Effectiveness of antipsychotic treatments for schizophrenia: interim 6-month analysis from a prospective observational study (IC-SOHO) comparing olanzapine, quetiapine, risperidone, and haloperidol

BACKGROUND: The Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study was designed to provide information regarding use and outcome of antipsychotic treatments in a large, diverse population in real practice settings. METHOD: Outpatients with schizophrenia (ICD-10 or DSM-IV) who initiated or changed to a new antipsychotic entered this 3-year, naturalistic, prospective observational study. Four monotherapy treatment groups were defined according to the antipsychotic prescribed at baseline, namely olanzapine, risperidone, quetiapine, and haloperidol. Efficacy was assessed using the Clinical Global Impressions-Severity of Illness rating scale (CGI-S), inclusive of subscales for positive, negative, depressive, and cognitive symptoms. Tolerability was assessed by adverse event questionnaires and weight measurements. Six-month findings are described. RESULTS: At baseline, 5833 participants were prescribed monotherapy and the mean severity of illness was moderate to marked (CGI-S). At 6 months, olanzapine resulted in significantly greater improvements in overall, positive, negative, depressive, and cognitive symptoms compared with quetiapine, risperidone or haloperidol (p <.001). Improvements in overall, negative, and cognitive symptoms were significantly higher for risperidone compared with haloperidol (p <.001), whereas improvements across all symptoms were comparable for quetiapine and haloperidol. Extra-pyramidal symptoms and tardive dyskinesia decreased compared with baseline in the olanzapine, quetiapine, and risperidone groups but increased in the haloperidol group (p <.001, likelihood of extrapyramidal symptoms with haloperidol compared with olanzapine, quetiapine, or risperidone). Sexual function adverse events were most prominent in the haloperidol and risperidone treatment groups. Weight change was significantly greater for olanzapine compared with the other antipsychotics (p <.001). CONCLUSION: Our results support the previously reported positive impact of atypical antipsychotics, particularly olanzapine, in patients with schizophrenia.     

抗精神病药对老年精神分裂症患者血清催乳素的影响

目的：探讨几种抗精神病药对老年精神分裂症患者血清催乳素（PRL）的影响。方法：随机选取抗精神病药治疗老年精神分裂症患者121例,分别在治疗前后测定血清PRL水平。结果：患者经舒必利、奋乃静、氟哌啶醇和利培酮治疗后血清PRL明显升高,各药物之间以及治疗前后比较差异均有显著性（F=15．95,P〈0．01）。PRL水平的升高与药物剂量呈正相关。氯氮平对PRL水平影响不明显。结论：典型和非典型抗精神病药对老年精神分裂症患者血清PRL水平的影响同样明显,强弱的顺序依次是舒必利、奋乃静、氟哌啶醇和利培酮。     

Ethnicity and prescription patterns for haloperidol, risperidone, and olanzapine

OBJECTIVE: Patients with schizophrenia may respond better to second-generation antipsychotics than to older antipsychotics because of their superior efficacy and safety profiles. However, the reduced likelihood among ethnic minority groups of receiving newer antipsychotics may be associated with reduced medication adherence and health service use, potentially contributing to poor response rates. This study examined whether ethnicity helped predict whether patients with schizophrenia were given a first- or a second-generation antipsychotic, haloperidol versus risperidone or olanzapine, and what type of second-generation antipsychotic was prescribed, risperidone or olanzapine, when other factors were controlled for. METHODS: Texas Medicaid claims were analyzed for persons aged 21 to 65 years with a diagnosis of schizophrenia or schizoaffective disorder who started treatment with olanzapine (N=1875), risperidone (N=982), or haloperidol (N= 726) between January 1, 1997 and August 31, 1998. The association between antipsychotic prescribing patterns among African Americans, Mexican Americans, and whites was assessed by using logistic regression analysis. Covariates included other patient demographic characteristics, region, comorbid mental health conditions, and medication and health care resource use in the 12 months before antipsychotic initiation. RESULTS: The results of the first- versus second-generation antipsychotic analysis indicated that African Americans were significantly less likely than whites to receive risperidone or olanzapine. Although not statistically significant, the odds ratio indicated that Mexican Americans were also less likely to receive risperidone or olanzapine. Ethnicity was not associated with significant differences in the prescribing patterns of risperidone versus olanzapine. CONCLUSIONS: When other factors were controlled for, African Americans were significantly less likely to receive the newer antipsychotics. Among those who received the newer antipsychotics, ethnicity did not affect medication choice.     

