Behavioral effects of sertindole,risperidone, clozapine and haloperidol inCebus monkeys

Extrapyramidal side effects (EPS) are major limitations to neuroleptic treatment of psychoses. To evaluate further the behavioral characteristics of the novel antipsychotic agents, a wide range of single intramuscular doses of sertindole (0.1–2.5 mg/kg IM), risperidone (0.01–0.25 mg/kg IM), clozapine (1.0–25.0 mg/kg IM), and haloperidol (0.01–0.25 mg/kg IM) were blindly evaluated at weekly intervals inCebus monkeys previously sensitized to neuroleptics. All drugs except clozapine produced dystonia and parkinsonian symptoms, but haloperidol and risperidone were 50–100 times more potent than sertindole in producing EPS. Sertindole, risperidone and haloperidol had no significant sedative effects, whereas clozapine produced dose related sedation. Risperidone, clozapine and haloperidol but not sertindole decreased locomotor activity. Sertindole, risperidone and clozapine had a calming effect at doses below the EPS threshold, unlike haloperidol. Sertindole has many behavioral effects in nonhuman primates that are similar to those seen with the new antipsychotics, risperidone and clozapine, which suggests a favorable antipsychotic benefit/risk ratio in the clinic, especially regarding EPS.     

Regional differences in the effect of haloperidol and atypical neuroleptics on interstitial levels of DOPAC in the rat forebrain: an in vivo microdialysis study

The effect of 'typical' and 'atypical' neuroleptics on interstitial levels of the dopamine metabolite 3,4- dihydroxyphenylacetic acid ([DOPAC]e) in the dorsolateral striatum (DLSt), the nucleus accumbens (NAc) and the medial prefrontal cortex (PFC) was investigated in awake rats by use of the microdialysis technique. All neuroleptics increased [DOPAC]e in the DLSt, NAc and in PFC. However, the 'atypical' neuroleptics clozapine, risperidone, sertindole and NNC 22-0031 showed an apparent cortical selectivity by preferentially elevating [DOPAC]e in the PFC compared with the DLSt and NAc, a feature which was not observed with the 'typical' neuroleptic haloperidol. Our data suggest that 'atypical' neuroleptics can be differentiated from the 'typical' neuroleptic, haloperidol, with respect to their ability to increase [DOPAC]e in PFC relative to DLSt and NAc.     

Interactions between neuroleptics and CYP2C6 in rat liver--in vitro and ex vivo study

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (promazine, levomepromazine, thioridazine, perazine 10, chlorpromazine, haloperidol 0.3, risperidone 0.1, sertindole 0.05), in the absence of the neuroleptics in vitro. Some of the neuroleptics added in vitro to control liver microsomes decreased the activity of CYP2C6. Sertindole and levomepromazine (Ki = 25 and 31 microM, respectively) were the most potent inhibitors of the rat CYP2C6 among the drugs studied. Their effects were more pronounced than those of the other phenothiazines tested: thioridazine and chlorpromazine (Ki = 88 and 91 microM, respectively), promazine and perazine (Ki = 322 and 341 microM, respectively), risperidone (Ki = 414 microM) or haloperidol (Ki = 606 microM). The investigated neuroleptics--when given to rats in vivo for one day or two weeks--did not produce any indirect effect on CYP2C6 via other mechanisms, except for levomepromazine, which increased the activity of the enzyme after 24-h exposure. Therefore, the direct inhibitory effect of levomepromazine on CYP2C6 may be attenuated by an indirect mechanism at the beginning of the neuroleptic therapy. In summary, the obtained results show direct inhibitory effects of some phenothiazine neuroleptics and sertindole on the activity of CYP2C6 in vitro in rat liver microsomes. Considering relatively high pharmacological doses and therapeutic concentrations of phenothiazines, it seems that the inhibitory effect of levomepromazine (and other phenothiazines with Ki values below 100 microM) found in vitro may be of physiological and pharmacological importance in vivo.     

