Paliperidone: quo vadis?

Transcription

1 doi: /j x DRUG FOCUS Paliperidone: quo vadis? L. Citrome SUMMARY 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 and for paliperidone and 9-hydroxy-risperidone was done, along with an examination of poster presentations at scientific meetings held in 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. Introduction Paliperidone is a second-generation antipsychotic and was approved on 20 December, 2006 by the US Food and Drug Administration for the treatment of schizophrenia. Also known as 9-hydroxy-risperidone, it is the major plasma metabolite of risperidone, a second-generation antipsychotic that was launched commercially in Risperidone is extensively used, and has received regulatory approval for the treatments of schizophrenia, bipolar mania, and more recently, irritability associated with autistic disorder in children and adolescents. Risperidone was demonstrated in a meta-analysis to be superior to first-generation antipsychotics for the treatment of schizophrenia (1). However, risperidone was inferior to clozapine in a large clinical trial that examined head-to-head multiple second-generation antipsychotics (2). It is anticipated that paliperidone will have an efficacy profile similar to risperidone when tested under the same conditions. Data sources Clinical trial information was accessed by on-line query of and Review Criteria On-line query of and for paliperidone and 9-hydroxy-risperidone. Poster presentations at scientific meetings held in Message for the Clinic Paliperidone, the 9-hydroxy metabolite of risperidone, was recently approved by the US Food and Drug Administration for the treatment of schizophrenia. It is also being tested for the treatment of bipolar mania. An intramuscular depot formulation is being developed as well. Advantages over risperidone are unclear. Cost may become the driving issue regarding its utilisation. for the search terms paliperidone and 9-hydroxy-risperidone. No date or language constraints were utilised. Proceedings of the following scientific meetings were searched for paper and poster presentations: 159th Annual Meeting of the American Psychiatric Association, Toronto, ON, Canada, May, 2006; 46th Annual Meeting of the NCDEU, Boca Raton, FL, June, 2006; 25th Congress of the Collegium Internationale Neuro-psychopharmacologicum, Chicago, IL, 9 13 July, 2006; 19th Congress of the European College of Neuropsychopharmacology, Paris, France, September, Where there are differences between the submitted abstract and the copy of the poster provided, the data from the poster copy is used. To ensure that all publicly available information was collected, a request for information was made to Ortho-McNeil Janssen Scientific Affairs, LLC of Titusville, NJ, USA and was fulfilled on 2 October, Mechanism of action and metabolism Paliperidone is the 9-hydroxy metabolite of risperidone. The pharmacological properties of paliperidone are comparable with risperidone itself (3). It is a monoaminergic antagonist that exhibits binding at Department of Psychiatry, New York University School of Medicine, and the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA Correspondence to: Dr Leslie Citrome, MD, MPH, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA Tel.: Fax: citrome@nki.rfmh.org Disclosures Leslie Citrome, MD, MPH, is a consultant for, has received honoraria from, or has conducted clinical research supported by the following: Abbott Laboratories, AstraZeneca Pharmaceuticals, Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals and Pfizer Inc. 653

2 654 Paliperidone dopamine type 2 and serotonin type 2A receptors (4), as generally expected for members of the class of second-generation antipsychotics. Other potentially important therapeutic receptor actions for risperidone and paliperidone include affinities for serotonin type 2C, 1D and 1A receptors (4,5). The different secondary binding affinities (i.e. other than at dopamine type 2 and serotonin type 2A receptors) for the different second-generation antipsychotics may explain individual patient differences in therapeutic response from drug to drug and from dose to dose (5). Binding affinities may also be helpful in predicting a medication s potential for adverse effects. Paliperidone is active as an antagonist at alpha 1 and alpha 2 adrenergic receptors and at histaminergic 1 receptors, which