Differential regulation of hippocampal BDNF mRNA by typical and atypical antipsychotic administration

Apart from their differential propensities to block dopamine D2 and serotonin 5-HT2 receptors, the molecular mechanisms underlying the clinical efficacy of typical and atypical antipsychotics in schizophrenia are largely unknown. Given recent interest in the effects of antipsychotics on neurotrophic and other growth related factors, the effects of antipsychotics on brain-derived neurotrophic factor (BDNF), a neurotrophin crucial to the structural integrity of adult neurons, were investigated in male Wistar rats. Chronic (19 day) but not acute (45 min) antipsychotic administration significantly altered levels of hippocampal BDNF mRNA. In addition, whereas chronic treatment with the strong D2 receptor-blocker haloperidol significantly downregulated hippocampal BDNF mRNA, the selective 5-HT2 receptor-blocker ritanserin significantly upregulated CA1 hippocampal BDNF mRNA in comparison to controls. Since high doses of risperidone and clozapine produce potent inhibition of both 5-HT2 and D2 receptors, while lower doses produce significantly greater 5-HT2 vs. D2 receptor blockade, a dose-response study was employed to determine whether low doses of these atypical antipsychotics would also upregulate hippocampal BDNF mRNA in the absence of significant D2 receptor blockade. Whereas chronic haloperidol and high-dose risperidone significantly downregulated hippocampal BDNF mRNA, intermediate and lower doses of risperidone and clozapine were, unlike ritanserin, without effect when compared to controls. Thus, although the long-term downregulation of hippocampal BDNF mRNA may underlie the different clinical profiles of certain antipsychotics, this effect seems to be associated with antipsychotic doses that not only cause significant D2 receptor inhibition, but are usually associated with side effects rather than therapeutic efficacies.     

Adverse effects of risperidone and haloperidol treatment in schizophrenia

PURPOSE: Side effects of pharmacological treatment in schizophrenia continue to be a major issue in spite of the development of new antipsychotics. The aim of this study is to explore the adverse effects of conventional and atypical antipsychotic drugs and their associated factors. METHODS: Over 3 months, 41 patients with schizophrenia were randomized to treatment with risperidone 1-12 mg (n=21) or haloperidol 2-20 mg (n=20) daily. Efficacy was assessed by improvement of psychotic symptoms, measured on the Positive and Negative Syndrome Scale (PANSS). The safety and tolerability were assessed with the Extrapyramidal Symptom Rating Scale, the UKU Side-Effect Rating Scale and clinical laboratory assessments. RESULTS: Each treatment reduced psychotic symptoms. PANSS total scores, positive scores, and general psychopathology scores declined as trial went on without significant differences between the two groups. While PANSS negative scores improved better in the risperidone group than in the haloperidol group. The tolerability of antipsychotics was statistical significantly better in the risperidone than in the haloperidol-treated patients. The most frequent adverse effects for both groups were tremor and rigidity. Antipsychotics, their doses, and hyperprolactinemia predict short-term extrapyramidal side effects. Serum prolactin levels could predict parkinsonism and dyskinesia severity. However, dyskinesia was best predicted by the doses of neuroleptics. The predictive factor of dystonia was the antipsychotic drug itself. After adjusting drug doses and concomitant medications, side effects could be markedly improved. CONCLUSIONS: This study suggested that risperidone was superior to haloperidol in improving negative symptoms and better tolerated during the 12 weeks' treatment of schizophrenia. Serum prolactin levels could predict the severity of parkinsonism and dyskinesia.     

Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse,who were treated with typical or atypical antipsychotics

Brain-derived neurotrophic factor signals and dopaminergic function in the brain are strongly associated, and research on BDNF in schizophrenia may enhance our insights on the pathophysiological mechanisms of this disease. In the present study we aimed to investigate the possible association between serum BDNF levels and schizophrenic relapses and the possible differential effects of treatment with typical and atypical antipsychotics on serum BDNF levels in the same group of patients. We measured serum BDNF levels in 47 patients with schizophrenia during a relapse and again 6 weeks after administration of antipsychotic treatment (14 on risperidone, 18 on haloperidol, 10 on olanzapine and five on amisulpride) and in 44 healthy volunteers. Patients with schizophrenia showed reduced serum BDNF levels in relation to healthy volunteers at study entry. No significant differences were revealed in BDNF serum levels after 6 weeks of antipsychotic treatment in the patients compared to their own levels at study entry. However, serum BDNF was significantly increased in the subgroup receiving olanzapine compared to the other antipsychotics. Our findings may indicate a differential effect of olanzapine on BDNF levels compared to haloperidol, risperidone, and amisulpride.     

Reduced basal and phencyclidine-induced expression of heat shock protein-70 in rat prefrontal cortex by the atypical antipsychotic abaperidone

The effect of antipsychotic treatment on basal and phencyclidine (PCP)-induced heat shock protein-70 (hsp70) mRNA expression was studied in the rat striatum and in the prefrontal cortex. Abaperidone, a novel drug with an atypical antipsychotic profile, was compared, at pharmacologically equivalent doses, with the atypical antipsychotics clozapine and risperidone and also with haloperidol, a classical antipsychotic. Abaperidone and clozapine reduced basal hsp70 mRNA expression in the rat striatum and in the prefrontal cortex. No change in either region was found after haloperidol, whereas risperidone reduced hsp70 mRNA in the striatum but not in the prefrontal cortex. The N-methyl-D-aspartate (NMDA) receptor antagonist PCP significantly elevated hsp70 mRNA levels in the prefrontal cortex, an elevation that was potentiated by haloperidol and prevented by all of the atypical antipsychotics tested. Since hsp70 has been associated to some schizophrenia symptoms, we suggest that reduced hsp70 in the prefrontal cortex, a cortical area that plays a critical role in the etiology of many schizophrenia symptoms, may be linked to an atypical profile of antipsychotics, such as clozapine, and possibly also abaperidone.     

Effects of atypical and typical antipsychotic treatments on sexual function in patients with schizophrenia: 12-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.

PURPOSE: Sexual dysfunction in patients with schizophrenia can reduce quality of life and treatment compliance. This report will compare the effects of selected atypical and typical antipsychotics on sexual function in a large, international population of outpatients with schizophrenia who were treated over 1 year. SUBJECTS AND METHODS: Outpatients with schizophrenia, who initiated or changed antipsychotic treatment, and entered this 3-year, prospective, observational study were classified according to the monotherapy prescribed at baseline: olanzapine (N=2638), risperidone (N=860), quetiapine (N=142) or haloperidol (N=188). RESULTS: Based on patient perception, the odds of experiencing sexual dysfunction during 1 year of therapy was significantly lower for patients treated with olanzapine and quetiapine when compared to patients who received risperidone or haloperidol (all P< or =0.001). Females on olanzapine (14%) or quetiapine (8%) experienced a lower rate of menstrual irregularities, compared to females on risperidone (23%) or haloperidol (29%). Significant discordance was evident between patient reports and psychiatrist perception of sexual dysfunction, with psychiatrists underestimating sexual dysfunction (P< or =0.001). CONCLUSION: These findings indicate clinically relevant differences exist in the sexual side effect profiles of these selected antipsychotics. These factors should be considered when selecting the most appropriate treatment for outpatients with schizophrenia.     

Procedural learning in schizophrenia can reflect the pharmacologic properties of the antipsychotic treatments.

