Somrak Choovanichvong, M.D.*
Wanchai Kitaroonchai, M.D.*
Chuthamanee Suthisisang, Ph.D.**
Suttipong Chinkrua, B.Sc. in Pharm.(Clinical Pharmacy)***
Santichai Chamchitchun, M.D. *
Pichitpong Ariyavong, M.D.*

Objective To evaluate the efficacy and safety of a atypical antipsychotic drug, risperidone, in comparison to a typical antipsychotic drug, haloperidol, in first-episode schizophrenic Thai patients.

Method Single blind, prospective 24-week clinical study was performed on 22 patients from Srithunya Hospital. Patients were randomly assigned to the treatment with either 2-6 mg of risperidone (N=11) or 10-40 mg of haloperidol (N=11) daily. Outcome measurements and efficacy were assessed by the Positive and Negative Syndrome Scale (PANSS) and side effects especially extrapyramidal symptoms (EPS) were evaluated by the Extrapyramidal Symptom Rating Scale (ESRS).

Results There were significant reduction in PANSS total scores, positive, negative, and general psychopathology scores in both groups when compared to the baseline (p<0.05). However, there was no statistical difference between risperidone and haloperidol. In defining a responder as a patient with at least a 20% reduction in PANSS total scores from base line. Risperidone-treated group had higher response rate than haloperidol-treated group at the end of week8 (3.5? 1.8 mg/day; 81.8% versus 12.6? 10.3 mg/day; 54.5%, p=0.15). The depression subscale score in risperidone-treated group had much more decrease than in haloperidol-treated group.

In considering the side effects during the 24-week follow-up periods, risperidone-treated patients experienced a higher incidence of drowsiness and tremor (p>0.05) whereas haloperidol-treated patients had a higher incidence of acute dystonia (p<0.05). Weight gain, a side effect limitation of both risperidone and haloperidol, may lead to loss of self-esteem in patients and result in noncompliance with the medication. Assessment of pulse rate, blood pressure, blood chemistry, complete blood count and physical examination revealed no clinically differences from baseline in both groups throughout the study.

Conclusions The results suggest that risperidone was at least as effective as haloperidol in the treatment of first-episode schizophrenia and risperidone had more advantage in having less incidence of acute dystonia. However the number of the patients is too small to have the statistical power to show the differences in terms of efficacy. Thus further study in higher numbers of subject needs to be confirmed.

J Psychiatr Assoc Thailand 2000; 45(2):165-177.

Key words: first-episode, schizophrenia, schizophreniform disorder, risperidone, haloperidol

* Psychiatric Unit, Srithanya Hospital, Nonthaburi 11000.

** Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400.

*** Faculty of Graduate Studies, Mahidol University, Bangkok 10400.

วิธีการศึกษา เป็นการศึกษาแบบไปข้างหน้าเป็นระยะเวลา 24 สัปดาห์ โดยการสุ่มตัวอย่างผู้ป่วยโรคจิตเภทครั้งแรกจำนวน 22 คนจากโรงพยาบาลศรีธัญญา เพื่อรักษาด้วยยาริสเพอริโดนในขนาด 2-6 มิลลิกรัมต่อวัน หรือยาฮาโลเพอริดอลในขนาด 10-40 มิลลิกรัมต่อวัน วัดประสิทธิผลการรักษาโดยมาตรวัด Positive and Negative Syndrome Scale (PANSS) และวัดผลข้างเคียงโดยเฉพาะผลข้างเคียงทางระบบเอกซ์ตร้าปิรามิดอล (EPS) โดยมาตรวัด Extrapyramidal Symptom Rating Scale (ESRS)