may explain weight gain, orthostatic hypotension or sedative side effects (5,6). Paliperidone has no muscarinic cholinergic antagonist properties, which would predict a low propensity for causing anticholinergic side effects, including cognitive dysfunction and gastrointestinal disturbances (5). In the rat, the distribution of paliperidone to the different brain regions was more limited than that of risperidone, and the conclusion was that paliperidone contributes to the in vivo activity of risperidone, but to a smaller extent than would be predicted by plasma levels (3). Mean residence times in the frontal cortex and striatum were 4 6 h for risperidone and about 12 h for paliperidone (3). These mean residence times were 3 5 times longer than what was observed in plasma and in the cerebellum (3). Paliperidone is primarily excreted renally (7), and hepatic metabolism is not the major clearance route. When the immediate release (IR) formulation of paliperidone (1 mg single oral dose) was administered to persons with moderate hepatic impairment, unbound plasma paliperidone concentrations were similar to that observed for healthy subjects (7). In essence, many patients taking risperidone are already being treated with paliperidone. When measuring plasma levels of risperidone, it is imperative to measure plasma levels of paliperidone, as a substantial percentage of patients may have non-detectable plasma levels of risperidone, yet have measurable amounts of paliperidone (8). Examining the relationship between paliperidone plasma levels and potential effects has been the focus of several studies of risperidone. In one study, there was no correlation between plasma levels of risperidone or paliperidone on antipsychotic response measured by the Positive and Negative Syndrome Scale (PANSS), but active moiety concentrations in plasma were higher in patients who developed clinically significant Parkinsonian symptoms (9). The effects of co-medication of risperidone with carbamazepine or valproate were examined in a pharmacokinetic study in patients with schizophrenia, schizoaffective disorder or bipolar disorder (10). Valproate co-administration did not impact plasma concentrations of risperidone or paliperidone; however, carbamazepine co-administration resulted in statistically significant decreases of paliperidone concentrations. Active moiety concentrations were reduced by approximately 70%, attributed to the induction of CYP3A4 metabolism by carbamazepine (10). The effect of risperidone and paliperidone on prolactin has also been examined. In a study of 25 patients with psychotic disorders, the plasma concentration of paliperidone, but not risperidone, correlated significantly with increases in plasma prolactin, leading the authors to conclude that paliperidone may play a predominant role in risperidone s effect on prolactin release (11). The investigators attribute this to the different pharmacokinetics of risperidone and paliperidone, namely protein binding being less for paliperidone (77.4% vs. 90.0%) (12) and paliperidone being less lipophilic. In addition, the half-life of paliperidone is substantially longer than that for risperidone (20 h vs. 2 4 h) (13). Formulations Several formulations of paliperidone have been tested, including an oral immediate-release formulation, an oral extended-release (ER) formulation, and a depot intramuscular formulation. Currently available is the oral ER formulation of paliperidone. It uses a patented technology called osmotic-controlled release oral delivery system (14). The ER formulation of paliperidone consists of an osmotically active trilayer core, composed of two drug layers and a push layer (14). The intent is to ensure a gradual rise in the blood concentrations of paliperidone so that a therapeutically effective starting dose can be given. The medication can be administered once daily and it is expected that by reducing the amplitude of the peaks and troughs, which are seen with IR oral therapies in general, it is thought that the risk of adverse effects can be reduced. Clinical trials Table 1 lists the clinical trials of paliperidone that have been registered on a repository operated by the US National Institutes of Health and the National Library of Medicine. Of the 22 studies registered, 18 are with patients with schizophrenia (including one study for patients age