Olanzapine: new preparation. Keep an eye on this neuroleptic

(1) Olanzapine, a neuroleptic, has obtained European marketing authorisation for the treatment of schizophrenia. (2) The clinical file is satisfactory, but in the absence of relevant trials it has not yet been demonstrated that olanzapine has a specific activity on the positive or negative symptoms of schizophrenia. (3) The global efficacy of olanzapine was not significantly different from that of haloperidol in two of the three comparative trials published to date. (4) The only relevant comparative trial fails to demonstrate the superiority of olanzapine over risperidone. (5) Olanzapine has fewer adverse neurological effects than haloperidol, but there is no evidence that it differs from other recent neuroleptics in this respect. (6) Olanzapine can have anticholinergic adverse effects and frequently causes weight gain. (7) Active pharmacovigilance is required, as subclinical cases of elevated transaminase levels, increased blood pressure and QT prolongation were observed in clinical trials (2,500 patients treated).     

A review of the efficacy, tolerability and safety of sertindole in clinical trials

Sertindole is a non-sedating atypical antipsychotic agent with high selectivity for dopaminergic neurons in the mesolimbic system. In pivotal clinical trials, sertindole has demonstrated significantly greater efficacy than placebo against both the positive and negative symptoms of schizophrenia. In addition, sertindole has had at least similar efficacy to haloperidol and risperidone against positive symptoms, and significantly greater efficacy than haloperidol and risperidone against negative symptoms. The incidence of extrapyramidal symptom (EPS)-related adverse events and the rate of medication used to treat EPS in patients receiving clinically effective doses of sertindole in clinical trials were similar to those observed in placebo recipients and significantly less than those in haloperidol recipients. The incidence of QTc interval prolongation of 500 ms or greater with therapeutic dosages of sertindole has also been low. In general, sertindole has been well tolerated in clinical trials. Unlike other antipsychotic agents, sertindole has not been associated with cognitive impairment, and can actually improve cognitive function. Observational studies have shown that the efficacy and tolerability of sertindole observed in the clinical trial situation are emulated in a naturalistic setting. Large cohort analyses (N > 8000) have shown that all-cause and cardiovascular mortality is no greater with sertindole than with risperidone or olanzapine.     

Influence of classic and atypical neuroleptics on caffeine oxidation in rat liver microsomes

Caffeine is a marker drug for testing the activity of CYP1A2 (3-N-demethylation) in humans and rats. Moreover, CYP3A seems to be essential for its metabolism (8-hydroxylation). In the case of 1-N- and, in particular, 7-N-demethylation of caffeine, apart from CYP1A2, other CYP isoenzymes play a considerable role, probably CYP2B and/or CYP2E1. The aim of the present study was to investigate the influence of two classic neuroleptics (promazine and haloperidol) and two atypical ones (risperidone and sertindole) on cytochrome P-450 activity measured by caffeine oxidation in rat liver microsomes. The obtained results showed that promazine, a phenothiazine neuroleptic with the simplest chemical structure, significantly inhibited 1-N- and 3-N-demethylation and 8-hydroxylation of caffeine via competitive or mixed mechanism (Ki = 21.8, 25.4 and 58.2 microM, respectively). This indicates inhibition by promazine of CYP1A2 (inhibition of 3-N- and 1-N-demethylation), and possibly CYP3A2 (inhibition of 8-hydroxylation), but not of other CYP isoenzymes involved in 7-N-demethylation of caffeine (e.g. CYP2B2 and/or CYP2E1). In contrast to promazine, haloperidol had no effect on the oxidation reactions of caffeine in the applied in vitro metabolic model. The potency of inhibition of caffeine oxidation by risperidone and sertindole resembled rather haloperidol than promazine. Risperidone appeared to be a very weak inhibitor of 3-N-demethylation and 8-hydroxylation (Ki = 202.5 microM) and had no effect on 1-N- and 7-N-demethylation of caffeine. Sertindole was a very poor inhibitor of 1-N- and 7-N-demethylations and 8-hydroxylation pathways of the marker substance (Ki = 132.1, 434.1 and 173.3 microM, respectively); even the observed in vitro inhibition of 3-N-demethylation of caffeine by sertindole (Ki = 68.9 microM) cannot be of practical significance in vivo, considering extremely low pharmacological and therapeutic doses of the neuroleptic. In summary, among the investigated neuroleptics, only promazine showed significant inhibitory activity towards caffeine metabolism in vitro (inhibition of CYP1A2 and possibly CYP3A), which may be of pharmacological and clinical importance in vivo. In contrast to promazine, haloperidol and the investigated atypical neuroleptics had no or very weak effect on caffeine oxidation in vitro,of no in vivo significance. Considering the results of the present and previous studies, it seems highly likely that promazine may cause pharmacokinetic interactions, while atypical neuroleptics seem to be safe in this respect. Moreover, the observed reaction-dependent effects of promazine and sertindole provide indirect evidence that CYP1A2 is not the only isoenzyme important for the metabolism of caffeine, which requires further pharmacological and clinical consideration.     

