Schizophrenia

Risperidone: Efficacy and Safety


By Daniel Umbricht and John M. Kane
Schizophrenia Bulletin, Vol. 21, No. 4, 1995
National Institute of Mental Health

Abstract

This article reviews the evidence for the efficacy and effectiveness of risperidone in persons with schizophrenia. Nine published double-blind studies compare risperidone with another antipsychotic medication and/or placebo. All were conducted in the acute phase of illness. Risperidone's antipsychotic efficacy is shown to be consistently superior to that of placebo and at least comparable to that of haloperidol and perphenazine for patients in the acute phase of schizophrenia. Further research is necessary to determine the effectiveness of risperidone and its efficacy both as a maintenance treatment and in treatment-refractory and deficit-state patients.

Schizophrenia Bulletin, 21(4): 593-606, 1995.


Risperidone is the first antipsychotic marketed in the United States since clozapine. Introduced to the U.S. market in 1994, risperidone is a benzisoxazol derivative with combined dopamine D2 and serotonin 5HT2 receptor-blocking properties. Risperidone has a potency comparable to haloperidol as a D2 antagonist, but it has a much greater affinity for 5HT2 receptor sites. It also has relatively high affinity for alpha-adrenergic and histamine receptors in contrast to haloperidol.

No comprehensive review on risperidone has been published to date. This review addresses the following questions:

1. What is the efficacy and effectiveness (vs. placebo and/or older conventional antipsychotics) of risperidone during acute symptom episodes on the reduction of positive symptoms and negative/deficit symptoms, and on other outcomes?
2. What is the efficacy (vs. placebo and/or conventional antipsychotics) of risperidone during maintenance treatment on the reduction of positive symptoms and negative/deficit symptoms, and on other outcomes?
3. Is risperidone efficacious for patients with schizophrenia who fail to respond to conventional antipsychotics?
4. What are the side effects and risks associated with risperidone?

Methods

Computerized searches of MEDLINE and PSYCLIT were conducted back to 1988. In addition, the references in the articles that were obtained from the computerized searches were checked to ensure that relevant articles otherwise not identified were included. Only nine existing double-blind studies were selected for this review.

Findings

Owing to the small number of studies and the fact that all are acute treatment trials, the findings from each study are summarized. The characteristics of the studies and study samples are shown in tables 1 and 2, respectively. Table 3 summarizes the outcomes of each study. Following this are answers to the review questions.

Table 1. Characteristics of risperidone acute treatment studies
Authors, year Study design Entry criteria Comparison
drug
Dosage (mg/day) Duration (weeks) Washout (days) Assessment instruments Comments
Diagnosis Level of psycho-
pathology
Borison et al. (1992) Double-
blind, placebo control
Schizophrenia (DSM-III-R) BPRS >= 30 with at least 2/4 positive symptoms items rated >= 4. Moderately ill on CGI HPL RSP:2-10
HPL: 4-20
7 7 BPRS, CGI, SANS, ESRS, AIMS During the last 24 days, the dosages were kept fixed
Claus et al. (1992) Double-
blind
Schizophrenia, chronic (DSM-III-R) -- HPL RSP:2-20
HPL: 4-20
12 1-7 PANSS, SADS-C, CGI, NOSIE-30. (Analog scale for one target symptom (=the most disturbing symptoms for an individual patient) and four subjective sleep parameters; ESRS During the last 6 weeks the dosages were kept fixed
Müller- Spahn (1992) Double-
blind
Schizophrenia, chronic (DSM-III-R) -- HPL RSP: 1,4,8,12,16
HPL: 10
8 7 PANSS, CGI, ESRS, UKU Side Effect Rating Scale --
Ceskova and Svestka (1993) Double-
blind
Schizophrenia (ICD-9) -- HPL RSP: 2-20
HPL: 2-20
8 -- BPRS, DVP Scale for Side Effects --
Chouinard et al. (1993) Double-
blind, placebo control
Schizophrenia, chronic (DSM-III-R) PANSS total score 60-120 HPL RSP: 2,6,10,16
HPL:20
8 7 PANSS, CGI, ESRS, UKU Side Effect Rating Scale --
Hoyberg et (al. (1993) Double-
blind
Schizophrenia, chronic with acute exacerbation (DSM-III-R) -- PER RSP:5-15 PER:16-48 8 -- PANSS, CGI, ESRS, UKU Side Effect Rating Scale During first 4 weeks, dose was titrated according to "needs" of the patient; dose was kept fixed for last 4 weeks
Min et al. (1993) Double-
blind
Schizophrenia, chronic (DSM-III-R) PANSS total score > 60 and < 120 HPL RSP:5-10
HPL:5-10
8 3-7 PANSS, CGI, ESRS, UKU Side Effect Rating Scale During first 2 weeks, dose was 5 mg/day for both groups, dose could then be raised to 10 mg/day in case of insufficient response, and be kept fixed there