ผลการศึกษา ยาริสเพอริโดนและยาฮาโลเพอริดอล มีประสิทธิภาพในการลดค่าคะแนน PANSS ของผู้ป่วย เมื่อเปรียบเทียบกับค่าคะแนนเริ่มต้นอย่างมีนัยสำคัญทางสถิติ (p<0.05) อัตราการตอบสนองต่อการรักษาที่ 8 สัปดาห์ ในกลุ่มผู้ป่วยที่ได้รับยาริสเพอริโดนขนาด 3.5? 1.8 มิลลิกรัมต่อวัน มีอัตราการตอบสนองต่อยาร้อยละ 81.8 ซึ่งมากกว่าในกลุ่มผู้ป่วยที่ได้รับยาฮาโลเพอริดอลขนาด 12.6? 10.3 มิลลิกรัมต่อวัน(ร้อยละ 54.5, p=0.15) และค่าคะแนนใน depression subscale ในกลุ่มผู้ป่วยที่ได้รับยาริสเพอริโดน ลดลงมากกว่ากลุ่มผู้ป่วยที่ได้รับยาฮาโลเพอริดอล

ในระยะ 24 สัปดาห์ของการติดตามผลการรักษา กลุ่มผู้ป่วยที่ได้รับยาริสเพอริโดนพบผลข้างเคียง drowsiness และ tremor บ่อยกว่า แต่ไม่มีนัยสำคัญทางสถิติ (p>0.05) ในขณะที่กลุ่มผู้ป่วยที่ได้รับยาฮาโลเพอริดอลพบผลข้างเคียง acute dystonia บ่อยกว่า อย่างมีนัยสำคัญทางสถิติ (p<0.05) น้ำหนักตัวที่เพิ่มขึ้นในผู้ป่วยทั้ง 2 กลุ่ม เป็นสาเหตุหนึ่งที่ทำให้ผู้ป่วยไม่ต้องการรับยาต่อเนื่องในระหว่างการติดตามผลการรักษา เมื่อทำการตรวจร่างกาย วัดชีพจร ความดันโลหิต และผลการตรวจทางห้องปฏิบัติการแล้ว ไม่พบความผิดปกติอื่นๆ ในผู้ป่วยทั้ง 2 กลุ่ม ตลอดระยะเวลาการรักษา

สรุป ในผู้ป่วยโรคจิตเภทครั้งแรก ยาริสเพอริโดนจะมีประสิทธิผลในการรักษาอย่างน้อยเทียบเท่ากับยาฮาโลเพอริดอล แต่การรักษาด้วยริสเพอริโดนจะเกิดอุบัติการณ์ของผลข้างเคียงชนิด acute dystonia ต่ำกว่าการรักษาด้วยฮาโลเพอริดอล แต่อย่างไรก็ตาม จำนวนผู้ป่วยในการศึกษาครั้งนี้มีน้อย จึงไม่สามารถแสดงค่าความแตกต่างของประสิทธิผลอย่างมีนัยสำคัญทางสถิติ จึงเป็นที่น่าสนใจในการทำการศึกษาในกลุ่มผู้ป่วยจำนวนมากขึ้นต่อไป

วารสารสมาคมจิตแพทย์แห่งประเทศไทย 2543; 45(2):165-177.

คำสำคัญ โรคจิตเภท ริสเพอริโดน ฮาโลเพอริดอล

** ภาควิชาเภสัชวิทยา คณะเภสัชศาสตร์ มหาวิทยาลัยมหิดล ถนนศรีอยุธยา กรุงเทพฯ 10400

*** บัณฑิตวิทยาลัย มหาวิทยาลัยมหิดล ถนนศรีอยุธยา กรุงเทพฯ 10400

Introduction

A first episode of psychosis is a traumatic experience for patients and families. The treatment response of first-episode patients is different from that of later stage of illness. These patients had been observed to have better therapeutic response to antipsychotic drugs, to require lower dose of medications, and to be more sensitive to develop side effects.^1-2 The first experience of antipsychotic drugs during the first episode of schizophrenia always have effects on a patient’s attitude toward medication and the use of drug that produces extrapyramidal symptoms (EPS) is associated with poor compliance.³ By using the lowest dose of antipsychotic medication side effects will be minimized leading to improve compliance, decrease relapse risk, a need for readmission, and subsequently will reduce the overall cost of health care. Initial pharmacological treatment may include high-potency typical antipsychotic agents, such as haloperidol 6 to 10 mg/day, or the available atypical antipsychotic medication, such as olanzapine 10 to 20 mg/day, or risperidone 4 to 8 mg/day.^4-5 The studies of effective treatment in first-episode schizophrenia have been focused on the comparative study of typical and atypical antipsychotic drugs (i.e. clozapine, olanzapine, or risperidone with haloperidol or chlorpromazine).^6-11 These studies suggested that atypical antipsychotic drugs had at least equal or better efficacy and more safety in treating first-episode schizophrenic patients.

