Oral Paliperidone Research Articles

Flexible dosing with paliperidone ER in the treatment of patients with acutely exacerbated schizophrenia: results from a single-arm, open-label study

Objective:To extend findings from fixed-dose, double-blind, placebo-controlled clinical trials in selected patient populations by using flexibly-dosed oral paliperidone extended-release (ER) in a more naturalistic setting.Methods:Adults hospitalized with an acute exacerbation of schizophrenia were prospectively treated with open-label flexibly-dosed paliperidone ER 3–12 mg/day for 6 weeks.Results:Overall, 294 patients were treated. The primary endpoint, defined as ≥30% improvement in Positive and Negative Syndrome Scale total scores from baseline to endpoint, was achieved by 66.3% of patients. The percentage of patients rated as at least ‘markedly ill’ in Clinical Global Impression of Severity scale decreased from baseline (74.1%) to endpoint (20.0%). Patient functioning, assessed by the Personal and Social Performance scale, improved significantly from 50.0 ± 14.3 at baseline to 63.6 ± 14.9 at endpoint (p < 0.0001). Concomitant benzodiazepines were newly initiated in 191 patients (65.0%), and new concomitant medications other than benzodiazepines were started after baseline for 133 patients (45.2%), most frequently paracetamol, zolpidem, and zopiclone. No unexpected adverse events were identified.Conclusions:These data support findings in more selected patient populations treated with fixed-dose paliperidone ER. Flexibly-dosed paliperidone ER administered in a naturalistic hospital setting to a more representative patient population experiencing an acute episode of schizophrenia, was associated with clinically meaningful treatment response. Strength of conclusions is limited by the open-label design and lack of a comparator group. Furthermore, some of the improvements observed may in part be associated with increased attention provided to patients and concomitant use of psychotropic medications, such as benzodiazepines, during this study.

Management of antipsychotic treatment discontinuation and interruptions using model-based simulations.

BackgroundMedication nonadherence is a well described and prevalent clinical occurrence in schizophrenia. These pharmacokinetic model-based simulations analyze predicted antipsychotic plasma concentrations in nonadherence and treatment interruption scenarios and with treatment reinitiation.MethodsStarting from steady state, pharmacokinetic model-based simulations of active moiety plasma concentrations of oral, immediate-release risperidone 3 mg/day, risperidone long-acting injection 37.5 mg/14 days, oral paliperidone extended-release 6 mg/day, and paliperidone palmitate 117 mg (75 mg equivalents)/28 days were assessed under three treatment discontinuation/interruption scenarios, ie, complete discontinuation, one week of interruption, and four weeks of interruption. In the treatment interruption scenarios, pharmacokinetic simulations were performed using medication-specific reinitiation strategies.ResultsFollowing complete treatment discontinuation, plasma concentrations persisted longest with paliperidone palmitate, followed by risperidone long-acting injection, while oral formulations exhibited the most rapid decrease. One week of oral paliperidone or risperidone interruption resulted in near complete elimination from the systemic circulation within that timeframe, reflecting the rapid elimination rate of the active moiety. After 1 and 4 weeks of interruption, minimum plasma concentrations were higher with paliperidone palmitate than risperidone long-acting injection over the simulated period. Four weeks of treatment interruption followed by reinitiation resulted in plasma levels returning to predicted therapeutic levels within 1 week.ConclusionDue to the long half-life of paliperidone palmitate (25–49 days), putative therapeutic plasma concentrations persisted longest in simulated cases of complete discontinuation or treatment interruption. These simulations may help clinicians better conceptualize the impact of antipsychotic nonadherence on plasma concentrations, and the impact of medication-specific reinitiation strategies after intermittent nonadherence.

Oral paliperidone extended-release: chemistry, pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability

Introduction: Paliperidone is a second-generation (atypical) antipsychotic approved for the treatment of schizophrenia in adults and in adolescents aged 12 – 17 years. It is also approved for the treatment of adults with schizoaffective disorder, both as a monotherapy and as adjunctive therapy to mood stabilizers and/or antidepressants. Paliperidone is the active metabolite of risperidone.Areas covered: The purpose of this review is to describe the pharmacokinetic profile of paliperidone and its clinical implications in the treatment of schizophrenia and schizoaffective disorder. Background information is also provided regarding chemistry, pharmacodynamics, clinical efficacy and safety/tolerability data.Expert opinion: The recommended dose of paliperidone extended-release (ER) in adults is 6 mg/day and no initial dose titration is required. Higher doses may provide additional benefit as well as dose-related increases in some adverse reactions. The maximum recommended dose is 12 mg/day. Peak plasma concentrations are reached approximately 24 h after dosing. Pharmacokinetics are dose-proportional. Terminal half-life is approximately 23 h. Renal excretion is the major route of elimination. Although paliperidone is the active metabolite of risperidone, paliperidone's route of metabolism and elimination is quite different from that for risperidone and paliperidone ER may be preferred over risperidone when liver disease, drug–drug interactions or other alterations in metabolism render the appropriate dosing of risperidone difficult to determine for an individual patient. The use of paliperidone ER will need to be considered within the context of its cost and availability as risperidone is now a generic product.