 

Heinrich et al. (1994) Double-
blind
Schizophrenia, acute phase (ICD-9) -- CLZ RSP:4,8
CLZ:400
4 -- BPRS, CGI, Simpson- Angus Scale, AMPD somatic scale --
Marder and (Meibach (1994) Double-
blind, placebo control
Schizophrenia, chronic (DSM-III-R) PANSS total score 60-120 HPL RSP: 2,6,10,16
HPL: 20
8 7 PANSS, CGI, ESRS, UKU Side Effect Rating Scale --

Note. -- AIMS = Abnormal Involuntary Movement Scale (Guy 1976);
AMPD = documentation system of the Association for Methodology and Documentation in Psychiatry (1979);
BPRS = Brief Psychiatric Rating Scale (Overall and Gorham 1962);
CGI = Clinical Global Impressions (Guy 1976);
DSM-III-R = Diagnostic and Statistical Manual of Mental Disorders, revised (American Psychiatric Association 1987);
DVP Side Effect Rating Scale (Vinar 1971);
ESRS = Extrapyramidal Symptom Rating Scale (Chouinard et al. 1980);
ICD-9 = International Classification of Diseases, 9th edition (World Health Organization 1978);
NOSIE-30 = Nurses' Observation Scale for Inpatient Evaluation (Guy 1976);
PANSS = Positive and Negative Syndrome Scale (Kay et al. 1987);
SADS-C = Schedule for Affective Disorders and Schizophrenia-Current Version (Endicott and Spitzer 1978);
SANS = Scale for the Assessment of Negative Symptoms (Andreasen 1984);
Simpson-Angus Scale (Simpson and Angus 1970);
UKU = Udvalg for Kliniske Undersogelser Side Effect Rating Scale (Scandinavian Society of Psychopharmacology Committee of Clinical Investigations 1987);
CLZ = clozapine;
HPL = haloperidol;
PER = perphenazine;
RSP = risperidone.

 
Table 2. Characteristics of study samples
Authors, year Subjects
n
Sex Mean age (yr) Race (%) Mean duration of illness (yr) Prior episodes
n
Mean psycho-
pathology score at study entry
Actual mean treatment dose (last week) (mg/day) Comments
Borison et al. (1992) 36 M=35
F=1
39 White (56) 14 -- 51 (BPRS) RSP: 9.7
HPL: 18.0
--
Claus et al. (1992) 44 Inpatients M=20
F=15
38 -- 14 -- 86 (PANSS) RSP: 17.0
HPL: 11.5
Study sample composed of partially refractory and intolerant patients. Patients in RSP group significantly more ill at baseline
Müller- Spahn (1992) 1,362 -- -- -- -- -- -- (fixed dose) --
Ceskova and Svestka (1993) 62 Inpatients M=45
F=17
36 -- 10 5 44 (BPRS) RSP: Mean min. dose 2.5(±0.9). Mean max. dose 9.5(±3.7)
HPL: Mean min. dose 2.9(±1.2). Mean max. dose 9.9(±4.2)
--
Chouinard et al. (1993) 135 Inpatients M=96
F=39
37 White (94) 16 7 94 (PANSS) (fixed dose) --
Hoyberg et al. (1993) 107 M=77
F=30
36 White (100) -- -- 93 (PANSS) RSP:85
PER:28
No differences between the two groups regarding age, sex, weight, height, and diagnosis at baseline
Min et al. (1993) 35 M=17
F=18
34 Asian (100) 10.6 3.1 90 (PANSS) RSP: 8 patients on 5 mg/day, 8 patients on 10 mg/day.
HPL: 4 patients on 5 mg/day, 15 patients on 10 mg/day (during last 6 weeks)
No differences between the two groups regarding age, sex, weight, height, and diagnosis at baseline
Heinrich et al. (1994) 59 M=31
F=28
-- -- -- -- 55 (BPRS) (fixed dose) No differences between the three treatment groups regarding age, sex, duration of illness, and BPRS total score at baseline
Marder and Meibach (1994) 388 Inpatients M=340
F=48
37 White (73) 16 9 85 (PANSS) (fixed dose) Sample included chronic, refractory, and newly admitted patients
Note. -- BPRS = Brief Psychiatric Rating Scale (Overall and Gorham 1962); PANSS = Positive and Negative Syndrome Scale (Kay et al. 1987); F = female; M = male; HPL = halopendol; max. = maximum; min. = minimum; PER = perphenazine: RSP = risperidone.
 