In Thailand, there were a few studies reporting the efficacy and safety of atypical antipsychotic drugs, risperidone and clozapine, in chronic schizophrenic patients.^12-15 However, there are no available data on atypical antipsychotic drugs treatment in first-episode schizophrenia. Risperidone, already launched in Thailand, was the first atypical agent with a risk benefit profile; this encouraged it to be used as first-line treatment. Thus, it is interesting to evaluate the clinical efficacy and the side effect profile of this drug in first-episode schizophrenia and schizophreniform disorder.

The data for these analyses were taken from the 24-week, single blind parallel study comparing risperidone and haloperidol in first-episode schizophrenic Thai patients. The protocol was approved by the review board of Srithunya Hospital.

First-episode neuroleptic-na๏ve (not more than 2 years) and/or neuroleptic-treated(not more than 4 weeks) schizophrenic and schizophreniform disorder patients (based on the DSM-IV criteria¹⁶) were recruited from Srithunya Hospital. Other inclusion criteria were: (i) age between 15-40 years and (ii) patient relatives, corporation by signing the consent form in front of a witness.

Exclusion criteria comprised: (i) patients who were diagnosed as having organic or neurologic disease, or psychoactive substance abuse or dependence except for alcohol dependence/abuse and tobacco. (each patient was screened for amphetamine usage by using methamphetamine test kit); (ii) patients with severe GI, liver, renal, cardiovascular disease, history of seizure disorder, clinically abnormal laboratory values of hematology and/or biochemistry, (iii) patients with child-bearing age who did not have adequate contraceptive control, and (iv) pregnant or breast-feeding patients.

After recruitment of subjects into the study according to the selection criteria, they were either admitted to the hospital or treated as outpatient depending on severity of symptoms. If subjects had previously received antipsychotic drugs, these drugs were withdrawn one week before the baseline evaluations. The following parameters were evaluated as baseline data: the Positive and Negative Syndrome Scale Scores (PANSS)¹⁷, the Extrapyramidal Symptom Rating Scale (ESRS)¹⁴, and physical and laboratory examinations. Simple random sampling was used and each patient was randomly assigned to receive either risperidone or haloperidol. This consisted of an initial dose adjustment period of 4 weeks. The starting dose of risperidone was 2 mg/day and haloperidol was 10 mg/day. Risperidone was titrated during the first 4-week as follow: 2 mg/day in the 1^st week, 4 mg/day in the 2^nd week, and 6 mg/day in the 3^rd week. Haloperidol could be adjusted to the maximum dose of 40 mg/day.

The dose of both medications could be adjusted by each psychiatrist in order to gain maximum response. The definition of a responder is a patient with at least 20% reduction in PANSS total score from baseline. If patients were clinically non-responsive after 4 weeks of treatment (as determined by lack of clinical improvement/or PANSS total score does not reach 20% reduction from baseline) and/or there were serious side effects, such subjects might be treated according to one of the management alternatives: 1) change the medication if they had poor prognosis or, 2) increase the dose of medication (maximum daily dose of 40 mg and 6 mg of haloperidol and risperidone, respectively) and evaluate the efficacy again after the additional 4 weeks. If the test medications were still ineffective, these nonresponsive subjects would be excluded and then treated with either new medications or therapeutic medication depending on each psychiatrist judgment.

Clinical efficacy of risperidone and haloperidol in each patient was assessed every 2 weeks for the first 4-week, and then every 4 weeks up to 24 weeks by using the PANSS scores and PANSS cluster scores.

