Risperidone in treatment-refractory schizophrenia.

OBJECTIVE: The purpose of this study was to evaluate the clinical safety and efficacy of risperidone compared to haloperidol in patients with treatment-refractory schizophrenia. METHOD: Sixty-seven medication-unresponsive subjects were randomly assigned to treatment with risperidone (N = 34) or haloperidol (N = 33). After a 3-7 day-placebo washout period, there was a 4-week, double-blind, fixed-dose comparison trial that was followed by a 4-week, flexible-dose phase. Measures of clinical change were quantified by standard psychopathologic and neuromotor instruments. RESULTS: Risperidone demonstrated clinical efficacy superior to that of haloperidol on the total Brief Psychiatric Rating Scale (BPRS) after the first 4 weeks of treatment. Risperidone did not show any advantage over haloperidol after an additional 4 weeks. Overall improvement on the BPRS at 4 weeks was significantly better for the risperidone group (24%) than for the haloperidol group (11%). Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks (20% versus 63%); they also had significantly les observable akathisia (24% versus 53%) and significantly less severe tardive dyskinesia. Baseline characteristics that correlated significantly with risperidone response were positive symptoms, conceptual disorganization, akathisia, and tardive dyskinesia. CONCLUSIONS: Risperidone was better tolerated and more effective in a subset of patients with treatment-refractory schizophrenia. Positive psychotic symptoms and extrapyramidal side effects at baseline appear to be powerful predictors of subsequent response to risperidone.     

Clinical profile of an atypical antipsychotic: risperidone

Stimulated by Dawkins and colleagues' (1999) and Remington and Kapur's (2000) calls to develop clinical profiles of the new atypical antipsychotic drugs and by Mattes's critiques (1997, 1998), we performed two sets of analyses for risperidone. First, we reanalyzed data from the North American risperidone trial: risperidone was superior to haloperidol to an equal degree in patients with and without the deficit syndrome, in patients with paranoid and nonparanoid schizophrenia, in treatment-resistant and treatment-responsive patients (patients hospitalized for longer and shorter periods), and in patients with or without weight gain. Moreover, risperidone was more effective than haloperidol on symptoms nonresponsive and responsive to haloperidol; its effects on negative symptoms were independent of its effects on extrapyramidal symptoms; and it was effective in treating depression in schizophrenia. Second, we performed a meta-analysis of 18 controlled risperidone trials: risperidone was consistently more effective than conventional antipsychotics in treating positive and negative symptoms.     

Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia.

BACKGROUND: Atypical antipsychotics, such as risperidone, have been shown to be more effective for the treatment of the symptoms of schizophrenia and have a greater beneficial effect on neurocognition compared to the conventional antipsychotics. The present study used [(15)O]H(2)O positron emission tomography imaging of regional cerebral blood flow to examine and compare the effects of haloperidol and risperidone on brain function. METHODS: Thirty-two subjects with schizophrenia participated in the study. Each subject was scanned in a medication-free state, and after being on a stable clinically assigned dose of either risperidone or haloperidol for 3 weeks. The off-medication scan was subtracted from the on-medication scan, using a within-subjects design. A randomization analysis was used to determine differences between the effects of haloperidol and risperidone on regional cerebral blood flow. RESULTS: Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol. CONCLUSIONS: The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.     

Risperidone versus haloperidol in the treatment of chronic schizophrenic inpatients: a multicentre double-blind comparative study.

Forty-four chronic schizophrenic inpatients participated in this multicentre 12-week parallel-group double-blind trial. After a run-in period of 2 weeks and a single-blind placebo wash-out of 1 week, they were randomly assigned to treatment with either the serotonin2 and dopamine-D2 antagonist risperidone or haloperidol. Two patients were excluded from the efficacy analysis. Five patients dropped out in the haloperidol group and 1 in the risperidone group. At the end of the trial, the mean daily dose was 12 mg for risperidone and 10 mg for haloperidol. The risperidone group showed greater improvement on the Positive and Negative Syndrome Scale for Schizophrenia, the Schedule for Affective Disorders and Schizophrenia-change version, and the Nurses' Observation Scale for Inpatient Evaluation. The improvement of negative symptoms was more pronounced in the risperidone group until week 8 of double-blind treatment. The consumption of antiparkinsonian medication was 10 times lower with risperidone. Both drugs were well tolerated and the laboratory, endocrinological and cardiovascular safety parameters were comparable. This study suggests that risperidone is comparable to haloperidol as an antipsychotic, but that it has a safer EPS profile.     

