#
2002 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2002 Volume 6 Pages 193 ± 197
193
Efficacy and safety of long-term risperidone treatment LJ HOTUJAC AND M SÏAGUD Department of Psychiatry, University Hospital Center Rebro, Zagreb, Croatia
While efficacy in treatment of the acute phase of schizophrenia is well established for so-called atypical antipsychotics, more data regarding long-term treatment are needed. INTRODUCTION:
In a naturalistic, open-label study, 32 patients were included in order to investigate the efficacy and safety of risperidone over 3 years of treatment; 26 of them were treatment-resistant to the previously used antipsychotic drugs (except clozapine). METHOD:
Correspondence Address Professor Dr Ljubomir Hotujac, University Hospital Center, Zagreb, Department of Psychiatry, Kispatic eva 12, 10000 Zagreb, Croatia Tel: +385 1 24 21 843 Fax: +385 1 23 88 329 E-mail: [email protected]
Received 10 November 1999; revised 14 September 2001; accepted for publication 7 August 2002
At the end of the first year, 20 of these 26 patients showed at least partial improvement. At the end of the third year, 17 patients were still being treated with risperidone. While eight patients were lost to follow-up, six relapsed in spite of good compliance. All the adverse events which occurred during treatment were strictly dose-dependent and disappeared when the dose was lowered to 4 mg daily. RESULTS:
Within the limits of naturalistic studies, it can be concluded that risperidone seemed to be an effective and safe drug for long-term treatment in the majority of our patients. (Int J Psych Clin Pract 2002; 6: 193 ± 197) CONCLUSIONS:
Keywords schizophrenia risperidone
INTRODUCTION
S
chizophrenia is a typically life-long, chronic illness, often requiring life-long medication. Patients who are kept in otherwise stable remission may be seriously disabled by a range of side-effects of antipsychotics, namely extrapyramidal side-effects (EPS). For the conventional antipsychotics, there may be a very small difference, if any, between the antipsychotic dose and the dose that produces 1 EPS. After the introduction of the atypical antipsychotic risperidone, the incidence of those side-effects is eliminated or significantly decreased. At the same time, antipsychotic efficacy is not only retained but spread to a broader range of symptoms. Risperidone and other atypical antipsychotics are highly effective against negative symptoms, where conventional antipsychotics have only a little, if any, 2±5 efficacy. The two pivotal clinical trials of risperidone, the North America Trial6 ,7 and the Multinational Trial,8 proved its efficacy and low liability to cause extrapyramidal side-
tolerability
effects. However, they were not designed to show the efficacy of risperidone over a long period of time. Data regarding the long-term use of risperidone are relatively sparse.9 Therefore we decided to determine the acute and long-term efficacy and safety of risperidone in patients with schizophrenia and schizoaffective disorders.
SUBJECTS AND METHODS STUDY DESIGN This was an open-label, non-comparative and prospective study, designed to determine the efficacy and safety of a 3year course of risperidone treatment.
INCLUSION CRITERIA To be eligible, patients had to have a diagnosis based on DSM-IV criteria for schizophrenia or schizoaffective
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disorder and a Positive and Negative Syndrome Scale (PANSS) total score of 60 or higher. No other primary Axis I diagnosis was permitted. All patients provided written informed consent. Patients needed to be at least 18 years old. Women of reproductive potential must have been using adequate contraceptive methods. Inpatient status was not mandatory. Patients showed no evidence of clinically significant Axis III disorder, which was confirmed by medical history, physical examination and normal haematological, biochemical and ECG parameters. After a screening assessment, a minimum washout of 3 days from oral antipsychotic agents or one cycle from a depot neuroleptic agent was required.
DOSING SCHEDULE The goal was to treat psychosis with risperidone monotherapy. Risperidone was given at an initial dose of 1 mg b.i.d. The dose was increased to 2 mg on the second day, and 3 mg b.i.d. on days 3 ± 7 of treatment. From day 8, the patients received 2 mg in the morning and 4 mg in the evening if their Clinical Global Impression score (CGI) was rated as improved. If the CGI was rated as unchanged or worsened, 4 mg of risperidone was given b.i.d. From day 14, the dosage could be further increased to 12 mg, and from day 21 to the maximum dosage of 16 mg, if no improvement on CGI was observed. From day 28 (week 4) to week 16 the dosage remained unchanged as much as possible. From week 16, the dosage could be gradually decreased to the maintenance dose, according to the judgement of the investigator. The use of benzodiazepines on a prn basis (up to 40 mg of diazepam or 2 mg of alprazolam daily) was allowed. The use of biperiden (2 ± 6 mg/day) if EPS emerged was also allowed, but also on a prn basis. The prophylactic use of anticholinergics was prohibited.