3 Paliperidone years and over), one in schizoaffective disorder, and three in bipolar, manic or mixed episodes. Twenty Phase III studies are listed, one Phase II study and one Phase I study. Fifteen studies are using the oral ER formulation of paliperidone, and seven are for the depot intramuscular formulation. According to the registry, seven studies are actively recruiting patients, two have not yet begun, nine are no longer recruiting and four have been completed. There are several more studies that have been done but have not been registered because the requirement for doing so has only recently been mandated in 2005, and then again, is necessary only if publication is desired in a journal that ascribes to standards promulgated by the International Committee of Medical Journal Editors (15,16). At the time of this review there has been only one published efficacy trial of paliperidone (17). In that study, the efficacy and safety of paliperidone ER was assessed over a 6-week period by comparing fixed doses of 6, 9 and 12 mg administered once daily vs. placebo. Olanzapine 10 mg administered once daily was used as an active control. In total, 628 patients with an acute episode of schizophrenia were randomised at 47 centres in Europe and six centres in India. The primary efficacy outcome measure was change in PANSS total score from baseline to end-point. Average age of the study participants was 37 years; 86% were white, and 52% male. The average age at diagnosis was 27 years and 42% had been hospitalised at least four times. Mean baseline PANSS score was 94. Only 45.6% of the patients randomised to placebo completed the 6-week double-blind period, compared with 65.0% of patients randomised to paliperidone 6 mg, 70.5% of patients randomised to paliperidone 9 mg, 77.7% of patients randomised to paliperidone 12 mg, and 70.3% of patients randomised to olanzapine 10 mg. This translates to number needed to treat (NNT) for completion vs. placebo of 6, 4, 4 and 4 for paliperidone 6, 9, 12 mg and olanzapine 10 mg respectively [for a discussion of NNT and related concepts see Ref. (18)]. The efficacy outcomes demonstrated that paliperidone was efficacious (17). The mean decreases in PANSS total scores were 4.1 for placebo, 17.9, 17.2 and 23.3 for paliperidone 6, 9 and 12 mg respectively, and 19.9 for olanzapine. Thus paliperidone demonstrated statistically significant improvements over placebo at all three doses tested. This was also the case for the factor scores examining positive symptoms, negative symptoms, depression/anxiety, uncontrolled hostility/excitement and disorganisation. Superiority over placebo was evident at day 4 for paliperidone 12 mg and at day 8 for the 6 and 9 mg doses. Responder analyses examining percentage improvement in PANSS as well as improvements in Clinical Global Impression-Severity scores were consistent with the above. Personal and social functioning were also tested using novel scales, and improvements were greater for paliperidone compared with placebo. Tolerability outcomes demonstrated that paliperidone is reasonably well tolerated (17). Treatment emergent adverse events led to study discontinuation in 7% of those randomised to placebo, 7%, 3% and 6% of those randomised to paliperidone 6, 9 and 12 mg respectively and 7% of those randomised to olanzapine. The most common adverse event that led to discontinuation was tachycardia (2% in the paliperidone 12 mg group vs. 1% in all other groups). Tachycardia itself occurred in 10% of those randomised to placebo, 18%, 14% and 22% of those randomised to paliperidone 6, 9 and 12 mg respectively and 14% of those randomised to olanzapine. The occurrence of serious adverse events was 2% of the placebo group, 4%, 1% and 5% for the paliperidone 6, 9 and 12 mg groups respectively, and 2% for the olanzapine group. Mean plasma prolactin levels increased among patients receiving paliperidone, from a baseline of 17.4 to 45.3 ng/ml for the men, and from 38.0 to ng/ml for the women. The changes in plasma prolactin for each dose of paliperidone were not reported, nor were the percentages of patients who experienced categorical shifts from a normal plasma prolactin level to an abnormally high level. Mean prolactin levels decreased from baseline to end-point in both men and women in the placebo and olanzapine groups. Potentially prolactin-related adverse events were reported by 1% of participants (three men, one