Extended-Release Intramuscular Paliperidone Palmitate

Extended-release intramuscular paliperidone palmitate (Xeplion®; Invega® Sustenna®) [henceforth referred to as intramuscular paliperidone palmitate] is a long-acting injectable (LAI) formulation of the well established atypical antipsychotic agent paliperidone (9-hydroxyrisperidone), which is the major active metabolite of risperidone. This article reviews, from an EU perspective, the therapeutic efficacy and tolerability of intramuscular paliperidone palmitate in the treatment of adults with schizophrenia, and the pharmacology of paliperidone that is relevant to the intramuscular formulation. Intramuscular paliperidone palmitate 25-150 mg equivalents (mg eq.) effectively reduced symptoms of schizophrenia in most short-term (9-13 weeks) placebo-controlled trials, as demonstrated by improvements in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint that were significantly greater in intramuscular paliperidone palmitate than placebo recipients. The onset of clinical response was 8 days in patients who received the recommended initial 150 mg eq. dose of intramuscular paliperidone palmitate into the deltoid muscle on day 1. In a longer-term (24-week maintenance phase and variable length double-blind phase) placebo-controlled trial, intramuscular paliperidone palmitate was associated with a significantly longer time to relapse than placebo in patients with schizophrenia at a preplanned interim analysis conducted after 68 relapse events. Because of these favourable results, the study was terminated early. In two 13-week trials, one of which was conducted in Chinese patients, intramuscular paliperidone palmitate administered using the recommended initiation dosage regimen was noninferior to LAI-risperidone in patients with schizophrenia in terms of the between-group treatment difference (intramuscular paliperidone palmitate vs LAI-risperidone) for the mean change from baseline to endpoint in PANSS total score. The tolerability of intramuscular paliperidone palmitate was generally acceptable in clinical trials of schizophrenia. No new safety concerns were revealed compared with oral paliperidone, except for injection site-related reactions. In conclusion, intramuscular paliperidone palmitate is a useful option for the treatment of patients with schizophrenia.

Oral Paliperidone

Oral paliperidone extended or prolonged release (Invega®) is an atypical antipsychotic, and is the first agent approved for the treatment of schizoaffective disorder. Paliperidone (or 9-hydroxyrisperidone) is the major active metabolite of the well known atypical antipsychotic risperidone, and its mechanism of action is thought to be the antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors. The clinical efficacy of paliperidone was demonstrated in two 6-week, randomized, double-blind, placebo-controlled, multicentre trials in patients with schizoaffective disorder. One trial was flexible dose in design (3-12 mg/day) and the other was fixed dose in design (3-6 and 9-12 mg/day). Compared with placebo, the change from baseline at study end in the Positive and Negative Syndrome Scale (PANSS) total score (primary endpoint) was significantly greater with paliperidone 3-12 mg/day in one trial and with 9-12 mg/day (but not 3-6 mg/day) in the other trial. However, pooled analyses reported a significantly greater change in PANSS total score across all paliperidone dosages than with placebo. Paliperidone was generally well tolerated in the 6-week trials, and no unexpected adverse events were reported. The most commonly reported treatment-emergent adverse events were headache, tremor, dizziness, insomnia, nausea, akathisia, dyspepsia, hypertonia, somnolence and sedation. Although long-term efficacy and tolerability data and comparisons with other antipsychotics are needed, paliperidone appears to be a useful agent for the short-term management of patients with schizoaffective disorder.