MEASUREMENT OF EFFICACY The efficacy of risperidone was measured with the Positive and Negative Syndrome Rating Scale for Schizophrenia (PANSS), which was performed at days 0 and 28, and at weeks 16, 28, 40 and 52 respectively, and thereafter every 3 months up to the end of month 36. The CGI score was recorded at days 0, 7, 14, 21, 28 and weeks 8, 12, 16, 20, 28, 40, 52 respectively, and thereafter every 3 months up to the end of month 36. CGI improvement was measured at each visit, the same as CGI, with the exception of day 0.
measured at days 0 and 28, and at weeks 8, 12, 16, 20, 28, 40 and 52, and every 3 months up to the end of month 36. Laboratory measurements (haematology, biochemistry, urinalysis and ECG) were performed at day 0, week 16 and whenever needed by the investigator. They were repeated at the end of the second and third year of risperidone treatment.
RESULTS Currently available are the results for 32 patients who were recruited in the time period from May 1996 to April 1998. Demographic characteristics of the study population are presented in Table 1. The patient population was heterogeneous regarding the diagnosis. The numbers of patients having different types of schizophrenia and schizoaffective disorder are presented in Table 2. Previous treatment is mentioned in Table 3. Table 1 Patients studied
Males Females
n
Mean age (years)
Mean duration of illness (years)
12 20
32.6 33.7
8.2 3.4
Table 2 Diagnoses of patients included in the study Diagnosis
No. of patients
Schizoaffective disorder Paranoid schizophrenia Disorganized schizophrenia Simple schizophrenia Catatonic schizophrenia
11 13 4 3 1
Table 3 Previous antipsychotic treatment
MEASUREMENT OF SAFETY
Treatment prior to entry
Extrapyramidal side-effects were estimated by using the Extrapyramidal Symptom Rating Scale (ESRS) at days 0 and 28, and at weeks 16, 28, 40, 52 and 104. All adverse events observed by the investigator or reported by the patient were recorded on a case report form. Vital signs (blood pressure and heart rate) were recorded at each visit. Weight was
Haloperidol Fluphenazine Fluphenazine depot Sulpiride None
No. of patients 9 11 2 4 6
Average dose, mg/day
Average duration of treatment, weeks
12.3 9.5 25.0 550
11.2 12.0 52.0 8.7
Efficacy and safety of long-term risperidone
Although resistance to antipsychotic agents was not mandatory, 26 out of 32 patients had not responded to their previous treatment. Four out of six patients who did not receive antipsychotics prior to this study had stopped taking drugs on their own initiative because of EPS.
EFFICACY The analysis of the 3-year risperidone treatment is available for 17 patients. During the first year of treatment, six patients dropped out because of protocol violation. While no worsening of psychopathology was observed in 25/32 patients during 12 months of risperidone treatment, during the second year of treatment four patients were withdrawn from the study because of psychotic relapse. Table 4 shows that significant improvement (420% reduction on the PANSS scale) was observed in 25/32 patients after one year of treatment. In the second year of treatment, the observed improvement was maintained in 19/25 patients. Four patients had a psychotic relapse in spite of regular risperidone intake, as confirmed by family members. While their psychotic symptoms did not improve after increasing the dose of risperidone up to 12 mg daily, they required treatment with other antipsychotics. While in the third year of risperidone treatment one patient relapsed, 17 out of 19 patients remained well. Negative subscale score on the PANSS also showed a gradual and sustained improvement during 36 months of risperidone treatment, and this tendency was observed even in the second and third year of treatment, for those patients who did not relapse. Table 5 presents a pattern of change of negative symptoms.
RISPERIDONE DOSE According to the protocol, each patient received 6 mg of risperidone daily at the end of the first week of treatment. The highest average daily dose of risperidone was given at the end of the third week (7.28 mg of risperidone daily); it started to be lowered gradually after week 16, and was found to be 3.95 mg at week 52. The average risperidone maintenance dose by the end of year 2 of treatment was 3.5 mg daily and by the end of year 3 was as low as 2.95 mg/day.
SAFETY During the 3-year study period, there were no discontinuations due to side-effects. Furthermore, there were no serious adverse events. The most common side-effects were EPS, which occurred in 23/32 (59%) of patients, requiring anticholinergic medication. All EPS were strictly dose-dependent and disappeared when the dose was reduced to 4 mg daily. All adverse events registered during one-year risperidone treatment are presented in Table 6.