in each of the paliperidone arms), and four women (one in each of the active treatment arms). The frequency of movement disorder-related adverse events was similar between paliperidone 6 mg and placebo, but more patients in the 9 and 12 mg groups reported these than those in the placebo group. This is consistent with what was observed with the Simpson Angus Scale (SAS), Barnes Akathisia Scale (BAS), and the Abnormal Involuntary Movement Scale (AIMS). At end-point the use of anticholinergic medication was 6% in the placebo group, 11%, 17% and 22% in the paliperidone 6, 9 and 12 mg groups respectively, and 8% in the olanzapine group. There were no glucose-related adverse events or substantial changes in glucose, insulin, low-density lipoprotein-cholesterol, highdensity lipoprotein-cholesterol or triglycerides for any of the groups. Weight increase 7% was seen in 2% of the placebo group, 5%, 7% and 3% of the

4 656 Paliperidone Table 1 Paliperidone clinical trials registered at ClinicalTrials. gov identifier Duration (weeks) Phase Condition N Paliperidone doses and comparator Comments NCT III Bipolar, manic or mixed 464 ER 3, 6 or 12 mg/day vs. placebo Began 1/2006, USA and international sites. Recruiting NCT Acute 3, total 12 III Bipolar, manic or mixed 475 ER 3 12 mg/day vs. quetiapine mg/day vs. placebo Began 4/2006, USA and international sites. Recruiting NCT III Bipolar, manic or mixed, and taking lithium or valproate 296 ER 3 12 mg/day vs. placebo, added to lithium or valproate Began 4/2006, USA and international sites. Recruiting NCT ? II Schizophrenia and schizophrenia-related insomnia, otherwise stable? ER 9 mg/day vs. placebo Began 2/2005. Completed. Conducted in a total of nine sites in France, Poland and Romania. Studied sleep architecture using polysomnography NCT ? III Schizophrenia 282 PD dose not listed Began 6/2005. Study sites not listed. No longer recruiting. Studies safety and tolerability comparing injection in shoulder vs. buttock muscles NCT III Schizoaffective disorder, 315 ER 6 vs. 12 mg/day vs. placebo Not yet recruiting psychotic disorder NCT Acute 2, III Schizophrenia 395 ER 9 12 mg/day vs. quetiapine Began 5/2006, USA sites. Recruiting total mg/day NCT III Schizophrenia 376 PD 50, 100 or 150 mg eq vs. placebo, 4 injections on days 1, 8, 36 and 64 Began 4/2005, USA and international sites. Recruiting NCT III Schizophrenia 350 Following a 6-week double-blind study comparing ER 6 or 12 mg/day vs. olanzapine 10 mg/day, subjects received open-label ER 3 12 mg/day open-label NCT III Schizophrenia 700 PD mg eq every 4 weeks vs. risperidone depot mg every 2 weeks Began 1/2004. Study sites not listed. No longer recruiting Began 2/2005. Study sites not listed. No longer recruiting NCT II Schizophrenia 45 Open-label ER 3, 9 or 15 mg/day for 6 weeks Began 2/2005. Done in Japan. No longer recruiting NCT ? III Schizophrenia? ER dose not listed vs. placebo, with optional Began 10/2004, USA sites. Completed open-label extension NCT III Schizophrenia 595 ER 6, 9 or 12 mg/day vs. olanzapine 10 mg/day vs. placebo, with optional open-label extension Began 3/2004, international sites. No longer recruiting NCT III Schizophrenia 595 ER 3, 9 and 15 mg/day vs. olanzapine 10 mg/day vs. placebo, with optional open-label extension Began 3/2004, USA and international sites. No longer recruiting NCT ? I Schizophrenia 72 PD open-label pharmacokinetic study of injections in the arm or buttock Began 8/2003. Done in Texas, USA. Completed NCT III Schizophrenia, age 65 years 105 ER flexible-dose (details not listed) vs. placebo, with optional open-label extension Began 7/2004, international sites. No longer recruiting NCT III Schizophrenia 300 ER 3 12 mg/day vs. olanzapine 5 15 mg/day To be done in China. Not yet recruiting NCT ? III Schizophrenia 440 ER doses not listed Begun 2/2004, only one USA site listed. Completed NCT III Schizophrenia 329 ER 6 mg/day vs. olanzapine 10 mg/day vs. Begun 6/2006, Japan. Recruiting placebo NCT ? III Schizophrenia 640 PD doses not listed Begun 3/2005, USA and international sites. Recruiting NCT ? III Schizophrenia 480 PD 25, 50 or 100 mg eq vs. placebo Begun 12/2004, USA and international sites. No longer recruiting NCT ? III Schizophrenia 376 PD 50, 100 and 150 mg eq vs. placebo Begun 6/2005, USA and international sites. No longer recruiting *Accessed 24 November, ER, extended release; PD, palmitate depot.