A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia

This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N=452) with schizophrenia were randomized (1:1) to either PP (N=229; deltoid injections on day 1 [150 mg eq.] and day 8 [100 mg eq.]; then once-monthly deltoid or gluteal injections, flexibly dosed [50, 100, or 150 mg eq.]), or RIS-LAI (N=223; once-biweekly gluteal injections, flexibly dosed [25, 37.5 or 50 mg]). RIS-LAI-treated patients received oral risperidone supplementation (1-6 mg/day) at initiation and with RIS-LAI dose increases. Mean (SD) Positive and Negative Syndrome Scale (PANSS) total score at baseline was 83.2 (12.44). Mean (SD) change from baseline to endpoint in PANSS total scores (primary efficacy measure) was: -23.6 (16.28) for PP group and -26.9 (15.43) for RIS-LAI group. PP was noninferior to RIS-LAI (least squares mean difference [95% CI]: -2.3 [-5.20; 0.63]; predetermined non-inferiority margin: -5.5). Mean (SD) change from baseline to endpoint in Clinical Global Impression-Severity scale score was: -1.5 (1.24; PP group), -1.7 (1.16; RIS-LAI group) and in Personal and Social Performance Scale scores was: 16.8 (14.76; PP group), 18.6 (13.92; RIS-LAI group). The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups (73% [PP]; 75% [RIS-LAI]). The most common TEAEs were akathisia, tremor, and insomnia. The study demonstrated the noninferiority of PP (50-150 mg eq., flexibly dosed, without oral paliperidone supplementation) to risperidone-LAI (25-50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population.

Paliperidone palmitate - review of the efficacy, safety and cost of a new second-generation depot antipsychotic medication

To describe the efficacy, safety and cost of paliperidone palmitate, a depot antipsychotic medication recently approved for the treatment of schizophrenia. A literature search was conducted by querying the websites http://www.pubmed.gov, http://www.fda.gov, http://www.accessdata.fda.gov/scripts/cder/drugsatfda and http://www.clinicaltrials.gov for the search term 'paliperidone palmitate'. Cost information was obtained from the pharmaceutical vendor servicing a local state-operated psychiatric facility. All available reports of studies were identified. Product labelling provided additional information. Descriptions of the principal results and calculation of the number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the study reports and synopses. Additional safety outcomes subject to NNH analysis were obtained from product labelling. Paliperidone palmitate is a newly available depot formulation of paliperidone (the 9-OH metabolite of risperidone). Upon injection into the deltoid or gluteal muscle, the release of the drug starts as early as day 1, reaches maximum plasma concentrations at 13 days and lasts for as long as 126 days. Maximum concentration following deltoid injection is approximately 28% higher compared with injection into the gluteal muscle, and thus paliperidone palmitate requires initiation by two initial deltoid injections spread 1 week apart to achieve therapeutic concentrations rapidly. Subsequent injections are at 4-week intervals. Acute efficacy was evidenced by four short-term double-blind, randomised, placebo-controlled, fixed-dose studies of acutely relapsed adult inpatients who met DSM-IV criteria for schizophrenia. NNT for a 30% or greater decrease in the Positive and Negative Syndrome Scale total score compared with placebo was consistently lower for the higher dose strengths of 156 and 234 mg, suggesting a therapeutic dose-response. Treatment with paliperidone palmitate at doses between 39 and 156 mg significantly delayed the time to recurrence of symptoms of schizophrenia after 24 weeks of maintained symptom stability. The NNT vs. placebo to avoid a recurrence of symptoms was 5 (95% CI 4-7). Overall, paliperidone palmitate was reasonably well tolerated, with low rates of extrapyramidal symptoms or body weight gain; however, these may be more common at higher doses. Injection site reactions occurred at a rate ranging from 4% to 10%, depending on the dose regimen, compared with 2% for the pooled placebo arms. The acquisition cost of a maintenance dose of paliperidone palmitate calculated on a per day basis is similar to that for risperidone microspheres, but about double the cost for oral paliperidone and approximately 19 times the cost of oral generic risperidone. Paliperidone palmitate is efficacious for the acute and maintenance treatment of schizophrenia and is reasonably well tolerated. It offers several advantages over other available second-generation depot antipsychotics: it comes in prefilled syringes in a number of different dosage strengths; it does not require refrigeration; it does not require supplementation with oral antipsychotics; it can be administered once monthly; it can be administered with a very small bore needle; the injection volume is small; the injection site can be either the deltoid or gluteal muscles; it does not require an additional precautionary observation period after the injection. For patients for whom oral risperidone or paliperidone is otherwise effective, paliperidone palmitate offers a guaranteed delivery system that enhances adherence. However, the high acquisition cost of paliperidone palmitate will likely be an important obstacle to its routine use.