Sertindole : a review of its use in schizophrenia

Oral sertindole (Serdolect) is an atypical antipsychotic approved in the EU for once-daily use in patients with schizophrenia who are intolerant to at least one other antipsychotic agent.Extensive data from post-marketing studies do not indicate an excess of overall mortality with sertindole. Sertindole is at least as effective as haloperidol and risperidone in the treatment of neuroleptic-responsive schizophrenia. Sertindole improves negative symptoms, and is also effective for the treatment of neuroleptic-resistant schizophrenia. Sertindole is generally well tolerated and is associated with a low rate of extrapyramidal symptoms (EPS). Thus, sertindole is a useful option in the treatment of patients with schizophrenia.     

The activity of cytochrome P450 CYP2B in rat liver during neuroleptic treatment

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2B measured as a rate of 16 beta-hydroxylation of testosterone. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (promazine, levomepromazine, thioridazine and perazine, 10 each; chlorpromazine 3; haloperidol 0.3; risperidone 0.1; sertindole 0.05), in the absence of the neuroleptics in vitro. ome of the neuroleptics added in vitro to control liver microsomes decreased the activity of CYP2B. The obtained Ki values indicated that thioridazine was the most potent inhibitor of the studied reaction (Ki = 26 microM). The inhibitory effects of chlorpromazine, perazine and sertindole were moderate (Ki = 45-75 microM), while promazine, haloperidol, levomepromazine, and risperidone were rather weak inhibitors of CYP2B activity (Ki = 125-225 microM, respectively). After a one-day (i.e. 24 h) exposure of rats to the investigated neuroleptics, the decreased CYP2B activity was observed after haloperidol, risperidone and sertindole. All the investigated neuroleptics did not produce any significant effect on CYP2B activity when administered in vivo for two weeks. Considering relatively high pharmacological/therapeutic doses and liver concentrations of phenothiazines, it seems that the direct inhibitory effect of those neuroleptics with Ki values below 100 microM found in vitro (thioridazine, chlorpromazine, perazine), as well as indirect effects produced by one-day treatment with haloperidol, risperidone or sertindole may be of some physiological, pharmacological or toxicological importance in vivo.     