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Table 4 Clinical course during 3 years of risperidone treatment
Year of treatment
No of patients with 420% No. of reduction in patients PANSS who relapsed
First Second Third
25/32 19/25 17/19
1/32 4/25 1/19
Patients lost to follow-up 6/32 2/25 1/19
Table 5 Change in negative PANSS score during 36 months of risperidone treatment Length of treatment
No. of patients estimated
Average PANNS negative
Baseline 4 weeks 16 weeks 52 weeks 2 years 3 years
32 30 27 25 19 17
28 23 21 19 16 15
Table 6 Adverse events in patients during 1-year risperidone treatment Adverse event Parkinsonism Akathisia Acute dystonia Weight gain Amenorrhoea Sexual dysfunction Galactorrhoea Increased salivation Nocturnal enuresis Headache Increased duration of sleep
No. of patients 9 5 3 4 6 5 3 1 1 1 1
There were no clinically significant changes in blood pressure and heart rate. There were no clinically significant laboratory (haematological and biochemical tests and urinalysis) or ECG abnormalities.
DISCUSSION In our study, mean PANSS negative subscale scores showed a tendency towards slow but continuous improvement over the 3 years. A long-term open-label study confirmed that the efficacy of risperidone against negative symptoms is not
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limited to the first 8 weeks of treatment.* This observation further suggests that the effect of risperidone against negative symptoms may develop more slowly than its effect on positive symptoms. Postmarking surveillance studies further confirmed the finding of the afore-mentioned very 10 gradual improvement. Significant and substantial reduction of negative symptoms during 12 months has also been found in other open-label trials.1 1 ,1 2 The question which arose from the latter studies was how far can further reduction in negative symptoms be expected in patients treated for more than one year. Our results suggest that in patients who did not have a relapse of their positive symptoms, a very gradual, but continuous, reduction in negative symptoms could be expected. After an acute-phase improvement, the daily dose of risperidone was gradually decreased from an average 7.62 mg/day at week 3 and 7.25 mg/day at week 16, to the lowest 2.95 mg/day. In spite of the dose decrease, negative symptoms continued to improve. This finding agrees with the results of factor analysis of PANSS in two double-blind trials conducted in North America, where risperidone at 2 mg/day was significantly more effective 13 than placebo in reducing negative symptoms. The most commonly reported side-effects were EPS, which were registered in 59% of the patients. They were firmly doserelated and disappeared when the dosage was reduced to 4 mg daily. This is completely in accordance with findings in other studies, where the frequency of EPS in patients receiving 4 ± 6 mg daily was similar to that in placebotreated patients.7 ,1 4 ,1 5 During safety assessment, we registered three patients who had a significant weight gain (14, 20 and 14 kg, respectively, during 4 months of 6 mg risperidone treatment). A very interesting and surprising finding is that none of those four patients expressed any of the EPS, while the 12 patients who expressed some form of EPS had no weight gain at all. While weight gain has been found to 9 ,1 2 increase slightly during risperidone treatment, we are not aware of similar findings in other risperidone studies. No case of tardive dyskinesia was reported during the trial. The incidence of tardive dyskinesia in patients treated with relatively high doses of risperidone (7.6 ± 9.4 mg/day) was estimated to be only 0.3% in 503 patients who had been treated with risperidone for at least one year.1 6 This is of particular importance, in considering the disturbing influence of those side-effects on patients in long-term treatment. No clinically relevant ECG changes, or any consistent changes in vital signs, have been detected in short- and 6 ± 8 ,1 2 ,1 6 long-term risperidone studies. In the current study, 20/26 treatment-resistant patients improved, at least partially, on risperidone during one year of treatment, in terms of a decrease in PANSS scale scores. Risperidone proved to be more effective than haloperidol in 17 treatment-resistant schizophrenia. Future studies will *Data on file, Janssen-Cilag, Titusville, NJ, USA
determine whether risperidone is effective in those hardto-treat patients. However, risperidone was found not to be effective in patients who were switched from clozapine to risper18 idone. While in the current study no patient had previously been treated with clozapine, they would be given clozapine if risperidone was not available to them. At least, it can be concluded that it is worthwhile starting a trial of risperidone before starting clozapine. On the other hand, risperidone has been found to be just as effective as 19 clozapine in treatment-resistant patients. Notwithstanding all the shortcomings of such an uncontrolled naturalistic trial, we want to point out its advantages. Unlike double-blind studies using highly sophisticated technology, the current study can apply descriptive psychiatry that has almost been forgotten. Herewith we provide two case reports. Case 1 A 35-year-old woman, an academic painter, had been treated with haloperidol a few years prior to this study. She had predominantly depressed and negative symptoms, with occasional outbursts of anger. She hit her mother a couple of times. She did not leave her house and was very difficult to live with. Three months after the institution of risperidone she started to show interest in the outside world and started to paint again. She came to her mother and said ``Forgive me for what I have done to you, that was my illness. Now I am well again.’’ Case 2 A 24-year-old woman, with a diagnosis of disorganized schizophrenia, had been treated with depot fluphenazine for the last 2 years. She continued to have disorganized speech and behaviour. In addition, she was seriously disabled by tardive dyskinesia, involving face, neck and trunk. Four months after the institution of risperidone, dyskinetic movements began to decrease, and a year later completely disappeared. The patient managed to complete her studies, and started to work. She is virtually free of dyskinetic, as well as of schizophrenic, symptoms. While clinical studies suggest that 4 ± 6 mg/day of risperidone is an appropriate dose range for patients with chronic schizophrenia,4 our patients remained stable on an average of 3.95 mg/day at the end of year 1, 3.5 mg/day at the end of year 2 and 2.95 mg/day at the end of year 3 of risperidone treatment. Our results are in agreement with a recently published naturalistic study, reporting an average daily dose of 3.7 mg of risperidone daily in hospitalized patients.2 1 However, five of our patients had a relapse of positive psychotic symptoms during the second and third year, in spite of risperidone treatment on a regular basis. While a slightly lower-than-average maintenance dose can contribute to the re-occurrence of psychotic symptoms, 3 mg/day of risperidone has been associated with 64% of striatal D2 occupancy rate.2 0 This risperidone dosage
Efficacy and safety of long-term risperidone
appears to be sufficient for antipsychotic efficacy, but insufficient for the emergence of EPS, which requires 80%, and prolactin elevation, which requires 72% of D2 receptor occupancy, respectively. Determining the optimal minimal dosage for maintenance treatment in schizophrenia continues to be a challenge for the physician.
CONCLUSION The benefits of risperidone that have been demonstrated in clinical practice are impressive. Our small study shows that these benefits can also be achieved in clinical practice where patients cannot be carefully selected. Notwithstanding all the limits of this open, naturalistic, descriptive and small-sample study of a mixed schizophrenic patient population, it can be concluded that our findings are consistent with those of other risperidone studies, regarding its ability to cause significant and substantial reduction of positive and negative symptoms, and its favourable side-effects. Whether this tendency towards a gradual improvement in negative symptoms will
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continue during further treatment, helping the patients to deal with their devastating illness, still remains to be determined. Risperidone also seems to be effective in at least some of the patients resistant to typical antipsychotics.
KEY POINTS . Gradual and sustained improvement of positive and negative symptoms of schizophrenia during three years of risperidone treatment in the majority of patients . At least partial improvement of patients resistant to typical antipsychotics . Dose-dependent EPS during risperidone treatment . No serious adverse events during 3 years of risperidone treatment . None of the three patients whose weight increased significantly, experienced EPS on high initial dose of risperidone
REFERENCES 1. McEvoy JP, Hogarty GE, Steingard S (1991) Optimal dose of neuroleptics in acute schizophrenia: a controlled study of the neuroleptic threshold and higher haloperidol dose. Arch Gen Psychiatry 48: 739 ± 45. 2. Wirshing WC, Marder SR (1998) Efficacy and dosing issues of novel antipsychotics. Int J Psychiatry Clin Pract 2: 35 ± 38. 3. Carman J, Peuskens J, Vangeneugden A (1995) Risperidone in the treatment of negative symptoms of schizophrenia: a metaanalysis. Int J Clin Psychopharmacol 10: 207 ± 13. 4. Kasper S (1998) How much do novel antipsychotics benefit the patients? Int Clin Psychopharmacol 13 (suppl 3): 71 ± 77. 5. Hilger E, Kasper S (2000) Atypical neuroleptics: new approaches to drug therapy of schizophrenic disorders. Wien Klin Wochenstr 112: 1031 ± 38. 6. Chouinard G, Jones B, Remington G et al (1995) A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 15 (Suppl 1): 365 ± 445. 7. Marder SR, Meibach R (1994) Risperidone in the treatment of schizophrenia.Am J Psychiatry 151: 825 ± 35. 8. Peuskens J for the Risperidone Study Group (1995) Risperidone in the treatment of chronic schizophrenic patients: a multinational, multicentre, double-blind, parallel group study versus haloperidol. Br J Psychiatry 166: 712 ± 16. 9. Gutierrez-Esteinou R, Grebb JA (1997) An analysis of the first three years in general use. Int Clin Psychopharmacol 12 (Suppl 4): 3 ± 10. 10. Albus M, Klauder CA, Linden M, Philipp M (1997) Dosing risperidone in daily practice; Interim results of a German postmarketing surveillance study. 6th Congress of Biological Psychiatry, Nice, France. 11. Lindstrom E, Erikkson B, Hellgren A, Von Knorring L, Eberhard G (1995) Efficacy and safety of risperidone in the long-term treatment of patients with schizophrenia. Clin Ther 17: 402 ± 17.
