treatment was mild akathisia, which was observed in two patients and well tolerated. Both treatment groups had mean initial corrected through dose adjustment, risperidone augmen- Am J Psychiatry 162:1, January 2005 RISPERIDONE AUGMENTATION OF CLOZAPINE THERAPY
FIGURE 3. SANS Scores Over the Study Period for 40
FIGURE 4. Simpson-Angus Scale Scores Over the Study Period
P a ti en ts Wi th Re fra cto r y Sc hi z o p hre ni a R a nd o m l y
for 40 Patients With Refractory Schizophrenia Randomly
Assigned to 12 Weeks of Double-Blind Treatment With
Assigned to 12 Weeks of Double-Blind Treatment With Cloza-
Clozapine Augmented With Either Risperidone or Placebo
pine Augmented With Either Risperidone or Placebo
e on Simpson-Angus Scale
Mean SANS Scor
Time From Baseline (weeks)
Time From Baseline (weeks)
a Significantly greater score reduction at 6 and 12 weeks relative to clozapine/placebo treatment per ANOVA (main effect for group: F= and others must be kept in mind. It is uncertain whether our study is sufficiently powered to identify treatment ef-fects of as yet uncertain magnitude. In one cautionary re- tation was not associated with any additional adverse ef- port, Stern et al. (33) reviewed 13 published trials of antip- sychotic augmentation and reported that the likelihood of To date, only a few controlled trials have evaluated cloz- finding a positive result by chance was 63%. These authors apine augmented with an antipsychotic agent of any type, concluded that augmentation trials require 40 to 100 pa- and to our knowledge, this is the first randomized con- tients, depending on the number and variability of out- trolled trial involving clozapine augmented with an atypi- come measures and effect size, and our investigation is at cal antipsychotic. Previous trials of this combination in- the lowest range of acceptable limits. Our study avoided clude case reports and three open-label, uncontrolled the pitfall of evaluating too many treatment outcomes in prospective studies that used standardized rating criteria, relation to the sample size, which could lead to chance all involving an approximate total of 50 patients. Inconsis- findings of statistically significant differences. Neverthe- tencies in the results of these earlier trials may be attrib- less, our findings must be regarded as preliminary. Al- uted to several factors beyond the tendency of small, un- though random assignment and blinding are important controlled studies to produce unconfirmed results. The strengths of our study, definitive conclusions about the ef- studies differed in the patients’ baseline severity of schizo- ficacy of clozapine combined with risperidone must await phrenia (two studies focused on outpatients and one on future studies with larger sample sizes.
inpatients), prior exposure to risperidone monotherapy (a A second important issue relates to the cause of the im- requirement in one study, undocumented in two studies), provement we observed. If a patient is observed to im- duration of augmentation treatment (4 weeks versus 12 prove after risperidone is added to his or her clozapine weeks), and measures of treatment outcome (BPRS in one therapy, it cannot be assumed that the effect of clozapine study, Positive and Negative Syndrome Scale in two stud- is augmented by risperidone. A substantial improvement ies). Taken together, the results of these studies suggest occurred over time in both treatment groups, possibly due that perhaps half of patients whose symptoms are refrac- to patients’ participation in the study and the benefits of tory to clozapine respond to risperidone augmentation.
weekly clinic visits. On the other hand, this improvement Our finding of a significant treatment-by-time interaction could have been an artifact of the fluctuating course of suggests that studies based on a short (i.e., 4-week) period schizophrenia and the tendency of extreme observations of observation are likely to produce unreliable results.
to regress toward the mean over time. However, our pa- Although the double-blind design of our investigation is tients did seem stable in their lack of clozapine responsiv- stronger than that of the others, several methodologic is- ity, as evidenced by the fact that all had received optimal sues raised by Freudenreich and Goff (8), Stern et al. (33), clozapine monotherapy for a considerable time (mean= Am J Psychiatry 162:1, January 2005 JOSIASSEN, JOSEPH, KOHEGYI, ET AL.
396.9 weeks, SD=174.4). The improvement associated with studied in prospective trials. Additional larger controlled risperidone was significantly greater than that seen with trials are required before firm clinical recommendations placebo, but the observed treatment effect could be due to can be made about clozapine augmentation strategies.
risperidone alone rather than to the combination. This Moreover, in an age in which neurocognitive and func- cannot be completely ruled out with our patient sample; tional state measures are becoming central to the discus- however, nine of the 20 patients in the risperidone aug- sion of clinical efficacy and effectiveness, a comprehen- mentation group were unresponsive to prior risperidone sive assessment that extends beyond psychopathology monotherapy, and of these nine unresponsive patients, and side effects would be a welcome addition to the exist- four responded to the combination of clozapine and ris- peridone. The improvement associated with risperidonecould also have been due to the fact that this randomly as- Presented in part at the 42nd annual meeting of the New Clinical Drug Evaluation Unit, Boca Raton, Fla., June 10–13, 2002; and at the signed group entered the study receiving a higher dose of ninth International Congress on Schizophrenia Research, Colorado clozapine (528.8 mg versus 402.5 mg). These higher doses Springs, Colo., March 29–April 2, 2003. Received Sept. 5, 2003; of clozapine, acting throughout the course of the study, revision received Jan. 13, 2004; accepted Feb. 4, 2004. From theArthur P. Noyes Research Foundation; the Department of Psychiatry, might account for the significant pattern of effects, al- Drexel University College of Medicine, Philadelphia; the Department though the group mean duration of clozapine treatment of Psychiatry, University of Pennsylvania, Philadelphia; and the was more than 7 years and raises the question of what Department of Psychiatry, Norristown State Hospital, Norristown, Pa.
Address correspondence and reprint requests to Dr. Josiassen, The might cause a treatment effect after such an extensive Arthur P. Noyes Research Foundation, Norristown State Hospital, 1001 Sterigere St., Norristown, PA 19401; [email protected] (e-mail). The risks of antipsychotic polypharmacy have not been This study was funded by Johnson & Johnson Pharmaceutical Re- well studied, and information about long-term risks is particularly sparse. Isolated case reports of agranulocyto-sis associated with the combination of clozapine and ris-peridone have been reported (34), as well as a pharmaco- References
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Chris Chapman, M.D. Cell phone 301-793-3771 E-mail: [email protected]_______________________________________________________Georgetown University School of Medicine 1987 Medical Doctor, MDGeorgetown University School of Medicine 1988 Internal Medicine Internship, CertificateGeorgetown University School of Medicine 1989 Anesthesiology Residency, CertificateGeorgetown University School of