BACKGROUND: Conventional and atypical antipsychotics have different affinities for D2 receptors, and these receptors are principally located in the striatum. Given that this cerebral structure was previously found to play a major role in procedural learning, the antipsychotic treatment in schizophrenia may be determinant for the procedural learning profile of these patients. OBJECTIVE: The current study was aimed at verifying whether procedural learning differs in patients with schizophrenia treated with conventional antipsychotics and patients treated with atypical antipsychotics. METHOD: Forty-five patients with schizophrenia were divided into 3 different groups according to their pharmacologic treatment: (1) haloperidol, a classical neuroleptic with high D2 receptor affinity; (2) clozapine, an atypical neuroleptic with practically no D2 receptor affinity; and (3) risperidone, an atypical neuroleptic that nevertheless shows high D2 receptor affinity. Patients were compared to 35 control subjects on a visuomotor procedural learning task (mirror drawing). RESULTS: All patients were able to learn the task. However, those treated with haloperidol showed some degree of learning impairment, while those treated with clozapine or risperidone did not show this impairment. In addition, performance per se, regardless of the learning, was found to be affected in the haloperidol and risperidone, but not in the clozapine groups. CONCLUSION: Procedural learning in schizophrenia may be differentially affected, depending on the pharmacologic profiles of the antipsychotics used for the treatment of this illness.     

Risperidone in acute and long-term therapy of schizophrenia--a clinical profile

Data from a range of well-controlled clinical trials, observational studies, and clinical use support the efficacy of risperidone for both acute and long-term therapy of schizophrenic psychoses. With regard to positive symptoms, the efficacy of risperidone was shown to be at least comparable with that of haloperidol. However, risperidone differs from conventional antipsychotics because it is more effective against the negative symptoms, has beneficial effects on affective and cognitive symptoms, and carries less risk of extrapyramidal side effects (EPS). To date, risperidone is the only atypical antipsychotic to have shown a significantly lower relapse rate compared with haloperidol in a long-term double-blind trial. This review describes comprehensive trial data and therapeutic observations gained with risperidone in the treatment of schizophrenia since its approval.     

Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia.

OBJECTIVE: This study compared the specific antiaggressive effects of clozapine with those of olanzapine, risperidone, and haloperidol. METHODS: A total of 157 inpatients with schizophrenia or schizoaffective disorder and a history of suboptimal treatment response were randomly assigned to receive clozapine, olanzapine, risperidone, or haloperidol in a double-blind 14-week trial. The trial was divided into two periods: eight weeks during which the dosage was escalated and then fixed, and six weeks during which variable dosages were used. The hostility item of the Positive and Negative Syndrome Scale (PANSS) was the principal outcome measure. Covariates included the items that reflect positive symptoms of schizophrenia (delusions, suspiciousness or feelings of persecution, grandiosity, unusual thought content, conceptual disorganization, and hallucinations) and the sedation item of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). RESULTS: Patients differed in their treatment response as measured by the hostility item of the PANSS. The scores of patients taking clozapine indicated significantly greater improvement than those of patients taking haloperidol or risperidone. The effect on hostility appeared to be independent of the antipsychotic effect of clozapine on other PANSS items that reflect delusional thinking, a formal thought disorder, or hallucinations and independent of sedation as measured by the NOSIE. Neither risperidone nor olanzapine showed superiority to haloperidol. CONCLUSION: Clozapine has a relative advantage over other antipsychotics as a specific antihostility agent.     

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.     

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.     

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.     

Factors influencing acute weight change in patients with schizophrenia treated with olanzapine, haloperidol, or risperidone

OBJECTIVE: Clinical factors predicting weight change in patients with schizophrenia and related disorders during acute treatment with the antipsychotic drugs olanzapine, risperidone, and haloperidol were sought through retrospective analyses. METHOD: Six-week body-weight data from 2 trials, study 1 comparing olanzapine and haloperidol (N = 1,369) and study 2 olanzapine and risperidone (N = 268), were analyzed. Effects of 8 clinically relevant covariates--therapy, clinical outcome (Brief Psychiatric Rating Scale), baseline body mass index (BBMI), increased appetite, age, gender, race, and dose--on weight were compared. RESULTS: In study 1, olanzapine (vs. haloperidol) therapy, better clinical outcome, lower BBMI, and nonwhite race significantly affected weight gain. Effects of increased appetite and male gender on weight gain were significant for olanzapine but not for haloperidol. In study 2, better clinical outcome, lower BBMI, and younger age significantly affected weight gain. Increased appetite was more frequent during olanzapine treatment than during haloperidol, but not significantly different from risperidone. Significant differences in effect on weight change were found between olanzapine and haloperidol but not between olanzapine and risperidone. No evidence was found that lower antipsychotic drug doses were associated with lower weight gain. CONCLUSION: This report identifies predictive factors of acute weight change in patients with schizophrenia. Similar factors across antipsychotic drugs in predicting greater weight gain included better clinical outcome, low BBMI, and nonwhite race. Factors differing between conventional (haloperidol) and atypical (olanzapine) agents included increased appetite and gender. Choice of atypical antipsychotic drug (olanzapine vs. risperidone) was of minor importance with regard to influence on acute weight gain.     