P03-194 Safety, tolerability and efficacy of flexible doses of paliperidone ER in non-acute patients with schizophrenia

Objective:To explore tolerability, safety and efficacy of flexible doses of oral paliperidone ER in adult non-acute patients with schizophrenia requiring a change in their medication due to lack of efficacy with their previous oral antipsychotic.Methods:Interim analysis of a prospective 6-month, open-label, international study. Patients completing the first 3 months of this study were analyzed. Endpoints were the change in the Positive and Negative Syndrome Scale (PANSS) from baseline to endpoint, Clinical Global Impression-Severity Scale (CGI-S), weight change and adverse events (AEs).Results:81 patients were included (57% male, mean age 41.3±13.6 years, 85% paranoid schizophrenia). 89% of the 81 patients completed the first 3 months of the study. Reasons for early discontinuation were lack of efficacy (3.7%), subject choice (2.5%), loss to follow-up (2.5%) and AE (1.2%). the mean mode dose of paliperidone ER was 6 mg/day. Mean total PANSS decreased from 82.8±16.0 at baseline to 69.2±19.1 at endpoint (mean change -13.6±15.6; 95% confidence interval [CI]-17.0;-10.1, p&lt; 0.0001). the percentage of patients rated mildly ill or less in CGI-S increased from 19.8% to 49.4%. AEs reported in ≥3% were insomnia (4.9%), somnolence (4.9%), extrapyramidal disorder (3.7%), restlessness (3.7%) and psychotic disorder (3.7%). Mean weight change from baseline to endpoint was 0.34 kg (95%CI -0.35;1.03, p=0.71).Conclusion:These interim open-label data support results from recent randomized controlled studies that flexibly dosed paliperidone ER is safe, well tolerated and effective in patients with schizophrenia requiring a change in medication due to lack of efficacy with their previous oral antipsychotic treatment.

P03-195 Safety, tolerability and treatment response of flexible doses of paliperidone ER in acutely exacerbated patients with schizophrenia

Objective:To explore tolerability, safety and treatment response of flexible doses of oral paliperidone ER in patients with schizophrenia suffering from an acute episode.Methods:Interim analysis of a 6-week prospective, open-label, international study. Endpoints were the rate of responders defined as a ≥30% improvement in the Positive and Negative Syndrome Scale (PANSS) from baseline to endpoint, the Clinical Global Impression-Severity Scale (CGI-S), weight change and adverse events (AEs).Results:100 patients were analyzed (51% male, mean age 39.0±11.6 years). 82% of patients completed the study. Most frequent reasons for early discontinuation were subject choice (10%) and lack of efficacy (7%). the mean dose of paliperidone ER was 5.9 mg/day at baseline and 7.9 mg/day at endpoint. an improvement of ≥30% in total PANSS was observed in 68% of patients (95% confidence interval [CI]58%;77%], with a decrease in mean total PANSS scores from 98.2±16.2 at baseline to 71.1±20.3 at endpoint (mean change -27.1±19.9; 95%CI -31.1;-23.2, p&lt; 0.0001) and onset of efficacy as of day 2. the percentage of patients rated as at least markedly ill in CGI-S decreased from 69% to 20.3%. AEs reported in ≥5% were insomnia (14%), tachycardia (10%), akathisia (6%), extrapyramidal disorder (6%), headache (5%) and schizophrenia (5%). Median weight gain was 0.7 kg (95% CI 0.19;1.96) from baseline to endpoint.Conclusion:This analysis supports data from recent controlled studies that flexibly dosed paliperidone ER is safe, well tolerated and associated with a clinically meaningful treatment response in patients with an acute schizophrenic episode.

Efficacy and safety of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 52-week open-label studies

Long-term efficacy and safety of paliperidone extended-release tablets (3-12 mg/day) were evaluated in pooled data from 52-week open-label extension (OLE) phases of three 6-week, placebo-controlled, double-blind (DB) trials involving 1083 schizophrenia patients. Forty-seven percent of patients completed the OLE phase. Outcome measures included Positive and Negative Syndrome Scale and Personal and Social Performance scale scores. Improvements observed on both scales in active treatment groups during the DB phases were maintained during the OLE phase. Most commonly (> or =10% patients) reported adverse events (AEs) were insomnia, headache, and akathisia. One or more serious AEs were reported by 16% of patients; two patients had a treatment-emergent AE that resulted in death (suicide). Extrapyramidal symptom-related AEs were reported by 25% of patients. Median maximum movement disorder rating scale scores indicated no severity change during the OLE. Mean (+/-SD) increase in body weight from OLE baseline to end point was 1.1+/-5.47 kg across treatment groups and there were no clinically meaningful changes for plasma glucose, insulin or lipid levels. This analysis shows that paliperidone extended-release can maintain improvements in symptoms and functioning and is generally well tolerated for up to 52 weeks in schizophrenia patients.