12. Moller HJ, Gagiano CA, Addington DE, Von Knorring L, Torrens-Plank JF, Gaussares C (1998) Long-term treatment of chronic schizophrenia with risperidone: an open label, multicenter study of 336 patients. Int J Clin Psychopharmacol 13: 99 ± 106. 13. Marder SM, Davis JM, Chouinard G (1997) The effects of risperidone on the five dimensions of schizophrenics derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 58: 538 ± 46. 14. Simpson GM, Lindenmayer JP (1997) Extrapyramidal symptoms in patients treated with risperidone. J Clin Psychopharmacol 17: 194 ± 201. 15. Barnes TRE, McPhillips MD (1998) Novel antipsychotics, extrapyramidal side effects and tardive dyskinesia. Int J Clin Psychopharmacol 13 (Suppl 1): 45 ± 57. 16. Brecher M (1996) Long-term safety of risperidone (Abstract P15-1). Eur Neuropsychopharmacol 6 (Suppl 3): 170. 17. Green MF, Marshall BD, Wirshing WC et al (1997) Does risperidone improve working memory in treatment-resistant schizophrenia?Am J Psychiatry 154: 799 ± 804. 18. Still DJ, Dorson PG, Crismon ML, Pousson C (1996) Effects of switching inpatients with treatment-resistant schizophrenia from clozapine to risperidone. Psychiatric Serier 17: 1382 ± 84. 19. Bondolfi G, Baumann P, Dufour H (1996) Treatment-resistant schizophrenia: clinical experience with new antipsychotics. Eur Neuropsychopharmacol 6 (Suppl 2): 21 ± 25. 20. Kasper S (1998) Risperidone and olanzapine: optimal dosing for efficacy and tolerability in patients with schizophrenia. Int Clin Psychopharmacol 13: 253 ± 62. 21. Huguelet P, Bonsack C, Stohler R, Bleuer S, BuÈnter M, Adrianssen I (2001) A Swiss naturalistic study comparing risperidone and olanzapine for treatment of schizophrenia (Abstract PO21-34). 7th World Congress of Biological Psychiatry, Berlin.
2002 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2002 Volume 6 Pages 193 ± 197
193
Efficacy and safety of long-term risperidone treatment LJ HOTUJAC AND M SÏAGUD Department of Psychiatry, University Hospital Center Rebro, Zagreb, Croatia
While efficacy in treatment of the acute phase of schizophrenia is well established for so-called atypical antipsychotics, more data regarding long-term treatment are needed. INTRODUCTION:
In a naturalistic, open-label study, 32 patients were included in order to investigate the efficacy and safety of risperidone over 3 years of treatment; 26 of them were treatment-resistant to the previously used antipsychotic drugs (except clozapine). METHOD:
Correspondence Address Professor Dr Ljubomir Hotujac, University Hospital Center, Zagreb, Department of Psychiatry, Kispatic eva 12, 10000 Zagreb, Croatia Tel: +385 1 24 21 843 Fax: +385 1 23 88 329 E-mail: [email protected]
Received 10 November 1999; revised 14 September 2001; accepted for publication 7 August 2002
At the end of the first year, 20 of these 26 patients showed at least partial improvement. At the end of the third year, 17 patients were still being treated with risperidone. While eight patients were lost to follow-up, six relapsed in spite of good compliance. All the adverse events which occurred during treatment were strictly dose-dependent and disappeared when the dose was lowered to 4 mg daily. RESULTS:
Within the limits of naturalistic studies, it can be concluded that risperidone seemed to be an effective and safe drug for long-term treatment in the majority of our patients. (Int J Psych Clin Pract 2002; 6: 193 ± 197) CONCLUSIONS:
Keywords schizophrenia risperidone
INTRODUCTION
S
chizophrenia is a typically life-long, chronic illness, often requiring life-long medication. Patients who are kept in otherwise stable remission may be seriously disabled by a range of side-effects of antipsychotics, namely extrapyramidal side-effects (EPS). For the conventional antipsychotics, there may be a very small difference, if any, between the antipsychotic dose and the dose that produces 1 EPS. After the introduction of the atypical antipsychotic risperidone, the incidence of those side-effects is eliminated or significantly decreased. At the same time, antipsychotic efficacy is not only retained but spread to a broader range of symptoms. Risperidone and other atypical antipsychotics are highly effective against negative symptoms, where conventional antipsychotics have only a little, if any, 2±5 efficacy. The two pivotal clinical trials of risperidone, the North America Trial6 ,7 and the Multinational Trial,8 proved its efficacy and low liability to cause extrapyramidal side-
tolerability
effects. However, they were not designed to show the efficacy of risperidone over a long period of time. Data regarding the long-term use of risperidone are relatively sparse.9 Therefore we decided to determine the acute and long-term efficacy and safety of risperidone in patients with schizophrenia and schizoaffective disorders.