Safety profile especially extrapyramidal symptoms were assessed by ESRS score (bradykinesia, rigidity, gait and posture, mask face, tremor, sialorrhea, postural stability, akathisia, dystonia, and dyskinetic movement) every week for the first 4-week peroid and then at each visit. Adverse event experiences were also assessed by spontaneous reports from the patients and/or caregivers. Blood pressure, heart rate, and body weight were measured at each visit. Hematology and blood biochemistry were analysed at baseline and the end of treatment. During the study period, all concomitant medications (drugs, dose, and duration) needed to be recorded. Drugs that were allowed to be used for agitation, akathisia, and EPS were:1) orally lorazepam, flunitrazepam, and temazepam, 2) clonazepam and diazepam injection, 3) trihexyphenidyl tablet, 4) propranolol tablet, and 5) hyoscine injection.

Analysis of efficacy and safety were conducted according to the intend-to-treat analysis method. Both observed case and last observation carried forward, or end point, analyses were performed.¹⁸ The end point analysis carried forward the last observation on each patient premature withdrawing from the study. The change from baseline to end point provide a more accurate measure of efficacy than an analysis of mean changes in trial completers, that omitting patients who premature discontinue the study.

Statistical analysis: 1) Chi-square test was used to analyse the distribution between the two treatment groups (gender, type of patients, and type of psychosis), 2) paired t-test was used to compare age, the change in mean PANSS score and PANSS cluster score within group, 3) unpaired t-test was used to compare age, the change in mean PANSS score and PANSS cluster score between the two treatment group, and 4) Fisher’s exact test was used to analyse treatment effects for categorical of safety measurement (adverse events, number of subjects requiring medications for EPS) and response rate. All p-value were significant at level of 0.05. Statistical analysis software, SPSS, was used for unpaired t-test and paired t-test analysis.

Four psychiatrists who participated in this trial were trained for rating technique of the PANSS before starting the study by viewing videotape of patients and/or interviewing patients. A comparison of four psychiatrists’ rating were accepted if scores of each items differed not more than one point and total score deviated not more than 20%.

During 7-month recruitment period, 43 patients conformed to the inclusion criteria. Of these, 33 patients decided to participate in the study by the agreement of their caregivers. Of the 33 patients, 11 patients were lost follow-up during the study period due to various factors: 1) the symptoms of some patients were improved after receiving antipsychotic medication for a few weeks which made their relatives to believe that the subjects had a complete remission from psychotic symptoms and so they terminated the treatment, 2) after discharging from the hospital, few subjects had a problem with drug abuse, which made them worse in regard to their symptoms and so it was necessary to exclude them from the study, 3) when ADRs, especially acute dystonia are experienced by the subjects, these sometimes left them with bad impression of antipsychotic drug, and such patients did not want to continue the medication and visit the psychiatrist again, 4) as it usually takes 2 to 4 weeks to see the antipsychotic effects, some caregivers did not satisfy with the test medication and requested to receive new therapy, 5) some families were superstitious for they thought that psychotic symptoms are caused by evil spirits, and therefore, they tried to find magical treatment such as holy water and stopped antipsychotic treatment for the subjects.

In total, 22 patients were eligible in this study. The demographic data of patients in each group were shown in table 1. No statistically significant differences were found between subjects in the two treatment groups with regard to demographic characteristics.

The average starting dose were 2 mg/day of risperidone and 7.2? 2.7 mg/day of haloperidol. Response rate of the two treatment-groups at week 4 and 8 were shown in table 2. No statistically significant differences between the two treatment groups in consideration of the number of subjects responding to the test medications (Fisher’s exact test, p>0.05). During the 8-week study period, the average dose of risperidone was 3.5? 1.8 mg/day and the average dose of haloperidol was 12.6? 10.3 mg/day.

Table 1 Demographic data of subjects in risperidone and

haloperidol-treated groups

^a Unpaired t-test, p>0.05

^b Chi-square test, p>0.05

Table 2 Response rate of risperidone and haloperidol-

treated group during the first 8 weeks

^a Fisher’s exact test, p>0.05

Efficacy

The average PANSS scores and percentage reduction in PANSS score during 24-week period were shown in table 3 and 4 and were illustrated in figure 1 to 4. No statistically significant difference was found between the two treatment groups with regard to PANSS scores and the mean percentage reduction in PANSS scores (unpaired t-test, p>0.05). PANSS cluster scores (anergia, thought disturbance, activation, paranoid/belligerence, and depression) were shown in table 5. Risperidone and haloperidol significantly decreased scores on anergia, thought disturbance and paranoid/belligerence by week 24 (paired t-test, p<0.05). Nevertheless, these two medications did not decrease scores on activation and depression (paired t-test, p>0.05).