Improvement in cognition associated with novel antipsychotic drugs: a direct drug effect or reduction of EPS?

BACKGROUND: Administration of novel, versus classic, antipsychotic agents to patients suffering from psychosis is associated both with moderately better scores on cognitive tests, and with fewer extrapyramidal symptoms (EPS). Because improved motor functioning may enable better performance on some components of cognitive test batteries, and because the advantages of the novel antipsychotics on cognitive performance are not very large, it is sometimes difficult to discern if improvement in a given cognitive task is due to a direct effect of the novel antipsychotic drug, or is secondary to the novel drug's decreased propensity to induce EPS. In an attempt to distinguish between these two possibilities, the present study examined the ability of patients suffering from schizophrenia receiving classic, versus novel antipsychotics, to perform a computerized visuo-motor test (VMT). VMT assesses planning capabilities, attention and executive functions known to be impaired in schizophrenia, which are suggested to be affected by novel antipsychotics. METHODS: Seventy-six patients suffering from schizophrenia or schizophreniform disorder, receiving haloperidol (23 patients, mean dose 10.01+/-6.1mg/day), olanzapine (26 patients, mean dose 10.56 +/- 4.9 mg/day) or risperidone (27 patients, mean dose 4.35 +/- 1.7 mg/day) were assessed for EPS using the parkinsonian subscale of the Extrapyramidal Symptom Rating Subscale (ESRS), and with the VMT. RESULTS: Cognitive functioning as measured by the VMT was better for patients receiving risperidone or olanzapine, compared with those receiving haloperidol (F=6.636, df=2,67, P=0. 002), while the patients receiving haloperidol or risperidone suffered from more severe EPS compared with the patients receiving olanzapine (F=3.996, df=2,71, P=0.023). DISCUSSION: Although the patients receiving risperidone suffered from EPS similar in severity to the EPS of the patients receiving haloperidol, their performance on a task involving visuo-motor and attentional skills was similar to that of the patients receiving olanzapine. This finding implies that there is a dissociation between the antipsychotic drug's ability to affect cognitive functioning, and EPS. This dissociation indirectly suggests that the advantages offered by novel antipsychotics on cognitive performance are a direct effect, rather than being entirely mediated by improved movement abilities.     

The effects of chronic administration of established and putative antipsychotics on natural prepulse inhibition deficits in Brattleboro rats

We previously reported that vasopressin deficient Brattleboro (BRAT) rats exhibit deficits in prepulse inhibition (PPI) of the startle reflex that are consistent with PPI deficits exhibited by patients with schizophrenia and other neuropsychiatric disorders. Preliminary evidence indicates that this may be the basis of a predictive model for antipsychotic drug efficacy. Here we report the effects of acute and chronic administration of established and putative antipsychotics on these PPI deficits. BRAT rats, compared to their derivative strain, Long Evans rats, exhibited significantly decreased PPI and startle habituation consistent with patients with schizophrenia and other neuropsychiatric disorders. The second generation antipsychotics, risperidone and clozapine as well as a neurotensin agonist (PD149163) increased BRAT rat PPI, whereas saline, the typical antipsychotic, haloperidol, and a vasopressin analog (1-desamino-D-arginine vasopressin) did not. Similar to their effects in humans, chronic administration of antipsychotic drugs produced stronger effects than acute administration. These results further support the BRAT rat as a model of sensorimotor gating deficits with predictive validity for antipsychotics. The model appears to be able to differentiate first generation from second generation antipsychotics, identify putative antipsychotics with novel mechanisms (i.e., peptides) and reasonably model the therapeutic time course of antipsychotic drugs in humans.     