SUBJECTS AND METHODS STUDY DESIGN This was an open-label, non-comparative and prospective study, designed to determine the efficacy and safety of a 3year course of risperidone treatment.
INCLUSION CRITERIA To be eligible, patients had to have a diagnosis based on DSM-IV criteria for schizophrenia or schizoaffective
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LJ Hotujac and M SÏ agud
disorder and a Positive and Negative Syndrome Scale (PANSS) total score of 60 or higher. No other primary Axis I diagnosis was permitted. All patients provided written informed consent. Patients needed to be at least 18 years old. Women of reproductive potential must have been using adequate contraceptive methods. Inpatient status was not mandatory. Patients showed no evidence of clinically significant Axis III disorder, which was confirmed by medical history, physical examination and normal haematological, biochemical and ECG parameters. After a screening assessment, a minimum washout of 3 days from oral antipsychotic agents or one cycle from a depot neuroleptic agent was required.
DOSING SCHEDULE The goal was to treat psychosis with risperidone monotherapy. Risperidone was given at an initial dose of 1 mg b.i.d. The dose was increased to 2 mg on the second day, and 3 mg b.i.d. on days 3 ± 7 of treatment. From day 8, the patients received 2 mg in the morning and 4 mg in the evening if their Clinical Global Impression score (CGI) was rated as improved. If the CGI was rated as unchanged or worsened, 4 mg of risperidone was given b.i.d. From day 14, the dosage could be further increased to 12 mg, and from day 21 to the maximum dosage of 16 mg, if no improvement on CGI was observed. From day 28 (week 4) to week 16 the dosage remained unchanged as much as possible. From week 16, the dosage could be gradually decreased to the maintenance dose, according to the judgement of the investigator. The use of benzodiazepines on a prn basis (up to 40 mg of diazepam or 2 mg of alprazolam daily) was allowed. The use of biperiden (2 ± 6 mg/day) if EPS emerged was also allowed, but also on a prn basis. The prophylactic use of anticholinergics was prohibited.
MEASUREMENT OF EFFICACY The efficacy of risperidone was measured with the Positive and Negative Syndrome Rating Scale for Schizophrenia (PANSS), which was performed at days 0 and 28, and at weeks 16, 28, 40 and 52 respectively, and thereafter every 3 months up to the end of month 36. The CGI score was recorded at days 0, 7, 14, 21, 28 and weeks 8, 12, 16, 20, 28, 40, 52 respectively, and thereafter every 3 months up to the end of month 36. CGI improvement was measured at each visit, the same as CGI, with the exception of day 0.
measured at days 0 and 28, and at weeks 8, 12, 16, 20, 28, 40 and 52, and every 3 months up to the end of month 36. Laboratory measurements (haematology, biochemistry, urinalysis and ECG) were performed at day 0, week 16 and whenever needed by the investigator. They were repeated at the end of the second and third year of risperidone treatment.
RESULTS Currently available are the results for 32 patients who were recruited in the time period from May 1996 to April 1998. Demographic characteristics of the study population are presented in Table 1. The patient population was heterogeneous regarding the diagnosis. The numbers of patients having different types of schizophrenia and schizoaffective disorder are presented in Table 2. Previous treatment is mentioned in Table 3. Table 1 Patients studied
Males Females
n
Mean age (years)
Mean duration of illness (years)
12 20
32.6 33.7
8.2 3.4
Table 2 Diagnoses of patients included in the study Diagnosis
No. of patients
Schizoaffective disorder Paranoid schizophrenia Disorganized schizophrenia Simple schizophrenia Catatonic schizophrenia
11 13 4 3 1
Table 3 Previous antipsychotic treatment
MEASUREMENT OF SAFETY
Treatment prior to entry
Extrapyramidal side-effects were estimated by using the Extrapyramidal Symptom Rating Scale (ESRS) at days 0 and 28, and at weeks 16, 28, 40, 52 and 104. All adverse events observed by the investigator or reported by the patient were recorded on a case report form. Vital signs (blood pressure and heart rate) were recorded at each visit. Weight was
Haloperidol Fluphenazine Fluphenazine depot Sulpiride None
No. of patients 9 11 2 4 6
Average dose, mg/day
Average duration of treatment, weeks
12.3 9.5 25.0 550
11.2 12.0 52.0 8.7
Efficacy and safety of long-term risperidone
Although resistance to antipsychotic agents was not mandatory, 26 out of 32 patients had not responded to their previous treatment. Four out of six patients who did not receive antipsychotics prior to this study had stopped taking drugs on their own initiative because of EPS.