利培酮口服液治疗老年期精神分裂症临床观察

目的:研究利培酮口服液治疗老年期精神分裂症的疗效和不良反应.方法:将51例老年期精神分裂症住院患者随机分为两组,分别给予利培酮口服液和氟哌啶醇治疗6周.以阳性与阴性症状量表(PANSS)评定疗效,用副反应量表(TESS)评定不良反应.结果:利培酮口服液与氟哌啶醇的疗效无显著差异.利培酮口服液的不良反应主要为失眠、恶心等,程度轻微,氟哌啶醇的锥体外系反应较严重.结论:利培酮口服液对老年期精神分裂症有效,不良反应轻微.     

Comparative efficacy of risperidone versus haloperidol on behavioural and psychological symptoms of dementia

BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) cannot be regarded as a single clinical syndrome, but rather as a heterogeneous group of symptoms, each of which can be considered as possible targets for therapy. OBJECTIVE: To compare the efficacy of risperidone and haloperidol on specific manifestations of BPSD. METHODS: A post-hoc analysis was conducted using data from an 18-week, randomized, double-blind, crossover head-to-head trial of risperidone vs haloperidol in treating 114 nursing-home residents with BPSD. Dependent variables were item scores of the Korean versions of the Behavioural Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD-K) and Cohen-Mansfield Agitation Inventory (CMAI-K). RESULTS: On the BEHAVE-AD-K, risperidone was significantly more effective than haloperidol in treating wandering (p = 0.0496), agitation (p = 0.0091), diurnal rhythm disturbances (p = 0.0137), anxiety regarding upcoming events (p = 0.0002), and other anxieties (p = 0.0088). On the CMAI-K, risperidone was significantly more effective in treating physical sexual advances (p = 0.0202), pacing and aimless wandering (p = 0.0123), intentional falling (p = 0.0398), hoarding things (p = 0.0499), performing repetitious mannerisms (p = 0.0048), repetitive sentence or questions (p = 0.0025), complaining (p = 0.0101), and negativism (p = 0.0027). Haloperidol was not significantly superior to risperidone on any individual item in either scale. CONCLUSIONS: When comparing treatment effects on individual symptoms frequently occurring in patients with dementia, risperidone significantly improved symptoms of agitation, wandering, diurnal rhythm disturbance and anxieties, among other symptoms, compared with haloperidol.     

Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder

OBJECTIVE: The authors compared the efficacy and safety of three atypical antipsychotics (clozapine, olanzapine, and risperidone) with one another and with haloperidol in the treatment of patients with chronic schizophrenia or schizoaffective disorder. METHOD: In a double-blind trial, 157 inpatients with a history of suboptimal treatment response were randomly assigned to treatment with clozapine, olanzapine, risperidone, or haloperidol for 14 weeks (an 8-week escalation and fixed-dose period followed by a 6-week variable-dose period). RESULTS: Clozapine, risperidone, and olanzapine (but not haloperidol) resulted in statistically significant improvements in total score on the Positive and Negative Syndrome Scale. Improvements seen in total and negative symptom scores with clozapine and olanzapine were superior to haloperidol. The atypical drugs, particularly olanzapine and clozapine, were associated with weight gain. CONCLUSIONS: The effects of atypical antipsychotics in this population were statistically significant but clinically modest. The overall pattern of results suggests that clozapine and olanzapine have similar general antipsychotic efficacy and that risperidone may be somewhat less effective. Clozapine was the most effective treatment for negative symptoms. However, the differences among treatments were small.     

Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial

OBJECTIVE: The first episode of psychotic illness is a key intervention point. The initial experience with medication can affect willingness to accept treatment. Further, relapse prevention is a treatment cornerstone during the first years of illness because active psychotic illness may affect lifetime outcomes. Thus, initial treatment of active symptoms and subsequent relapse prevention are central goals of pharmacotherapy. This study compared long-term effectiveness of risperidone versus haloperidol in first-episode psychosis patients. METHOD: First-episode psychosis patients (N=555, mean age=25.4 years) participated in a double-blind, randomized, controlled flexible-dose trial that compared risperidone (mean modal dose=3.3 mg) and haloperidol (mean modal dose=2.9 mg). The median treatment length was 206 days (maximum=1,514). RESULTS: Positive and Negative Syndrome Scale scores and Clinical Global Impression ratings improved significantly relative to baseline, with no significant differences between groups. Three-quarters of the patients achieved initial clinical improvement, defined as >20% reduction in total Positive and Negative Syndrome Scale score. However, among those who achieved clinical improvement, 42% of the risperidone group experienced a relapse compared with 55% of the haloperidol group. The median time to relapse was 466 days for risperidone-treated subjects and 205 days for those given haloperidol. These differences were statistically significant based on Kaplan-Meier survival analysis. Adverse effects distinguished the treatments: there were significantly more extrapyramidal signs and symptoms and adjunctive medication use in the haloperidol group and greater prolactin elevation in the risperidone group. There was less weight gain with haloperidol initially but no significant differences between groups at endpoint. CONCLUSIONS: Relatively low doses of antipsychotic drugs lead to significant symptom amelioration in the majority of first-episode psychosis patients. In the long term, risperidone prevents relapse in more patients and for a longer time and also induces less abnormal movements than haloperidol.     

Risperidone versus haloperidol in long-term hospitalized chronic patients in a double blind randomized trial: a post hoc analysis

BACKGROUND: Patients who remain in hospital for an extended time pose a special therapeutic challenge. OBJECTIVES: The goal of this study was to examine whether the acute response of long-term hospitalized schizophrenic patients differs between haloperidol and risperidone based on a post hoc, sub-analysis of data from a large double blind pivotal trial. METHOD: Data on chronic schizophrenic patients who had been hospitalized for at least 60 days (median 351 days) prior to entering this 8-week randomized double blind controlled trial were examined. This included 75 patients treated with 4 mg of risperidone and 69 treated with 10mg of haloperidol. Changes in symptoms were assessed with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinical Global Impression (CGI). Data were analyzed using analysis of variance. RESULTS: The analyses revealed that patients receiving risperidone improved significantly more than those treated with haloperidol. CONCLUSIONS: Results suggest that the most often prescribed dose of risperidone, 4 mg, might be more effective for long-stay chronic schizophrenic patients than haloperidol 10mg.     

利培酮治疗老年期精神分裂症双盲对照研究

目的：探讨利培酮治疗老年期精神分裂症的有效性及安全性。方法：分别用利培酮和氟哌啶醇对62例老年期精神分裂症患者进行8周治疗。疗效评定采用阳性与阴性症状量表(PANSS)，不良反应评定用副反应量表(TESS)和Sampson锥体外系反应量表。结果：两组治疗前后比较PANSS总分和各因子分均具有显著差异、两组在治疗第1、2、4、6、8周PANSS总分及各因子分比较差异均无显著性，但利培酮组较氟哌啶醇组在治疗阴性症状方面起效早2周。不良反应震颤、肌强直、活动减退发生率利培酮组显著低于氟哌啶醇组。结论：利培酮和氟哌啶醇均为治疗老年期精神分裂症有效、安全的药物。利培酮治疗阴性症状起效较早，氟哌啶醇锥体外系反应较显著。     

Risperidone versus haloperidol in psychotic patients with disturbing neuroleptic-induced extrapyramidal symptoms: a double-blind, multi-center trial