Sertindole: efficacy and safety in schizophrenia

Sertindole is an antipsychotic drug with affinity for dopamine D2, serotonin 5-HT2A and 5-HT2C, and alpha1-adrenoreceptors. Preclinical studies suggest that sertindole acts preferentially on limbic and cortical dopaminergic neurons and clinical trials have confirmed that sertindole is effective at a low dopamine D2 occupancy level. The active substance has a long half-life. Oral administration once daily yields highly stable plasma levels. These features may explain the clinically observed low frequency of extrapyramidal side effects, including tardive dyskinesia. In contrast to most antipsychotics, sertindole seems to be void of sedative effects. However, although not strictly proven by objective neuropsychological tests, this asset of sertindole does not add to the cognitive problems inherent in schizophrenia. Administration of sertindole is more often associated with prolongation of QTc compared with most other currently used antipsychotics. However, large cohort analyses do not suggest that all-cause mortality is higher with sertindole than with, for example, risperidone or olanzapine. The effective antipsychotic dose range of sertindole is 12-20 mg/day, with small variations among patients. The frequency of most adverse events, for example extrapyramidal symptoms and somnolence, with such a dose does not differ from placebo. Three side effects have been more common than with placebo/haloperidol in short-term studies: weight gain, rhinitis and a decreased ejaculation volume. Two head-to-head comparisons (one in treatment-resistant patients) of sertindole and risperidone showed equivalent effects on positive symptoms. For negative symptoms, one study obtained equivalent effects and one a superior effect of sertindole. Sertindole should not be used as first-line treatment for first-episode patients with schizophrenia because of the QTc prolongation. It has a side-effect profile that makes it an interesting alternative for many patients who do not respond well to the initial choice of antipsychotic drug.     

Paliperidone: new drug. Just a metabolite of risperidone, a neuroleptic soon off-patent

(1) For patients with schizophrenia, risperidone is one of many available neuroleptics. It has no tangible advantages over conventional neuroleptics such as haloperidol. (2) Paliperidone, the main active metabolite of risperidone, has now arrived on the European market, in the form of sustained-release osmotic tablets. Clinical evaluation is based on 3 placebo-controlled trials lasting 6 weeks. As expected, paliperidone was effective in relieving symptoms of schizophrenia. However, it was no more effective than olanzapine and has not been compared with risperidone. (3) The adverse effect profile of paliperidone in these trials was predictable, consisting mainly of short-term neurological effects and dose-dependent weight gain. Paliperidone also provokes tachycardia and lengthens the QT interval in some patients. The rigid osmotic tablets can cause gastrointestinal complications. (4) Paliperidone does not represent a therapeutic advance. It is better to continue using a conventional neuroleptic such as haloperidol.     

Inhibition of rat liver CYP2D in vitro and after 1-day and long-term exposure to neuroleptics in vivo-possible involvement of different mechanisms.

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2D measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally (i.p.) for 1-day or 2-weeks (twice a day) with pharmacological doses of the drugs (promazine, levomepromazine, thioridazine, perazine 10 mg kg(-1); chlorpromazine 3 mg kg(-1); haloperidol 0.3 mg kg(-1); risperidone 0.1 mg kg(-1); sertindole 0.05 mg kg(-1)), in the absence of the neuroleptics in vitro. Neuroleptics added in vitro to control liver microsomes decreased the activity of the rat CYP2D by competitive or mixed inhibition of the enzyme. Thioridazine (Ki=15 microM) was the most potent inhibitor of the rat CYP2D among the drugs studied, whose effect was more pronounced than that of the other neuroleptics tested: phenothiazines (Ki=18-23 microM), haloperidol (Ki=32 microM), sertindole (Ki=51 microM) or risperidone (Ki=165 microM). The investigated neuroleptics-when given to rats in vivo-also seemed to exert an inhibitory effect on CYP2D via other mechanisms. One-day exposure of rats to the classic neuroleptics decreased the activity of CYP2D in rat liver microsomes. After chronic treatment with the investigated neuroleptics, the decreased CYP2D activity produced by the phenothiazines was still maintained, while that caused by haloperidol diminished. Moreover, risperidone decreased the activity of that enzyme. The obtained results indicate drug- and time-dependent interactions between the investigated neuroleptics and the CYP2D subfamily of rat cytochrome P-450, which may proceed via different mechanisms: (1) competitive or mixed inhibition of CYP2D shown in vitro, the inhibitory effects of phenothiazines being stronger than those of haloperidol or atypical neuroleptics, but weaker than the effects of the respective drugs on human CYP2D6; (2) in vivo inhibition of CYP2D, produced by both 1-day and chronic treatment with phenothiazines, which suggests inactivation of enzyme by intermediate metabolites; (3) in vivo inhibition of CYP2D by risperidone, produced only by chronic treatment with the drug, which suggests its influence on the enzyme regulation.     