EFFICACY The analysis of the 3-year risperidone treatment is available for 17 patients. During the first year of treatment, six patients dropped out because of protocol violation. While no worsening of psychopathology was observed in 25/32 patients during 12 months of risperidone treatment, during the second year of treatment four patients were withdrawn from the study because of psychotic relapse. Table 4 shows that significant improvement (420% reduction on the PANSS scale) was observed in 25/32 patients after one year of treatment. In the second year of treatment, the observed improvement was maintained in 19/25 patients. Four patients had a psychotic relapse in spite of regular risperidone intake, as confirmed by family members. While their psychotic symptoms did not improve after increasing the dose of risperidone up to 12 mg daily, they required treatment with other antipsychotics. While in the third year of risperidone treatment one patient relapsed, 17 out of 19 patients remained well. Negative subscale score on the PANSS also showed a gradual and sustained improvement during 36 months of risperidone treatment, and this tendency was observed even in the second and third year of treatment, for those patients who did not relapse. Table 5 presents a pattern of change of negative symptoms.
RISPERIDONE DOSE According to the protocol, each patient received 6 mg of risperidone daily at the end of the first week of treatment. The highest average daily dose of risperidone was given at the end of the third week (7.28 mg of risperidone daily); it started to be lowered gradually after week 16, and was found to be 3.95 mg at week 52. The average risperidone maintenance dose by the end of year 2 of treatment was 3.5 mg daily and by the end of year 3 was as low as 2.95 mg/day.
SAFETY During the 3-year study period, there were no discontinuations due to side-effects. Furthermore, there were no serious adverse events. The most common side-effects were EPS, which occurred in 23/32 (59%) of patients, requiring anticholinergic medication. All EPS were strictly dose-dependent and disappeared when the dose was reduced to 4 mg daily. All adverse events registered during one-year risperidone treatment are presented in Table 6.
195
Table 4 Clinical course during 3 years of risperidone treatment
Year of treatment
No of patients with 420% No. of reduction in patients PANSS who relapsed
First Second Third
25/32 19/25 17/19
1/32 4/25 1/19
Patients lost to follow-up 6/32 2/25 1/19
Table 5 Change in negative PANSS score during 36 months of risperidone treatment Length of treatment
No. of patients estimated
Average PANNS negative
Baseline 4 weeks 16 weeks 52 weeks 2 years 3 years
32 30 27 25 19 17
28 23 21 19 16 15
Table 6 Adverse events in patients during 1-year risperidone treatment Adverse event Parkinsonism Akathisia Acute dystonia Weight gain Amenorrhoea Sexual dysfunction Galactorrhoea Increased salivation Nocturnal enuresis Headache Increased duration of sleep
No. of patients 9 5 3 4 6 5 3 1 1 1 1
There were no clinically significant changes in blood pressure and heart rate. There were no clinically significant laboratory (haematological and biochemical tests and urinalysis) or ECG abnormalities.
DISCUSSION In our study, mean PANSS negative subscale scores showed a tendency towards slow but continuous improvement over the 3 years. A long-term open-label study confirmed that the efficacy of risperidone against negative symptoms is not
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limited to the first 8 weeks of treatment.* This observation further suggests that the effect of risperidone against negative symptoms may develop more slowly than its effect on positive symptoms. Postmarking surveillance studies further confirmed the finding of the afore-mentioned very 10 gradual improvement. Significant and substantial reduction of negative symptoms during 12 months has also been found in other open-label trials.1 1 ,1 2 The question which arose from the latter studies was how far can further reduction in negative symptoms be expected in patients treated for more than one year. Our results suggest that in patients who did not have a relapse of their positive symptoms, a very gradual, but continuous, reduction in negative symptoms could be expected. After an acute-phase improvement, the daily dose of risperidone was gradually decreased from an average 7.62 mg/day at week 3 and 7.25 mg/day at week 16, to the lowest 2.95 mg/day. In spite of the dose decrease, negative symptoms continued to improve. This finding agrees with the results of factor analysis of PANSS in two double-blind trials conducted in North America, where risperidone at 2 mg/day was significantly more effective 13 than placebo in reducing negative symptoms. The most commonly reported side-effects were EPS, which were registered in 59% of the patients. They were firmly doserelated and disappeared when the dosage was reduced to 4 mg daily. This is completely in accordance with findings in other studies, where the frequency of EPS in patients receiving 4 ± 6 mg daily was similar to that in placebotreated patients.7 ,1 4 ,1 5 During safety assessment, we registered three patients who had a significant weight gain (14, 20 and 14 kg, respectively, during 4 months of 6 mg risperidone treatment). A very interesting and surprising finding is that none of those four patients expressed any of the EPS, while the 12 patients who expressed some form of EPS had no weight gain at all. While weight gain has been found to 9 ,1 2 increase slightly during risperidone treatment, we are not aware of similar findings in other risperidone