BACKGROUND: A randomized, double-blind, multi-center trial was started to compare the severity of extrapyramidal symptoms (EPS) during risperidone and haloperidol treatment in schizophrenic patients who had disturbing EPS during their previous neuroleptic treatment. Additional objectives of this trial were comparing the antipsychotic effectiveness of the two treatments and the use of antiparkinsonian medication. METHODS: Effects of flexible doses of risperidone and haloperidol were compared in 77 psychotic patients (83% with chronic schizophrenia) with disturbing neuroleptic-induced EPS (risperidone 40 patients, haloperidol 37). The trial was completed by 47 patients: 25 in the risperidone group (12 women, 13 men), and 22 in the haloperidol group (10 women, 12 men). RESULTS: An adequate antipsychotic effect was obtained in most patients by both treatments. The primary aim of this trial was comparing parkinsonism measured with the extrapyramidal syndrome rating scale (ESRS) during treatment with risperidone and haloperidol. Two primary parameters were selected: the change from baseline to the worst score during treatment of ESRS II (parkinsonism) and ESRS VI (clinical global impression of severity of parkinsonism). The CGI of severity of parkinsonism was better with risperidone (P=0.025), while the parkinsonism total score tended to be better with risperidone (P<0. 10). Before the double-blind treatment, 34 (of the 77) had used antiparkinson medication (risperidone 18, haloperidol 16). During the double-blind treatment phase, 21 patients had used antiparkinson medication (risperidone 11, haloperidol 10). The larger reduction of parkinsonism in the risperidone group was not due to a difference in the use of anti-parkinsonian medication. CONCLUSIONS: In this group of schizophrenic patients with disturbing EPS during previous neuroleptic treatment, a stronger reduction of parkinsonism was observed with risperidone than with haloperidol.     

A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R²=0.50–0.51,p<0.001). Only depressive symptoms did not contribute significantly to these results (p>0.10). Path analysis showed that the greater mean change (p<0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.     

Olanzapine,risperidone and haloperidol in the treatment of adolescent patients with schizophrenia

Summary. Objectives: To evaluate and compare the drug response and side effects of adolescents with schizophrenia treated with olanzapine, risperidone, and haloperidol. Methods: Forty-three patients were treated with olanzapine (n = 19), risperidone (n = 17) and haloperidol (n = 7) for 8 weeks in an open clinical trial. Clinical improvement was evaluated with the Positive and Negative Syndrome Scale (PANSS), and side effects with the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Results: Significant clinical improvement was observed by week 4 for all medications. Olanzapine and haloperidol induced fatigability more frequently than risperidone. Haloperidol was associated with a higher frequency of depression and more severe extrapyramidal symptoms. Conclusions: To the best of our knowledge this is the first study in adolescents to compare the efficacy and side effects of three most commonly prescribed antipsychotic medications. Olanzapine, risperidone and haloperidol appear to be equally effective for the treatment of schizophrenia in adolescent inpatients but have different side effect profiles. Received June 6, 2002; accepted December 3, 2002 Published online February 19, 2003 Authors' address: Dr. A. Apter, Richard E. Feinberg Department of Psychiatry, Schneider Children's Medical Center of Israel, 14 Kaplan St., P.O.Box 559, Petah Tiqwa 49202, Israel, e-mail: eapter@clalit.org.il     

A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia.