Sertindole: pharmacological and clinical profile and role in the treatment of schizophrenia

BACKGROUND: Sertindole is a second-generation antipsychotic recently reintroduced in the market for the treatment of schizophrenia after a reevaluation of its risks and benefits. OBJECTIVE: This article provides an overview of the pharmacological properties of sertindole as well as of its efficacy, tolerability and safety profile. METHODS: Several clinical trials and large-scale epidemiological studies have evaluated the efficacy and tolerability of sertindole in patients with schizophrenia. RESULTS/CONCLUSIONS: Findings from controlled clinical trials have demonstrated that sertindole is at least as effective as haloperidol and risperidone against the positive symptoms of schizophrenia, while it appears superior against negative symptoms. Preliminary evidence suggests that sertindole has beneficial effects on cognitive function. Sertindole is associated with a low rate of extrapyramidal side effects, lacks sedative properties, and may induce a moderate weight gain. No clinically relevant elevations in serum prolactin, glucose or lipid levels have been so far documented in sertindole-treated patients. On the other hand, administration of sertindole may result in a prolongation of the QTc interval, with subsequent risk of serious arrhythmias. However, postmarketing surveillance studies have recently indicated that sertindole is not associated with a higher rate of cardiovascular mortality than other antipsychotic agents.     

Direct effects of neuroleptics on the activity of CYP2A in the liver of rats

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2A measured as a rate of testosterone 7alpha-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally (i.p.) for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (promazine, levomepromazine, thioridazine, perazine 10, chlorpromazine, haloperidol 0.3, risperidone 0.1, sertindole 0.05), in the absence of the neuroleptics in vitro. Most of the neuroleptics added in vitro to control liver microsomes decreased the activity of the rat CYP2A. Chlorpromazine (Ki = 11 microM) was the most potent inhibitor of the rat CYP2A among the studied drugs, whose effect was more pronounced than that of the other tested phenothiazines (Ki = 41-83 microM), haloperidol (Ki = 190 microM) or sertindole (Ki = 78 microM). Risperidone was not active in this respect. The investigated neuroleptics when given to rats in vivo for one day or two weeks--did not produce any indirect inhibitory effect on CYP2A via other mechanisms. The obtained results show direct inhibitory effects of phenothiazine neuroleptics on the activity of CYP2A in rat liver, which may be of physiological importance for the metabolism of testosterone, considering simultaneous inhibition of CYP2C11 and CYP3A by those drugs.     

Pharmacogenetics of classical and new antipsychotic drugs

Several classical antipsychotic drugs, i.e., chlorpromazine, haloperidol, perphenazine, thioridazine and zuclopenthixol; and some new neuroleptic drugs, i.e., risperidone and sertindole, are metabolized predominantly by cytochrome P450 (CYP) 2D6. Significant relationships have been reported between the steady state plasma concentrations (Css) of some classical neuroleptics and the CYP2D6 activity or genotype. Several of these drugs also potently inhibit the CYP2D6 activity. These facts explain several drug metabolic interactions of the classical drugs. Two studies failed to show that the CYP2D6 activity predicts the therapeutic effects of haloperidol or perphenazine. Some studies have suggested that the poor metabolizer phenotype is associated with the development of oversedation during treatment with the classical drugs, but other studies have been inconsistent or negative. The CYP2D6 phenotyping and genotyping appear to be useful in predicting the Css of some classical drugs, but their usefulness in predicting clinical effects must be further explored.     