studies. No case of tardive dyskinesia was reported during the trial. The incidence of tardive dyskinesia in patients treated with relatively high doses of risperidone (7.6 ± 9.4 mg/day) was estimated to be only 0.3% in 503 patients who had been treated with risperidone for at least one year.1 6 This is of particular importance, in considering the disturbing influence of those side-effects on patients in long-term treatment. No clinically relevant ECG changes, or any consistent changes in vital signs, have been detected in short- and 6 ± 8 ,1 2 ,1 6 long-term risperidone studies. In the current study, 20/26 treatment-resistant patients improved, at least partially, on risperidone during one year of treatment, in terms of a decrease in PANSS scale scores. Risperidone proved to be more effective than haloperidol in 17 treatment-resistant schizophrenia. Future studies will *Data on file, Janssen-Cilag, Titusville, NJ, USA
determine whether risperidone is effective in those hardto-treat patients. However, risperidone was found not to be effective in patients who were switched from clozapine to risper18 idone. While in the current study no patient had previously been treated with clozapine, they would be given clozapine if risperidone was not available to them. At least, it can be concluded that it is worthwhile starting a trial of risperidone before starting clozapine. On the other hand, risperidone has been found to be just as effective as 19 clozapine in treatment-resistant patients. Notwithstanding all the shortcomings of such an uncontrolled naturalistic trial, we want to point out its advantages. Unlike double-blind studies using highly sophisticated technology, the current study can apply descriptive psychiatry that has almost been forgotten. Herewith we provide two case reports. Case 1 A 35-year-old woman, an academic painter, had been treated with haloperidol a few years prior to this study. She had predominantly depressed and negative symptoms, with occasional outbursts of anger. She hit her mother a couple of times. She did not leave her house and was very difficult to live with. Three months after the institution of risperidone she started to show interest in the outside world and started to paint again. She came to her mother and said ``Forgive me for what I have done to you, that was my illness. Now I am well again.’’ Case 2 A 24-year-old woman, with a diagnosis of disorganized schizophrenia, had been treated with depot fluphenazine for the last 2 years. She continued to have disorganized speech and behaviour. In addition, she was seriously disabled by tardive dyskinesia, involving face, neck and trunk. Four months after the institution of risperidone, dyskinetic movements began to decrease, and a year later completely disappeared. The patient managed to complete her studies, and started to work. She is virtually free of dyskinetic, as well as of schizophrenic, symptoms. While clinical studies suggest that 4 ± 6 mg/day of risperidone is an appropriate dose range for patients with chronic schizophrenia,4 our patients remained stable on an average of 3.95 mg/day at the end of year 1, 3.5 mg/day at the end of year 2 and 2.95 mg/day at the end of year 3 of risperidone treatment. Our results are in agreement with a recently published naturalistic study, reporting an average daily dose of 3.7 mg of risperidone daily in hospitalized patients.2 1 However, five of our patients had a relapse of positive psychotic symptoms during the second and third year, in spite of risperidone treatment on a regular basis. While a slightly lower-than-average maintenance dose can contribute to the re-occurrence of psychotic symptoms, 3 mg/day of risperidone has been associated with 64% of striatal D2 occupancy rate.2 0 This risperidone dosage
Efficacy and safety of long-term risperidone
appears to be sufficient for antipsychotic efficacy, but insufficient for the emergence of EPS, which requires 80%, and prolactin elevation, which requires 72% of D2 receptor occupancy, respectively. Determining the optimal minimal dosage for maintenance treatment in schizophrenia continues to be a challenge for the physician.
CONCLUSION The benefits of risperidone that have been demonstrated in clinical practice are impressive. Our small study shows that these benefits can also be achieved in clinical practice where patients cannot be carefully selected. Notwithstanding all the limits of this open, naturalistic, descriptive and small-sample study of a mixed schizophrenic patient population, it can be concluded that our findings are consistent with those of other risperidone studies, regarding its ability to cause significant and substantial reduction of positive and negative symptoms, and its favourable side-effects. Whether this tendency towards a gradual improvement in negative symptoms will
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continue during further treatment, helping the patients to deal with their devastating illness, still remains to be determined. Risperidone also seems to be effective in at least some of the patients resistant to typical antipsychotics.
KEY POINTS . Gradual and sustained improvement of positive and negative symptoms of schizophrenia during three years of risperidone treatment in the majority of patients . At least partial improvement of patients resistant to typical antipsychotics . Dose-dependent EPS during risperidone treatment . No serious adverse events during 3 years of risperidone treatment . None of the three patients whose weight increased significantly, experienced EPS on high initial dose of risperidone
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