OBJECTIVE: To compare effects of risperidone with placebo (efficacy and tolerability) and haloperidol (tolerability) for treating demented patients with aggression and other behavioral symptoms. METHODS: A 13-week double-blind study involving 344 patients with dementia randomly assigned to receive placebo or flexible doses (0.5 to 4 mg/d) of risperidone or haloperidol. Behavioral symptoms were assessed by the Behavior Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the Cohen-Mansfield Agitation Inventory (CMAI), and the Clinical Global Impression (CGI) scale. Tolerability assessments included the Extrapyramidal Symptom Rating Scale, sedation levels, Functional Assessment Staging, Mini-Mental State Examination, and incidence of adverse events. RESULTS: The mean dose at endpoint was 1.1 mg/d of risperidone and 1.2 mg/d of haloperidol. Although not significant, a higher percentage of patients receiving risperidone than those receiving placebo showed clinical improvement (> or =30% reduction from baseline to endpoint in BEHAVE-AD total score) at endpoint and week 12. Reductions in the BEHAVE-AD total score were significantly greater with risperidone than with placebo at week 12. In a further analysis of aggression, the most dominant symptom in these patients, BEHAVE-AD and CMAI aggression cluster scores were significantly reduced compared with placebo at endpoint and week 12. CGI scores were also significantly reduced at endpoint and week 12. Severity of extrapyramidal symptoms with risperidone did not differ significantly from that of placebo and was less than that of haloperidol. A post hoc analysis showed significantly greater reductions in the BEHAVE-AD aggressiveness score with risperidone than haloperidol at week 12. CONCLUSION: Low-dose risperidone (mean 1.1 mg/d) was well tolerated and associated with reductions in the severity and frequency of behavioral symptoms, particularly aggression, in elderly patients with dementia.     

利培酮口服液治疗老年期痴呆患者病理性行为对照研究

目的：对具有病理性行为的老年期痴呆患者分别给予利培酮和氟哌啶醇治疗的疗效进行比较。方法：65例伴有病理性行为的老年期痴呆患者随机分为研究组33例和对照组32例,分别给予利培酮口服液和氟哌啶醇针剂治疗。疗程2周。于治疗前及治疗2h、24h、72h、1周和2周采用痴呆病理行为评定量表（BEHAVE-AD）和治疗中出现的症状量表（TESS）评定疗效及不良反应,并观察服药依从性。结果：利培酮口服液与氟哌啶醇针剂疗效相仿（P〉0.05）,但利培酮不良反应更小,依从性更好（P〈0.05或P〈0.01）。结论：利培酮口服液更适用于老年期痴呆患者的病理性行为的治疗。     

Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol

Summary. The neurotoxicity of conventional antipsychotic drugs has emerged as a potential pathogenic event in extrapyramidal side effects (EPS) and in their limited efficacy for negative-cognitive symptoms in schizophrenic patients. The atypical antipsychotics, recently developed, have superior therapeutic efficacy to treat not only positive symptoms but negative symptoms and cognitive dysfunctions with much lower potentials of side effects, although the influence of atypical antipsychotics on the regulation of neuronal survival has been less investigated. It is important to clarify the effects of typical and atypical antipsychotics on neuronal survival and their contributions to the therapeutic development and understanding of the pathophysiology of schizophrenia. We measured the neurotoxicity of two antipsychotic drug treatments, haloperidol and risperidone, in primary cultured rat cortical neurons. Immunoblotting and pharmacological agent analyses were used to determine the signal transduction changes implicated in the mechanisms of the neurotoxicity. Haloperidol induced apoptotic injury in cultured cortical neurons, but risperidone showed weak potential to injure the neurons. Treatment with haloperidol also led the reduction of phosphorylation levels of Akt, and activated caspase-3. The D2 agonist bromocriptine and 5-HT_2A antagonist, ketanserin attenuated the haloperidol-induced neuronal toxicity. Moreover, brain-derived neurotrophic factor (BDNF) reduced the caspase-3 activity and protected neurons from haloperidol-induced apoptosis. BDNF also reversed the reduced levels of phosphorylation of Akt caused by treatment with haloperidol. Haloperidol but not risperidone induces caspase-dependent apoptosis by reducing cellular survival signaling, which possibly contributes to the differential clinical therapeutic efficacy and expression of side effects in schizophrenia.     