Table 3. Summary of outcomes of risperidone studies
Authors, year Efficacy Dropout rate Extrapyramidal side effects (EPS) Autonomic and central nervous system side effects
Borison et al. (1992) * Decrease of BPRS total score and CGI scores equal for RSP and HPL, but significantly (p < 0.05  * % of patients with >= 20% reduction of BPRS total score:
  RSP 58%
  HPL 25%
  PBO 0%
* No significant changes of SANS scores in all 3 groups
-- * Overall RSP < PBO * RSP showed marked suppression of dyskinesia compared to PBO
* High EPS scores of PBO group due to increased restlessness 2° to psychotic exacerbation
* RSP = HPL = PBO
Claus et al. (1992) * Decrease of SADS-C score significantly greater for RSP than HPL (12.1 vs. -0.8; p=0.05)
* Within-group decrease of PANSS total score significant for RSP, but not for HPL; between-group difference in reduction of PANSS total score not significant
* % of patients with "clinically significant" improvement on PANSS total score:
Among all patients:
  RSP 33%
  HPL 24%
Among patients with prominent negative symptoms:
  RSP 33%
  HPL 13%
* At endpoint more patients rated as good or very good in RSP group, but mroe patients rated as extremely ill in HPL group on CGI severity scale
20% * Overall RSP = HPL
* RSP group required 10 × less antiparkinsonian medication than HPL group
* RSP > HPL: Blurred vision, vertigo, postural dizziness, impaired concentration, decreased appetite, disturbances of erection and ejaculation
* RSP * No significant differences in growth hormone, T3, and cortisol throughout study between and within groups
Müller-Spahn (1992) * RSP with bell-shaped dose-response curve: 1 mg least effective; 4 and 8 mg optimal response; 12 and 16 mg lower response rates and more side effects than 4 and 8 mg
* In patients' subgroup with high anxiety/depression subscore, 4 and 8 mg significantly better than HPL
-- * Linear dose response relationship with HPL at the upper end of the curve * In optimal RSP dose range (4 mg; 8 mg) fewer adverse experiences than in HPL group
* Dose-proportional weight increase in RSP group
Chouinard et al. (1993) * % of patients in the different treatment groups with >= 20% reduction of PANSS total score:
  RSP 2 mg 50.0% p < 0.01   RSP 6 mg 72.7% p < 0.01   RSP 10 mg 36.4%
  RSP 16 mg 50.0% p < 0.01   HPL 20 mg 47.6%
  PBO 13.6%
* % of patients with >= 20% reduction of BPRS total score plus BPRS total score of >= or CGI severity score of <=   RSP 2 mg 29.1%
  RSP 6 mg 45.4% p < 0.006   RSP 10 mg 36.6% p < 0.0   RSP 16 mg 20.8%
  HPL 20 mg 23.8%
  PBO 9.0%
* On CGI Severity Scales all active treatments significantly superior (p < 0.05) * Mean reduction of PANSS total score:
  RSP 2 mg 11.1
  RSP 6 mg 25.7 p < 0.001  p = 0.04 vs. HPL
  RSP 10 mg 10.6
  RSP 16 mg 14.3
  HPL 20 mg 9.3
  PBO -4.6
* On PANSS negative subscale only RSP 6 mg significantly better than PBO
RSP 2 mg 71%
RSP 6 mg 23%
RSP 10 mg 36%
RSP 16 mg 25%
HPL 20 mg 62%
PBO 73%
* RSP 10 mg = HPL 20 mg > PBO
* RSP 2 mg = RSP 6 mg = RSP 16 mg < HPL * Use of anticholinergics: HPL 20 mg > RSP 2 mg = RSP 6 mg = RSP 10 mg = RSP 16 mg = PBO
  • Significant linear increase of anticholinergic drug use with increase of RSP dose
  • Linear relationship between parkinsonism total score and RSP dose RSP 2 mg = RSP 6 mg = RSP 10 mg = RSP 16 mg = HPL 20 mg = PBO
  •  