Table 3 Mean PANSS score (SD) during the 24-week treatment period

* Paired t-test, p<0.05 compared with baseline

** Unpaired t-test, p<0.05

Table 4 Mean percentage reduction in PANSS score (SD) during the 24-week treatment period

Table 5 Mean PANSS cluster scores (SD) during 24-week treatment period

* Paired t-test, p<0.05 compared with baseline

Figure1 Mean PANSS Score                                          Figure2 Mean Positive Score

Figure3 Mean Negative Score                                       Figure4 Mean General psychopathology Score

The medications used for EPS and the number of subjects requiring these medications were shown in table 6.

Table 6 No. of subjects requiring concomitant medications for EPS/agitation

^a Fisher’s exact test, p<0.05

Table 7 Adverse events of risperidone and haloperidol

Adverse events that occurred in both groups during 24-week period were shown in table 7. In considering body weight, the average increasing was 3.9? 2.7 kg and 5.4? 2.6 kg in risperidone and haloperidol-treated subjects, respectively. Assessment of pulse rate, blood pressure, blood chemistry (BUN, Cr., alkaline phosphatase, AST, ALT), Complete Blood Count (CBC) and physical examination revealed no clinically differences from baseline in both groups.

In haloperidol-treated subjects, the major problems were rigidity, dystonia, and sialorrhea especially acute dystonia that was the main reason that made the subjects discontinued the medication.

The calculated sample size of subjects in this study was 72 (36 subjects in each group). However, after 7 months of patients’ recruitment, there were only 43 patients who met the inclusion criteria. The factors, which might contribute to the small number of patients conforming to the inclusion criteria were: 1) the first-episode schizophrenic patients at Srithunya Hospital usually had problems with psychoactive substance abuse especially amphetamine; 2) some patients lived too far to go on with the follow-up period; and 3) some neuroleptic-na๏ve patients had a psychotic episode for more than 2 years. Of these, 33 patients agreed to take part in the study. The main reason of denial was that their families thought of the clinical study as an experiment of new drug treatment that may cause serious side effects (even after thorough explanation from the physician). At the end of the study, there were only 22 evaluable cases. Concerning lost follow-up patients, one should be consider providing education on schizophrenia especially for first-episode schizophrenic patients. It is generally accepted that these patients have better therapeutic response than chronic schizophrenic patients and 10 to 30% of the first-episode patients will not have recurrence if they receive adequate and long term antipsychotic drug treatment. Therefore, giving education to such a population continuously may eventually reduce the likelihood of noncompliance and discontinuation of antipsychotic therapy. Understanding causes of schizophrenia is an important factor for caregivers and patients’ families because if they realize that schizophrenia is not associated with superstitions, then they will not seek for magical treatments. Ongoing education such as printed information on this disorder and its treatments has an important role in the care of patient with schizophrenia. It is also important to emphasize to the patients and caregivers that long-term maintenance therapy is very crucial since it will reduce the relapse rate in these patients.

The hypothesis of the present study was proposed that risperidone would demonstrate an efficacy and safety profile superior to that of haloperidol in the treatment of first-episode schizophrenia and schizophreniform disorder. However, our study indicated that risperidone was as effective as haloperidol, similar to the result of other studies.^6-7 The average daily dose of risperidone during the first 8-week in our study was 3.5? 1.8 mg, same range as the dose of risperidone used in other clinical trials.^6-7,19-20 This dose range produced the best antipsychotic effects with minimal EPS. In haloperidol-treated subjects, the mean starting dose was about 7 mg/day, higher than the suggested dose by Kapur²¹ and Schooler²², that low dose of haloperidol (2-4 mg/day) can be used with considerable effectiveness in first-episode schizophrenic patients. The average daily dose of haloperidol was 12.6? 10.3 mg, which might cause more side effect, was somewhat higher than the recommended dose of 6-10mg/day.⁴

The number of subjects responded to the test medications is also an important indicator in evaluating the efficacy of antipsychotic medications. Risperidone-treated subjects had higher response rate than haloperidol-treated subjects at the end of week 8 (81.8% vs. 54.5%). This figure might be changed if the nonresponsive subjects in haloperidol group continued the medication after the 4-week and 8-week evaluations, because the dose of haloperidol would be increased in order to gain the maximum effects for those subjects. Nevertheless, patients usually could not tolerate the side effects of haloperidol such as acute dystonia and rigidity.