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Efficacy and Tolerability of Oral Paliperidone Extended-Release Tablets in the Treatment of Acute Schizophrenia

To evaluate the efficacy and safety of an extended-release (ER) formulation of paliperidone in patients with an acute episode of schizophrenia, in the dosage range of 3 to 15 mg daily. A pooled analysis of 3 similarly designed 6-week, multicenter, double-blind, randomized, fixed-dose, placebo-controlled studies in 1326 patients with acute schizophrenia (Positive and Negative Syndrome Scale [PANSS] total score of 70-120) was performed. Patients were randomly assigned to receive 3, 6, 9, 12, or 15 mg daily of paliperidone ER or placebo. Efficacy and safety assessments were performed. The primary endpoint was change in PANSS total score from baseline to endpoint. PANSS total, PANSS subscale factor, and Personal and Social Performance scale scores significantly improved at endpoint for all doses of paliperidone ER relative to placebo (p <or= .001). A significantly greater proportion of paliperidone ER-treated patients at all doses achieved a clinical response compared with placebo (p <or= .001). Treatment-emergent adverse events (TEAEs) occurred in 66% to 77% of patients in the paliperidone ER groups and 66% of patients in the placebo group; serious TEAEs occurred in 6% of patients who received placebo and 5% to 6% of paliperidone ER-treated patients. Regardless of treatment group, median Simpson-Angus Rating Scale global, Abnormal Involuntary Movement Scale total, and Barnes Akathisia Rating Scale scores were 0 at both baseline and endpoint. There were no clinically relevant differences in measures of body weight gain, glucose handling, lipid metabolism, or proportion of patients with abnormal corrected QT intervals on electrocardiography and no important differences between the proportion of patients who received paliperidone ER or placebo who reported potentially glucose- or prolactin-related events. Paliperidone ER given once daily for 6 weeks appears to be a safe, well-tolerated, and effective treatment for patients with acute schizophrenia.

Oral paliperidone for schizophrenia

Paliperidone, risperidone's active metabolite, is now available in an oral formulation for daily use, and an intramuscular formulation for monthly administration may follow shortly. To compare effects of oral paliperidone with any other treatment for people with schizophrenia and schizophrenia-like illnesses. We searched the Cochrane Schizophrenia Group's Register (December 2006), and inspected references of identified studies for further trials. We contacted the manufacturers of paliperidone, the Food and Drug Administration, and authors of relevant trials for additional material. We included all relevant randomised trials. We independently selected and critically appraised studies, extracted data and analysed on an intention-to-treat basis. Where possible and appropriate, we calculated risk ratios (RR) and their 95% confidence intervals (CI) with the number needed to treat (NNT). We calculated Weighted Mean Differences (WMD) for continuous data. Five studies compared paliperidone with placebo. Fewer people left the studies early if they were randomized to paliperidone (n=1647, 5 RCTs, RR 0.68 CI 0.61 to 0.76, NNT 7 CI 6 to 9) and those receiving any dose of paliperidone were significantly more likely to have an improvement in global state (n=1420, 4RCTs, RR 0.69 CI 0.63 to 0.75, NNT 5 CI 4 to 6). People randomised to paliperidone were less likely to experience a recurrence of psychosis (n=1638, 5 RCTs, RR 0.45 CI 0.31 to 0.66, NNT 16 CI 13 to 26) than those allocated to placebo. Adverse effect data were not well reported but paliperidone does seem to produce a greater incidence of tachycardia than placebo (n=1638, 5 RCTs, RR1.88 CI 1.28 to 2.76, NNH 21 CI 11 to 90) and a consistent, significant elevation in serum prolactin was found for both men (n=413, 3 RCTs, WMD 27.68 CI 23.66 to 31.69) and women (n=252, 3 RCTs, WMD 87.39 CI 74.27 to 100.51). People receiving paliperidone were more likely to experience extrapyramidal disorders (n=1638, 5 RCTs, RR 2.21 CI 1.26 to 3.88, NNH 28 CI 12 to 129) and weight gain (n=769, 4 RCTs, WMD 1.07 CI 0.65 to 1.49, I-squared 78%) compared with those allocated to placebo. When compared with 10 mg/day olanzapine we found no differences between paliperidone and olanzapine for leaving in the short term (n=1332, 3 RCTs, RR 1.04 CI 0.89 to 1.21; 40% in both groups left by six weeks). Those receiving any dose of paliperidone were no more likely to have a recurrence of psychotic symptoms than those receiving 10 mg/day olanzapine (n=1327, 3 RCTs, RR 0.1.07 CI 0.64 to 1.76). Data from all three studies found paliperidone was less likely to produce a weight change than olanzapine (n=660, 3 RCTs, WMD -0.88 CI -1.38 to -0.37). Results for various movement disorders all favoured olanzapine. There are no clear data relating to social functioning, services use, quality of life, satisfaction and cost. In short-term studies, oral paliperidone is an antipsychotic that is more efficacious than placebo. We found its adverse effects to be similar to those of its parent compound, risperidone, with movement disorders, weight gain, and tachycardia all more common with paliperidone than placebo. In addition, paliperidone is associated with substantial increases in serum prolactin that may be associated with sexual dysfunction, although sexual functioning outcomes were not reported. At doses greater than 3 mg per day, oral paliperidone appears comparable in efficacy to oral olanzapine 10 mg per day. Regarding the critical comparison of oral paliperidone to risperidone, we have no information and are thus unable to determine if paliperidone has any advantages or disadvantages compared to its well-known parent compound.