    Ceskova and Svestka (1993) * % of patients with "very good" remission (50% - 100% change of BPRS score):
      RSP 45% NS
      HPL 45% NS
    * % of patients with "partial" response (25%-46% change of BPRS score):
      RSP 32% NS
      HPL 42% NS
    * Decrease of BPRS total score:
      RSP 13.1 NS
      HPL 14.5 NS
    -- Use of antiparkinsonian drugs: HPL > RSP RSP = HPL
    Hoyberg et al. (1993) * % of patients with >= 20 % reduction of PANSS total score:
      RSP 74% NS
      PER 50% NS
    * % of patients with >= 20% reduction of CPRS total score:
      RSP 78% p < 0.05   PER 59%
    * CGI severity scores comparable in both treatment groups throughout the whole study; CGI improvement favored RSP
    * Change of PANSS total and subscale scores comparable in both groups. Changes of BPRS total and factor scores comparable in both groups except for hostility factor, RSP > PER p < 0.01 * In 76 patients with higher scores on the negative than positive PANSS subscale ("negative subtype patients") the % of patients with >= 20% reduction of PANSS total score significnatly higher in RSP group (76%) than PER group (53%)
    37% RSP = PER Overall RSP = PER except for "asthenia" and "weight gain" RSP > PER
    Min et al. (1993) * % of patients with >= 20% reduction of PANSS total score:
      RSP 62.5% NS
      HPL 73.7% NS
    * Mean decrease of PANSS total score, PANSS subscale score, BPRS total score and CPRS factor score comparable in both groups
    * % of patients considered "improved" on the CGI:
      RSP 56% NS
      HPL 70% NS
    9% * Overall RSP = HPL
    * RSP < HPL * Overall RSP = HPL
    * Systolic BP HPL < RSP * Significant increase of QTc in RSP group

     

    Marder and Meibach (1994) * % of patients with >= 20% reduction of PANSS total score:
      RSP 2 mg 35%
      RSP 6 mg 57% p < 0.005   RSP 10 mg 40% p < 0.005   RSP 16 mg 51% p < 0.005   HPL 20 mg 30%
      PBO 22%
    * % of patients with >= 20% reduction of BPRS total score plus either BPRS total score of <=  RSP 2 mg 22%
      RSP 6 mg 41% p < 0.05   RSP 10 mg 27% p < 0.05   RSP 16 mg 33% p < 0.05   HPL 20 mg 22%
      PBO 11%
    * Mean reduction of PANSS Total Score:
      RSP 2 mg -1.8
      RSP 6 mg 16.1 p < 0.001   RSP 10 mg 8.9 p < 0.01   RSP 16 mg 14.5 p < 0.001   HPL 20 mg 4.1 p < 0.005   PBO -3.3
    * On PANSS negative subscale RSP 6 mg and RSP 16 mg with significantly lower endpoint values than PBO
    RSP 2 mg 54% RSP 6 mg 45%
    RSP 10 mg 48%
    RSP 16 mg 44%
    HPL 20 mg 58%
    PBO 68%
    * RSP 6 mg = PBO
    * RSP 16 mg = HPL 20 mg > PBO
    Fatigue, sedation, accommodation disturbance, orthostatic dizziness, tachycardia, weight gain, diminished sexual desire, erectile dysfunction significantly related to RSP dose
    Heinrich et al. (1994) * Mean reduction of BPRS total score:
      RSP 4 mg 16.8 NS
      RSP 8 mg 11.4 NS
      CLZ 400 mg 17.1 NS
    * % of patients rated as "very much improved" and "much improved" on CGI Scale:
      RSP 4 mg 60% NS
      RSP 8 mg 42% NS
      CLZ 400 mg 60% NS
    -- * Gait disturbance RSP 4 mg < RSP * Salivation:
    RSP 4 mg < RSP * Appetite, gastrointestinal and central-respiratory disturbances:
    RSP 4 mg = RSP 8 mg < CLZ

     

    Note. -- BPRS = Brief Psychiatric Rating Scale (Overall and Gorham 1962); CGI = Clinical Global Impressions (Guy 1976); PANSS = Positive and Negative Syndrome Scale (Kay et al. 1987); SADS-C = Schedule for Affective Disorders and Schizophrenia -- Current Version (Endicott and Spitzer l97a); SANS = Schedule for Assessment of Negative Symptoms (Andreasen 1984); BP = blood pressure; CLZ = clozapine; HPL = haloperidol; PER = perphenazine, PBO = placebo; RSP = risperidone; QTc = interval corrected; NS = not significant.