Sertindole and several antipsychotic drugs differentially inhibit the discriminative stimulus effects of amphetamine, LSD and St 587 in rats

The effects of sertindole, clozapine, Cis(Z)-flupentixol and haloperidol on the discriminative stimulus properties of d-amphetamine (dopamine DA stimulant), d-LSD (5-HT(2) agonist) and St 587 (alpha(1)-adrenoceptor agonist; 2-chloro-5-trifluoromethyl-phenylimino)-imidazolidine) have been studied. Sertindole, a putative antipsychotic compound with limbic selectivity, antagonized the effects of d-LSD and St 587, whereas that of d-amphetamine was unchanged. Clozapine preferentially inhibited St 587, but also antagonized d-LSD and d-amphetamine, together with increases in reaction time. Cis(Z)-flupentixol antagonized d-amphetamine and St 587 effects, whereas haloperidol antagonized d-amphetamine only. Behavioural disruption was induced by haloperidol in St 587 and d-LSD-trained animals. The 5-HT(2) antagonist ketanserin selectively inhibited the effect of d-LSD, and the selective alpha(1)-adrenoceptor antagonist prazosin partially inhibited the effect of St 587, but did not inhibit d-LSD or d-amphetamine. The partial inhibition of St 587 effects by prazosin was not further increased by co-treatment with haloperidol. Prazosin partially substituted for the training dose of St 587. The results indicate that drug discrimination techniques can be used to demonstrate different activity profiles of typical and atypical neuroleptics. The classical neuroleptics have preferential amphetamine antagonistic activity, whereas clozapine has a broad activity profile. Furthermore, the atypical neuroleptic sertindole fails to induce acute DA antagonism in doses much higher than those inhibiting d-LSD and St 587.     

Quetiapine. A me-too neuroleptic; no panacea

Quetiapine, a so-called atypical neuroleptic, is authorised in the European Union for use in the standard indications of neuroleptics. However, it is the only neuroleptic licensed for the treatment and prevention of depressive episodes in patients with bipolar disorder, and as add-on therapy for depressive episodes inadequately improved by an antidepressant. In patients with schizophrenia, the authors of two meta-analyses, one including 12 trials (3443 patients) and the other 21 trials (4101 patients), concluded that quetiapine was not clearly more effective than other conventional or atypical neuroleptics. In bipolar patients with manic episodes, the results of two trials suggest that quetiapine monotherapy is not more effective than haloperidol or lithium. Two placebo-controlled trials of add-on quetiapine therapy in patients receiving a mood stabiliser (lithium or divalproate sodium) yielded conflicting results. In bipolar patients with a depressive episode, the only available trial, versus placebo and versus paroxetine in 740 patients, failed to provide conclusive evidence. In two trials with controversial designs, in which quetiapine was added to a mood stabiliser in order to prevent new depressive or manic episodes in bipolar patients, quetiapine appeared to be more effective than placebo: about 15% to 20% more patients were stabilised on quetiapine than on placebo. There are no trials to show whether quetiapine is more effective in preventing manic episodes than a neuroleptic. In a trial including 1226 patients in whom quetiapine was effective during a first depressive or manic episode, quetiapine appeared to be more effective than lithium in preventing a depressive episode (relapse rate 8.9% versus 13.5%) but not a manic episode. These comparisons may be biased, however. Two placebo-controlled trials assessed quetiapine add-on therapy in patients in whom an antidepressant was inadequately effective. The conflicting results obtained in these two trials rule out drawing firm conclusions as to the efficacy of quetiapine. Overall, quetiapine has the adverse effect profile common to atypical neuroleptics. However, hypercholesterolaemia is more frequent than with risperidone, and both clinical trials and post-marketing data have shown that quetiapine carries a risk of hypothyroidism. Animal studies suggested a risk of cataracts, but this adverse effect has not yet been confirmed in humans. The risk of sudden cardiovascular death appears similar to that reported with other neuroleptics. A retrospective survey suggests that the consequences of acute overdose are more severe with quetiapine than with other neuroleptics. Quetiapine is metabolised by cytochrome P450 isoenzyme CYP3A4, creating a high risk of pharmacokinetic interactions. In practice, quetiapine has not been shown to provide a therapeutic advantage over other treatments, although additional trials in the prevention of depressive episodes are warranted in selected patients.     