The efficacy of risperidone and haloperidol in this study were assessed based on PANSS scores and PANSS cluster scores. The significant improvement was observed in all PANSS scores by week-4 in both treatment groups and continued over the 24 weeks follow-up period. There were no significant differences between the two treatment groups in the mean percentage reduction in each scale of the PANSS scores. In considering the negative scores, haloperidol-treated group did better than risperidone-treated group (see table 4). The reason for this result might be due to the greater severity in the baseline negative symptoms of haloperidol-treated subjects than that of risperidone treated-subjects. The subjects responded well to haloperidol and their negative symptoms were reduced to normal baseline, negative score of haloperidol-treated subjects had mean percentage reduction greater than risperidone-treated subjects. This effect might be terminated if the number of subjects in the study conformed to the calculated sample size about 36 subjects in each group.

Regarding the efficacy of drugs on five cluster scores (anergia, thought disturbance, activation, paranoid/belligerence, and depression), table 5 showed that risperidone did better than haloperidol in decreasing depression score. However, this reduction was not significantly different. The result suggested that risperidone might be effective in first–episode schizophrenic patients with depression. ²³

Objective assessment of EPS with the ESRS is the way to detect the baseline movement disorders and side effects occurred to the subjects during treatment with the test medications. In this study, risperidone-treated subjects had lower incidence of acute dystonia, rigidity, and sialorrhea, than haloperidol-treated subject did. This result can be explained based on the serotonin and dopamine antagonist property of risperidone.

In risperidone-treated group, one subject developed akathisia and rigidity at the dose of 6 mg/day. In the study by Kapola et al.¹⁹, risperidone at the dose higher than 4 mg/day could induce EPS in first-episode schizophrenic patients and this effect readily diminished after dose reduction. The other serious side effect for male patients was erectile dysfunction and this was a non-compliant factor with risperidone. In the present study, drowsiness was also the problem in risperidone-treated patients who had to work and/or study. Some subjects tolerated this effect after a couple of weeks. Regarding this effect, the physician prescribed risperidone to patients at bedtime and/or addition time after dinner.

In haloperidol-treated subjects, the major problems were rigidity, dystonia, and sialorrhea especially acute dystonia that usually occurred within the first week of dosage adjustment. With typical antipsychotic drugs, EPS occur in the same dose range of therapeutic dose and making it difficult to gain clinical benefits without side effects.²⁴ Subjects in both treatment groups experienced weight gain. The study showed that haloperidol-treated subjects had higher average weight gain than that of risperidone-treated subjects (5.4? 2.6kg VS 3.9? 2.7 kg). Weight gain is a common problem with all antipsychotic drugs, which can have an adverse psychological impact, contributing to loss of self-esteem, which may then result in noncompliance with the medication. Baseline weight should be established before initiating medication. Patients should be told that the treatment may stimulate appetite. Dietary advice is important in counseling and patients should be warned to avoid high calorie drink and foods, and advised to exercise regularly.

This study indicated that risperidone was shown to be as effective as haloperidol in the treatment of first-episode schizophrenic patients. In addition, risperidone was associated with a significantly lower incidence of acute dystonia when compared with haloperidol. However, risperidone had akathisia, irregular menstrual cycle, and erectile dysfunction side effects, which were main problems for patients’ noncompliance.

It is also confirmed that compliance with antipsychotic medications is diminished by the occurrence of EPS. Our study has shown that most subjects who stopped the treatment did so because of EPS. Given that many first-episode patients would require continuous and possibly lifelong medication to control psychotic symptoms, One should use compounds that are less likely to induce EPS.

This study was supported by a grant from Janssen-Cilag Ltd. (Thailand).

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