    Findings of the Studies.
    Heinrich et al. (1994) compared two doses of risperidone with 400 mg of clozapine and found a similar reduction of scores on the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham 1962) in all three treatment groups. The percentage of patients rated "very much improved" or "much improved" on the Clinical Global Impressions (CGI; Guy 1976) scale was 60 percent for the 4-mg risperidone group, 42 percent for the 8-mg risperidone group, and 60 percent for the clozapine group. However, clozapine tended to cause more side effects than were observed in the two risperidone groups, especially in those patients taking 4 mg of risperidone. The investigators conclude that 4 mg of risperidone represents an effective alternative to clozapine based on its superior side effect profile. Unfortunately, this report does not indicate how many (if any) patients had a history of treatment refractoriness.

    Borison et al. (1992) compared 2 to 10 mg of risperidone with 4 to 20 mg of haloperidol and placebo. They found a significant reduction of BPRS total scores in both the risperidone and the haloperidol group but no change in the placebo group. Fifty-eight percent of all patients in the risperidone group showed at least a 20-percent reduction of their BPRS total score, while only 25 percent of patients in the haloperidol group showed such a reduction. Risperidone also produced a superior result on the CGI: 83 percent of the risperidone group were rated as improved compared with 58 percent of the haloperidol group. Both treatments were significantly more effective than placebo. With regard to negative symptoms, no significant changes in scores on the Scale for the Assessment of Negative Symptoms (SANS; Andreasen 1984) were observed in any treatment group.

    Claus et al.(1992) reported results that tended to favor risperidone over haloperidol. The risperidone group showed a significant improvement on the Positive and Negative Syndrome Scale (PANSS; Kay et al. 1987) total score and the positive and general psychopathology subscale scores on the Schedule for Affective Disorders and Schizophrenia (SADS-C; Endicott and Spitzer 1978) total scale score, and on the Nurses' Observation Scale for Inpatient Evaluation (NOSIE-30; Guy 1976) total scale score, while the haloperidol group did not. Between-group differences were significant for the SADS-C but not for the PANSS total score, the PANSS positive symptom subscale score, or the NOSIE-30. There was, however, a statistical trend in favor of risperidone on the general psychopathology subscale of the PANSS. More patients in the risperidone group than in the haloperidol group (33% vs. 24%) were rated as showing "clinically significant" improvement (not defined by authors) on the PANSS total scores. Among patients with a high initial rating on the PANSS negative subscale at baseline, the proportion improving remained the same in the risperidone group (33%) but dropped to 13 percent in the haloperidol group.

    The large European multicenter study (Müller-Spahn 1992) revealed a bell-shaped dose-response curve as measured
    by the PANSS and the CGI; that is, 1 mg of risperidone proved to be least effective, the 4- and 8-mg doses showed an optimal response, and the 12- and 16-mg doses were less effective. A 20-mg dose of haloperidol was as effective as a 16-mg dose of risperidone. If only patients with initial high anxiety/depression scores are considered, 4 and 8 mg of risperidone proved to be significantly better than haloperidol on a number of outcomes, including the PANSS and BPRS total scores, the PANSS general psychopathology subscale, the BPRS activity and anxiety/depression clusters, and the percentage of patients reaching clinical improvement on the PANSS and BPRS. In the high anxiety/depression subgroup, haloperidol lost the superiority over 1 mg of risperidone evident in the intention-to-treat analysis. Results for the patients with low anxiety/depression scores were not given.

    Similar results were found in the two North American multicenter studies (Chouinard et al. 1993; Marder and Meibach 1994). Using the percentage of patients with a reduction of the PANSS total score greater than 20 percent as their primary outcome measure, the Canadian study (Chouinard et al. 1993) found that 6 mg of risperidone led to the highest rate of responders (73%). This was significantly better than placebo (14%) but not better than 20 mg of haloperidol (48%). Risperidone doses of 2 and 16 mg also showed significantly higher rates of responders than placebo.