A double-blind, controlled study of sertindole versus risperidone in the treatment of moderate-to-severe schizophrenia

Sertindole is a non-sedating atypical antipsychotic effective in the management of schizophrenia and is associated with placebo-level incidence of extrapyramidal symptoms (EPS). In this randomized, double-blind, parallel-group, flexible-dose, multi-centre study, the efficacy and tolerability of sertindole was directly compared with another atypical antipsychotic in patients with schizophrenia. A total of 187 patients were randomly assigned to treatment with sertindole (12-24 mg/day, n=98) or risperidone (4-10 mg/day, n=89) for 12 weeks. Although early termination reduced the power of the study, some significant between-group differences were evident. Sertindole reduced the mean Positive and Negative Syndrome Scale total scores to a greater extent than risperidone, and the difference reached statistical significance at endpoint for the Observed Cases (OC) dataset. Moreover, sertindole was superior for the treatment of negative symptoms compared to risperidone (P<0.05, Last Observation Carried Forward and OC). Both treatment groups were similarly effective in improving Clinical Global Impression (Severity and Improvement), the Drug Attitude Inventory and Global Assessment of Functioning scores. Sertindole and risperidone were both well tolerated. Numerically, fewer patients in the sertindole group (19%) reported EPS-related adverse events than in the risperidone group (28%), although significantly more sertindole-treated patients reported QT prolongation and abnormal ejaculation volume (P<0.05). In conclusion, sertindole was well tolerated and demonstrated clinically relevant efficacy advantages over risperidone.     

Aripiprazole: new drug. Just another neuroleptic

(1) Neuroleptics are the standard treatment for schizophrenia. The first drugs of this class, such as haloperidol, were marketed nearly 50 years ago, and neuroleptics released over the past 15 last years have provided no major advance. (2) Aripiprazole is a new neuroleptic licensed for the treatment of schizophrenia. (3) Five double-blind placebo-controlled trials lasting 4 to 6 weeks showed that aripiprazole was a little more effective than placebo at daily doses of 10 mg to 30 mg, without a clear dose-response relationship. Based on the least demanding definition of "treatment response" (a 30% reduction in the PANSS global score), less than 50% of patients responded to aripiprazole. (4) In a double-blind trial lasting 6 months, aripiprazole 15 mg/day was more effective than placebo in preventing acute relapses of schizophrenia (34% versus 57%), but the clinical relevance of the combined endpoint used to define relapse is unclear. (5) The only double-blind comparison versus another neuroleptic (haloperidol) involved two trials that were pooled for analysis. Haloperidol was provided at a moderate dose (10 mg/day). These trials were designed to demonstrate the superiority of high-dose aripiprazole (30 mg/day), but failed to do so. The proportion of patients who "responded" during an acute episode, based on the least stringent definition, was about 70% in both groups. In both groups, response persisted in approximately three-quarters of patients. (6) Aripiprazole exhibits the adverse effects classically seen with neuroleptics. In clinical trials, daily doses of aripiprazole, ranging from 15 mg to 30 mg, provoked fewer extrapyramidal disorders than haloperidol 10 mg/day. In contrast, there was no difference in the frequency of extrapyramidal disorders with aripiprazole 20 or 30 mg/day and risperidone (6 mg). Aripiprazole has no proven advantage over haloperidol in terms of the risk of tardive dyskinesia. One trial showed no difference between aripiprazole and olanzapine in the risk of diabetes. Weight gain appears to be comparable with aripiprazole and haloperidol. Aripiprazole provoked postural hypotension and neuroleptic malignant syndrome, but the precise risk relative to other neuroleptics has not been documented. Supra-therapeutic doses of aripiprazole cause dose-dependent QT prolongation. (7) Increased mortality was seen in elderly patients treated with aripiprazole. (8) Animal studies have shown retinal degeneration in rats and biliary lithiasis in monkeys. These adverse effects have not been observed in clinical trials, but they have not been specifically assessed in humans. (9) Animal studies raised the possibility of fetal toxicity and teratogenicity. (10) The aripiprazole dose must be either halved or doubled during co-administration with inhibitors or inducers of cytochrome P450 isoenzymes CYP 3A4 and CYP 2D6. (11) In practice, there are too many unanswered questions to recommend aripiprazole for patients with schizophrenia.     