341 – Oral paliperidone extended-release treatment: Long-term metabolic outcomes in patients with schizophrenia

341 – Oral paliperidone extended-release treatment: Long-term metabolic outcomes in patients with schizophrenia

Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week placebo-controlled studies (PAL-SCH-303/304/305)

Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: pooled data from three 6-week placebo-controlled studies (PAL-SCH-303/304/305)

Paliperidone for treatment of schizophrenia.

In short-term studies, oral paliperidone is an antipsychotic that is more efficacious than placebo. We found its adverse effects to be similar to those of its parent compound, risperidone, with movement disorders, weight gain, and tachycardia all more common with paliperidone than placebo. In addition, paliperidone is associated with substantial increases in serum prolactin that may be associated with sexual dysfunction, although sexual functioning outcomes were not reported. At doses greater than 3 mg per day, oral paliperidone appears comparable in efficacy to oral olanzapine 10 mg per day. Regarding the critical comparison of oral paliperidone to risperidone, we have no information and are thus unable to determine if paliperidone has any advantages or disadvantages compared to its well-known parent compound.

Paliperidone: quo vadis?

Paliperidone, the 9-hydroxy metabolite of risperidone, was approved on 20 December, 2006 by the US Food and Drug Administration for the treatment of schizophrenia. It is also being tested for the treatment of bipolar mania. An on-line query of http://www.pubmed.gov and http://www.clinicaltrials.gov for 'paliperidone' and '9-hydroxy-risperidone' was done, along with an examination of poster presentations at scientific meetings held in 2006. Three 6-week pivotal clinical trials of paliperidone extended-release at fixed doses ranging from 3 to 15 mg administered orally once daily in the treatment of acute schizophrenia demonstrated superior efficacy to placebo. A favourable tolerability profile was also evidenced, except for prolactin elevation and dose-related extra-pyramidal effects. A relapse prevention study provides evidence of superiority of paliperidone over placebo in the maintenance of response. Safety has also been assessed in patients with schizophrenia who are 65 years or older. At present there are no studies available that are powered to directly compare paliperidone to other second-generation antipsychotics, including risperidone. With the impending availability of oral risperidone as a generic medication, cost of oral paliperidone will likely become a significant obstacle to its use.

P.3.a.039 Onset of action of oral paliperidone extended-release tablets in patients with acute schizophrenia: pooled results from three 6-week controlled studies

This contribution reports on the first characterization of the venom proteome and the bioactivity screening of Vipera anatolica, the Anatolian Meadow Viper. The crude venom as well as an isolated dimeric disintegrin showed remarkable cytotoxic activity against glioblastoma cells. Due to the rare occurrence and the small size of this species only little amount of venom was available, which was profiled by means of a combination of bottom-up and top-down mass spectrometry. From this analysis we identified snake venom metalloproteases, cysteine-rich secretory protein isoforms, a metalloprotease inhibitor, several type A2 phospholipases, disintegrins, a snake venom serine protease, a C-type lectin and a Kunitz-type protease inhibitor. Furthermore, we detected several isoforms of above mentioned proteins as well as previously unknown proteins, indicating an extensive complexity of the venom which would have remained undetected with conventional venomic approaches.