    In the U.S. study (Marder and Meibach 1994), significantly more patients in the risperidone 6-, 10-, and 16-mg groups were classified as responders (57%, 40%, and 51%, respectively) than in the placebo group (22%). When compared with the 20-mg haloperidol group, which had a response rate of 30 percent, significantly more patients in the risperidone 6- and 16-mg groups were classified as responders. When using the response criteria defined by Kane et al. (1988),1 only the 6-mg group showed a significantly higher response rate than the 20-mg haloperidol group (41% in the 6-mg risperidone group vs. 22% in the haloperidol group).


    1In both North American studies, a post-hoc analysis also used as a criterion for response a 20-percent reduction on the PANSS-derived BPRS total score -- either a CGI severity of illness score less than 3 or a (PANSS-derived) BPRS total score less than 35.


    On changes in PANSS total scores, 6 mg of risperidone proved significantly better than 20 mg of haloperidol in the study by Chouinard et al. (1993), while Marder and Meibach (1994) found both 6 and 16 mg of risperidone to have superiority over 20 mg of haloperidol. Six milligrams of risperidone in the Canadian study (Chouinard et al. 1993) and 6 and 16 mg of risperidone in the U.S. study (Marder and Meibach 1994) were also found to be significantly better than placebo on the positive and negative symptom subscale of the PANSS. In the Canadian study (Chouinard et al. 1993), all active treatments were found to be significantly better than placebo on change of the CGI. Six milligrams of risperidone tended to be better than 20 mg of haloperidol. On the same outcome measure, the U.S. study (Marder and Meibach 1994) found all active treatments with the exception of 2 mg of risperidone to be significantly better than placebo. In both studies, the 6-, 10-, and 16-mg risperidone groups and the 20-mg haloperidol group showed significantly higher rates of improved patients as rated on the CGI scale than did the placebo group (Chouinard et al. 1993; Marder and Meibach 1994). In addition, in the Chouinard et al. (1993) study, significantly more patients were classified as improved in the 6-mg risperidone group than in the 20-mg haloperidol group.

    The study by Ceskova and Svestka (1993) comparing 2 to 20 mg of risperidone with 2 to 20 mg of haloperidol (mean maximal dose = 9.9 mg; mean minimal dose = 2.9 mg) found similar efficacy for the two treatments. In the risperidone group, 45 percent of the patients showed a very good response and 32 percent showed a partial response, while the corresponding results for haloperidol were 45 and 42 percent, respectively. Both treatments led to a statistically significant reduction of BPRS total scores with no between-group differences. The haloperidol groups showed significantly lower scores on BPRS anxiety and depression items (and on the anxiety/depression factor) than the risperidone group.

    The study by Hoyberg et al. (1993) used perphenazine as the comparison drug. The mean daily treatment doses were 8.5 mg for risperidone and 28 mg for perphenazine. The two treatments were equally effective in reducing PANSS total scores, negative and positive symptom subscale scores, and PANSS-derived BPRS factor scores. Only on the BPRS hostility factor did risperidone lead to a significantly greater improvement than perphenazine. When clinical improvement was defined as a 20 percent reduction of the PANSS total scores, there was no significant group difference. However, when a 20-percent BPRS reduction is used as the criterion for response, the rate is slightly higher in the risperidone group (78%) and significantly different from the perphenazine treatment group. On the CGI, improvement scores between the two groups did not significantly differ.

    In a post-hoc analysis, the authors divided the study patients into "negative" or "positive" subtypes, depending on whether the patients showed higher scores on the PANSS negative or positive symptom subscales. Among the positive subtype patients, the two treatments fared equally. Among the negative subtype patients, the percentage of patients rated as responding (using 20-percent reduction of either PANSS or BPRS total scores as the criterion) was significantly higher in the risperidone than in the perphenazine group. Also, risperidone led to a significantly greater improvement on the BPRS hostility factor.

    Finally, the study by Min et al. (1993) using a "semi-fixed" dosage did not find any significant differences between risperidone and haloperidol on reductions of PANSS total score and positive and negative symptom subscale scores, on PANSS-derived BPRS factor scores, and on CGI severity of illness ratings.

    What Is the Efficacy and Effectiveness of Risperidone (vs. Placebo and/or Older Conventional Antipsychotics) During Acute Symptom Episodes on the Reduction of Positive Symptoms and Negative/Deficit Symptoms, and on Other Outcomes? The studies reviewed demonstrate equivalent if not superior efficacy of risperidone compared with haloperidol and perphenazine in the treatment of schizophrenia patients. The available data appear to indicate that 4 to 8 mg is the most effective dose for risperidone. This range is based on both fixed-and adjusted-dose studies.