Neurochemical and in vivo pharmacological profile of sertindole,a limbic-selective neuroleptic compound

Sertindole (5-chloro-1-(4-fluorophenyl)-3-[1-[2-(2-imidazolidinon-1-yl)ethyl]-4-Piperidyl]-1H-indole) is a new neuroleptic with a very high selectivity for dopamine (DA) neurones in the ventral tegmental area compared to DA neurones in substantis nigra pars compacta (Skarsfeldt, T., and Perregaard, J. Eur. J. Pharmacol. 182 :613–614, 1990). Neurochemical and behavioural effects of sertindole have been investigated in comparison with the classical neuroleptics haloperidol and fluphenazine and the atypical neuroleptic clozapine. In vitro sertindole has high affinity for serotonin S₂ (5-HT₂) receptors, DA D-2 receptors, and α₁-adrenoceptors, moderate affinity for DA D-1 receptors; low affinity for α₂-adrenoceptors, histamine H₁ receptors and sigma receptors; and no affinity for 5-HT_1A, muscarine cholinergic receptors, and β-adrenoceptors. The in vivo pharmacology is atypical, i.e., a remarkably weak or no effect in acute tests for DA antagonism, and the cataleptogenic potential is very low. Sertindole shows a very potent and long-acting antagonism at central as well as peripheral 5-HT₂ receptors. The antagonistic effect at peripheral α₁-adrenoceptors is relatively weak in comparison with the 5-HT₂ antagonistic potency in vivo and in vitro. Sertindole shows no anticholinergic effects. In conclusion the pharmacological profile suggests that sertindole is an atypical neuroleptic compound with a low potential for extrapyramidal, autonomic, and anticholinergic side effects.     

Effect of neuroleptics on cytochrome P450 2C11 (CYP2C11) in rat liver

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of cytochrome P450 2C11 (CYP2C11), measured as a rate of testosterone 2α- and 16α-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in the microsomes of rats treated intraperitoneally (ip) with pharmacological doses of the drugs (promazine, levomepromazine, thioridazine and perazine 10 mg/kg; chlorpromazine 3 mg/kg; haloperidol 0.3 mg/kg; risperidone 0.1 mg/kg; sertindole 0.05 mg/kg) for one day or two weeks (twice a day), in the absence of the neuroleptics in vitro. The investigated neuroleptics added to control liver microsomes produced some inhibitory effects on CYP2C11 activity, which were moderate (thioridazine: K(i) = 55), modest (sertindole and perazine: K(i) = 76 and 94 μM, respectively) or week (promazine, levomepromazine, haloperidol and chlorpromazine: K(i) = 285, 280, 223 and 157 μM, respectively). Risperidone had the weakest inhibitory effect on the CYP2C11 activity (K(i) = 641 μM). One-day exposure of rats to the neuroleptics did not significantly change the activity of CYP2C11 in liver microsomes. Of the neuroleptics studied, only chronic treatment with levomepromazine, perazine and thioridazine diminished CYP2C11 activity; those effects were positively correlated with the observed decreases in the protein level of the enzyme. The in vivo inhibition of CYP2C11 by chronic treatment with the three phenothiazines suggests their influence on the enzyme regulation. A possible mechanism of CYP2C11 regulation by the neuroleptics and its pharmacological significance are discussed.