Risperidone in the treatment of schizophrenia: results of a study of patients from Germany, Austria, and Switzerland

Results of a subanalysis of data from the multinational risperidone trial (RIS-INT-2) are reported. Patients with chronic schizophrenia were treated with risperidone at 1 mg/day (n = 25), 4 mg/day (n = 27), 8 mg/day (n = 29), 12 mg/day (n = 31), or 16 mg/day (n = 29), or 10 mg/day of haloperidol for 8 weeks. According to the Positive and Negative Syndrome Scale (PANSS) total and subscale scores, improvements were noted in each treatment group from baseline to treatment endpoint. On each scale the magnitude of improvement was greater in the risperidone patients than in the haloperidol patients. The onset of action of risperidone was faster than haloperidol. By treatment week 2, over half of the patients receiving ≥ 4 mg/day of risperidone were clinically improved (≥ 20% reduction in total PANSS scores). This rate of improvement was not seen until week 6 in the haloperidol patients. Severity of extrapyramidal symptoms (scores on the Extrapyramidal Symptom Scale) was significantly lower in patients receiving 1 or 4 mg/day of risperidone than in patients receiving higher risperidone doses and in haloperidol patients. The optimal dose of risperidone, in terms of both efficacy and safety, was 4 mg/day. These results confirm the findings of the controlled trials of risperidone conducted in North America and the multinational trial.     

利培酮与氟哌啶醇治疗双相躁狂的对照研究

目的比较利培酮与氟哌啶醇治疗双相躁狂的疗效和安全性。方法82例双相躁狂患者随机分配至利培酮组和氟哌啶醇组,在治疗前、治疗第1周末、第2周末、第4周末分别进行Bech-Rafaelsen躁狂量表(BRMS)、不良反应症状量表(TESS)、锥体外系副反应量表(RSESE)评定。结果利培酮组患者有效率为82．5%,氟哌啶醇组为80．9%；与药物有关的不良事件发生率：利培酮组为57．5%,氟哌啶醇组为66．7%；两组差异无统计学意义(P＞0．05)。利培酮组锥体外系反应的发生率(40%)明显低于氟哌啶醇组(57%),差异有统计学意义(P=0．039)。结论利培酮单药治疗双相躁狂的疗效与氟哌啶醇相当,且锥体外系不良反应少于氟哌啶醇。     

Risperidone-induced increase of plasma norepinephrine is not correlated with symptom improvement in chronic schizophrenia.

BACKGROUND: Previous studies have shown an increase in plasma levels of norepinephrine (NE) after clozapine treatment of schizophrenia. This effect has been suggested to relate to improvement in symptoms. METHODS: To test whether other novel antipsychotic drugs have such an effect, the present experiment examined schizophrenic symptoms and plasma levels of NE before and after 5 weeks of treatment with risperidone or haloperidol. RESULTS: Risperidone, but not haloperidol, significantly increased plasma NE; however, there was no correlation of this effect with clinical improvement on any symptom scale. CONCLUSIONS: This finding suggests that risperidone shares similar properties with clozapine in enhancing peripheral NE, but that these changes in plasma NE may not be a consistent indicator of atypical antipsychotic drug efficacy.     

Effectiveness and safety of antipsychotics in early onset psychoses: a long-term comparison

The effectiveness and safety of various antipsychotics was evaluated in a long-term study on 47 patients, 29 with schizophrenia and 18 with schizoaffective disorder, aged 10 to 17 years (mean 15.5) at onset. Follow-up ranged from 3 years (all 47 patients) to 11 years (19 patients). Data were collected on the following antipsychotics: haloperidol, risperidone, olanzapine, quetiapine, aripiprazole and clozapine. Cases with positive response were significantly more frequent with clozapine as compared to haloperidol, risperidone and olanzapine. Risperidone was significantly better than haloperidol at the 3-year follow-up. A comparison of the degree of clinical improvement evaluated with PANSS and CGI in patients treated with drugs in subsequent periods showed clozapine led to significantly greater improvement as compared to haloperidol, risperidone and olanzapine, and risperidone as compared to haloperidol. Data on long-term functioning significantly favored clozapine as compared to all the other drugs. Discontinuation due to side effects involved 20% patients with clozapine, lower percentage with the other drugs. The results of this study on early-onset schizophrenic and schizoaffective disorders confirm that even in the long-term, clozapine is more effective than haloperidol, risperidone and olanzapine. Despite a relevant incidence of adverse effects, clozapine seems to have unique effectiveness in treating children and adolescents with early-onset schizophrenic disorders.