    The finding by Marder and Meibach (1994) that 16 mg is as effective as 6 mg may indicate that for certain patients, a higher dose is required to get the full benefit of the treatment. Given the heterogeneity of the patients included in these trials, further analyses (or additional studies) focusing on both refractory and more acute subgroups may be helpful in targeting dosages to specific patient subgroups. However, in view of the finding discussed below that risperidone in dosages of less than 10 to 12 mg produces significantly fewer extrapyramidal symptoms (EPS), an initial dose range between 4 and 8 mg seems reasonable. If a patient does not show improvement after 3 to 4 weeks, an increase to a higher dose can be considered.

    It has been suggested that risperidone may have a special role in the treatment of negative symptoms. Claus et al. (1992) found clinically significant improvement in 33 percent of the total risperidone group as well as in 33 percent of the subgroup of patients with high negative symptom scores at baseline. The corresponding data for haloperidol were 33 percent for all patients but only 13 percent for patients with predominantly negative symptoms. In the Canadian study (Chouinard et al. 1993) and the U.S. multicenter study (Marder and Meibach 1994), it was found that 6 mg (in both studies) and 10 and 16 mg (in the U.S. study only) of risperidone were significantly better than placebo in reducing negative symptoms, whereas 20 mg of haloperidol was not. Because EPS easily can be rated as negative symptoms, it will be important for future research to determine whether this finding reflects lower symptoms of EPS for risperidone in doses below 10 mg.

    Similarly interesting is the finding of Hoyberg et al. (1993) that among patients with higher ratings of negative than positive symptoms on the PANSS subscales, the rate of responders was significantly higher in the risperidone than in the perphenazine group. Again, however, this is difficult to interpret since a decrease in EPS in the risperidone group could have contributed to this result. Such a possibility was not addressed by the authors by, for example, covarying for change in EPS during treatment or baseline EPS. Also, the authors' criteria for assigning patients to a positive or negative subgroup only determined the relative predominance of negative or positive symptoms and did not necessarily indicate that a given patient scored high or low on the positive or negative symptom subscales. For this reason, it is unclear whether the negative subtype patients in fact have a deficit state.

    Another target population for risperidone may be patients with prominent symptoms of anxiety and depression. The European multicenter study (Müller-Spahn 1992) found that among this subgroup, risperidone in doses of 4 and 8 mg proved to be significantly superior to 10 mg of haloperidol.

    No data are available at this point to determine the effectiveness of risperidone.

    What Is the Efficacy of Risperidone (vs. Placebo and/or Conventional Antipsychotics) During Maintenance Treatment on the Reduction of Positive Symptoms and Negative/Deficit Symptoms, and on Other Outcomes? To date, no double-blind studies using risperidone for maintenance treatment have been reported.

    Is Risperidone Efficacious for Patients With Schizophrenia Who Fail to Respond to Conventional Antipsychotics? There are no published reports of studies in well-characterized treatment-refractory patients. Of particular interest would be comparisons with clozapine, as well as trials in schizoaffective patients and in patients selected for predominant negative/deficit symptoms.

    What Are the Side Effects and Risk Associated With Risperidone? A consistent finding across all studies is that risperidone below 10 mg/day did not produce more EPS than placebo. Risperidone at 16 mg produced as much EPS as 20 mg of haloperidol in the U.S. multicenter study (Marder and Meibach 1994) but not in the Canadian study (Chouinard et al. 1993), which found 10 mg to cause the most EPS among the different risperidone doses. However, like all studies reporting on this factor, Chouinard et al. (1993) found that the use of anticholinergic medication was significantly higher in the 20-mg haloperidol group than in any risperidone group. Also, a linear relationship between risperidone dose and EPS scores was found in both the European and Canadian multicenter studies. In the study by Min et al. (1993), in which risperidone was compared with equal dose ranges of haloperidol, risperidone treatment was not associated with a greater decrease of the global EPS rating as compared with haloperidol. Only on certain subitems and subscores was there a trend in favor or risperidone. Overall, it seems justified to conclude that, in general, doses below 10 mg are less likely to cause EPS than doses above 10 mg. However, more work is needed in this area.