The use of PET imaging in studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia

Positron emission tomography (PET) offers a strategic imaging platform to provide a map of functional neural correlates associated with the underlying cognitive deficits in schizophrenia. It enables regional cerebral glucose metabolism and dopaminergic and serotonergic receptor function to be studied. PET neuroimaging can therefore be used in drug development and to study putative treatments. Recent PET studies of the first-generation antipsychotics flupentixol and haloperidol, and of the second-generation antipsychotics risperidone, aripiprazole, quetiapine, sertindole, ziprasidone, paliperidone and olanzapine, have been carried out; modulation of limbic circuitry has been found to be a predictor of treatment response. PET can also be used to predict and monitor likely extrapyramidal side effects from antipsychotic treatment. PET and neuropsychological testing can together also allow the study of putative molecular genetic changes associated with schizophrenia. Advances in the imaging, cognition and molecular genetics are likely to lead to the development of future diagnostics, treatments and novel pharmacological agents.     

Present data and treatment schedule of aripiprazole in the treatment of schizophrenia

Among the second generation antipsychotics, aripiprazole presents a new pharmacological profile, basically differentiated by a partial agonist effect on the D2 and D3 dopaminergic receptors. Five short-term efficacy studies, conducted on 1648 patients presenting with schizophrenia or acute relapse of schizoaffective disorders, demonstrated the greater efficacy of aripiprazole than the placebo and comparable efficacy to that of haloperidol and risperidone. The short-term tolerance profile was characterised by a lesser incidence of the extrapyramidal side effects and drowsiness than with haloperidol. Two thousand six hundred and eighty five patients were followed-up over a period of 26 to 52 weeks in five clinical trials versus a placebo and haloperidol, olanzapine, quetiapine and risperiodone: demonstrated efficacy in maintaining the response to treatment and on the delay before relapse was comparable to the other antipsychotics. The classical side effects of antipsychotics decreased in the long-term. Versus olanzapine, a glucid and lipid profile, clearly in favour of aripiprazole, was completed by a lesser incidence of hyperprolactinaemia. Aripiprazole is effective on all the dimensions of schizophrenia: the positive and negative and depressive and anxious symptomatology. It appears to be of interest, notably on the cognitive dimension, which should motivate more in-depth exploration of its place in the treatment in the early stages of schizophrenia. Its therapeutic schedule and the methods of initiation are an essential criterion to the success of treatment, notably during the substitution of other antipsychotics. The clinical and pharmacological originality of aripiprazole would justify the terminology of a "third generation antipsychotic".     

Functional effects of antipsychotic drugs: comparing clozapine with haloperidol.

BACKGROUND: Using positron emission tomography (PET) with (15)O water, we compared regional cerebral blood flow (rCBF) patterns induced by clozapine or haloperidol in individuals with schizophrenia. Based on the known clinical characteristics of each drug, we hypothesized that brain regions where the drugs show similar rCBF patterns are among those mediating their antipsychotic actions; whereas, regions where the drugs produce different rCBF patterns are among those mediating their different drug actions, namely, haloperidol's motor side effects or clozapine's unique therapeutic action. METHODS: Persons with schizophrenia were scanned using PET with (15)O water, first after withdrawal of all psychotropic medication (n = 6), then again after treatment with therapeutic doses of haloperidol (n = 5) or clozapine (n = 5). RESULTS: Both drugs increased rCBF in the ventral striatum and decreased rCBF in hippocampus and ventrolateral frontal cortex. The rCBF increase associated with haloperidol was greater than that with clozapine in the dorsal and ventral striatum; the rCBF increase with clozapine was greater than that with haloperidol in cortical regions, including anterior cingulate and dorsolateral frontal cortex. CONCLUSIONS: These data suggest that the rCBF increase in ventral striatum and/or the decrease in hippocampus and/or ventrolateral frontal cortex mediate a common component of antipsychotic action of these drugs. The increased rCBF in dorsal striatum by haloperidol could well be associated with its prominent motor side effects, whereas the increased rCBF in the anterior cingulate or dorsolateral frontal cortex may mediate the superior antipsychotic action of clozapine. The proposals based on these preliminary observations require further study.