    At the recommended dose of 6 mg, risperidone appears to be well tolerated. The adverse effects most commonly associated with treatment discontinuation in the US and Canadian studies were dizziness (1.5%), nausea (1.2%), and agitation (1.0%). The most common adverse effects among patients receiving 10 mg/day or less of risperidone in the North American studies were insomnia (26%), agitation (22%), EPS (17%), headache (17%), anxiety (12%), and rhinitis F(10%). In most cases, these rates did not differ significantly from those for placebo, but 6 mg of risperidone did produce significantly fewer EPS than 20 mg of haloperidol.

    Risperidone is a potent alpha-adrenergic antagonist. Therefore, it is important to closely follow blood pressure early in treatment to evaluatefor the presence of postural hyppotension. To date, no confirmed cases of neuroleptic malignant syndrome or tardive dyskinesia have occurred in association with risperidone. However, more long-term experience is necessary before drawing any conclusions on these sequelae.

    In the study by Hoyberg et al. (1993), a high percentage of patients on risperidone were noted to show "asthenia" (49% vs. 28% in the perphenazine group) and weight gain (52% vs. 24% in the perphenazine group). A moderate increase in body weight (mean of 2.3 kg over an average period of 7.4 months) has been reported and is likely due to the drug's antagonism of serotonin receptors. Risperidone is also associated with significant increases in prolactin. However, it does not appear to produce hypersalivation, persistent tachycardia, cataplexy, myoclonus, or seizures.

    Discussion

    The large-scale clinical trials conducted with risperidone demonstrate its antipsychotic efficacy to be consistently superior to that of placebo and at least comparable to that of haloperidol and perphenazine. The extend to which risperidone might be considered superior to haloperidol rests on the interpretation of the existing data base. The majority of studies conducted used multiple fixed doses of risperidone and one fixed dose of haloperidol. The analyses in which risperidone was found to be superior to haloperidol were by and large conducted with the optimal dose of risperidone. In the one study (Min et al. 1993) in which risperidone was compared with a similar dose of haloperidol, and in the European multicenter study (Müller-Spahn 1992) in which fixed doses of risperidone were compared with 10 mg of haloperidol, risperidone was not found to show superior efficacy. One could therefore argue that, before concluding that risperidone is superior to haloperidol, haloperidol should be used in more than one fixed dose as well. Despite the fact that haloperidol has been widely used for more than two decades, debate continues as to what dosage is optimal. The issue is important not purely from an efficacy standpoint but also with regard to adverse effects, given that EPS can easily be mistaken for, or add to negative symptoms or tension and agitation.

    Risperidone shares some receptor-binding proportions with clozapine but not with other drugs. Whether risperidone will prove to be as useful as clozapine in treatment-refractory patients remains to be seen. Studies are being planned to compare risperidone directly with clozapine in refractory patients.

    How much of an advance does risperidone represent? To some extent, this question is difficult to answer until we have more experience with the drug. At the recommended dosage of 6 mg/day, it appears to produce fewer EPS than haloperidol at a dosage of 20 mg/day and not significantly more EPS than seen in the placebo control group. Whether 6 mg/day will prove to be the optimal dosage for the general population of patients with acute episodes or exacerbations remains to be determined. If higher doses are required, the advantages in terms of EPS may disappear. As previously mentioned, data need to be generated in deficity-state patients or patients with predominant persistent negative symptoms as well as in treatment-refractory patients. Such studies will help to identify risperidone's appropriate place in the treatment of schizophrenia.

    It is clear that the marketing of this drug has tapped into a potentially large, pent-up demand for new antipsychotic drugs. How the compound succeeds, particularly in this era of cost containment, will depend on whether initial expectations are realized in routine clinical practice.

    In conclusion, research questions that remain to be answered include the following:

    1. What is the efficacy of risperidone in treating deficit symptoms?
    2. What is the effectiveness of risperidone in typical clinical treatment settings?
    3. Is risperidone an effective maintenance therapy?
    4. Is risperidone efficacious among patients with illness refractory to conventional antipsychotics?
    5. What is the cost-effectiveness of risperidone relative to conventional antipsychotics and clozapine, taking into consideration impacts on positive and negative symptoms, side effects, enhancement of functional status, quality of life, and costs?

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    The Authors

    Daniel Umbricht, M.D., is Research Fellow, Hillside Hospital, Long Island Jewish Medical Center.

    John M. Kane, M.D., is Professor of Psychiatry, Albert Einstein School of Medicine, and Chairman of Psychiatry at the Long Island Jewish Medical Center, Glen Oaks, NY.


    This article, originally from the Schizophrenia Bulletin, is in the public domain and may be reproduced or copied without requesting the author's permission.

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