5 Paliperidone 657 paliperidone 6, 9 and 12 mg groups respectively, and 13% of the olanzapine group. There were no instances of patients randomised to paliperidone developing prolonged QT intervals as measured by electrocardiogram. There are two other short-term efficacy studies of paliperidone ER for acute schizophrenia that have been presented as posters, and hence not subject to peer review (19,20). They are similar in design to the study described above in that they are of 6-week duration, placebo-controlled and used olanzapine 10 mg/day as an active control (17). All active treatment arms demonstrated superiority over placebo in terms of reductions in PANSS total scores. The highlights are presented in Table 2, and contrast all three of these pivotal trials. The safety and efficacy of flexible doses of paliperidone ER in patients with schizophrenia age 65 years or older was tested in a 6-week placebo-controlled clinical trial and presented as a poster (21). This is of interest because it would be expected that older people would be more sensitive to adverse effects of medications. A total of 114 patients were randomised to receive paliperidone 6 mg or placebo once daily. After 7 days, patients could receive flexible dosing in the range of 3 12 mg daily, in 3 mg dose increments. Mean age was 70 years. Mean modal paliperidone daily dose was 8.3 mg. Completion rates were high: 68% for placebo and 84% for paliperidone (NNT 7). Study discontinuation because of adverse events occurred in 7% of the paliperidone group and 8% of the placebo group. Serious adverse events occurred in 3% of the paliperidone group and 8% in the placebo group. The most common adverse event was tachycardia, reported in 16% of the paliperidone group and in none of the patients receiving placebo. Median global scores on the SAS and median AIMS total scores showed no change from baseline in either treatment group. Akathisia, as measured by the BAS, was absent in 85.5% of the paliperidone patients and in 86.8% of the placebo patients at endpoint. No substantial changes in mean glucose or mean bodyweight were noted. Efficacy measures were secondary in this study. Patients receiving paliperidone had greater improvement in PANSS total scores from baseline to end-point compared with patients receiving placebo. Responder analysis (response defined as an improvement in the total PANSS score by at least 30% from baseline to end-point) revealed response rates of 38% for paliperidone and 29% for placebo (NNT 12). A small study (N ¼ 36) of paliperidone ER vs. placebo was conducted at nine sites in Europe among patients with schizophrenia to examine changes in sleep architecture. The results were presented as a poster (22). Patients with schizophrenia and schizophrenia-related insomnia, but without signs of acute psychosis, were randomised to receive paliperidone 9 mg or placebo for 2 weeks. Improvements in sleep continuity were noted for paliperidone vs. placebo, including mean total sleep time and decreases in latency to sleep onset. Once a patient with acute schizophrenia is stabilised, the goal of treatment is to prevent relapse. Paliperidone s potential utility for this was examined in a double-blind placebo-controlled trial, and presented as a poster (23). A total of 530 patients with acute schizophrenia were enrolled and began an 8-week open-label run-in phase where they received a starting daily dose of paliperidone 9 mg. Increases of 3 mg could occur every 7 days (maximum dose 15 mg daily). Decreases of 3 mg were permitted at any time if there were tolerability problems. The run-in phase was followed by a 6-week stabilisation phase where the fixed dose established in the run-in phase was continued. The poster did not specify the specific response criteria for patients to be eligible to enter the stabilisation phase. A total of 312 patients entered the stabilisation phase and 207 patients subsequently entered the double-blind phase where they were randomised to receive placebo or paliperidone at the dose they were receiving in the stabilisation phase. The poster did not specify the specific response criteria for patients to be eligible to enter the double-blind phase. Participation in the double-blind phase was to be of variable duration, and would continue until the patient experienced a recurrence (defined as hospitalisation, specified increase in PANSS, specified dangerous behaviour or specified worsening on the Clinical Global Impression-Severity scale) or until the study was terminated. The poster does not indicate how the quickly patients were converted from active drug to placebo once they were randomised to placebo. A prespecified interim analysis was performed after 43 recurrence events, and the study was terminated on the basis of significant efficacy results. Recurrence occurred more swiftly for patients randomised to placebo 25% of patients experienced a predefined recurrence at 23 days with placebo vs. 68 days with paliperidone (Kaplan Meier, p < 0.001). Overall, recurrence occurred in 52% of patients on placebo vs. 22% of patients receiving paliperidone (NNT 4). Post hoc analyses Several post hoc analyses combining the datasets from the three acute schizophrenia trials (17,19,20) have been presented as posters (24 28). They have focused

6 658 Paliperidone Table 2 The three pivotal 6-week efficacy trials of paliperidone extended-release for the treatment of acute schizophrenia (17,19,20) Kane et al. (17) Marder et al. (19) Davidson et al. (20) N (randomised) Number of sites, location 53, Europe and India 45, USA 74, International (14 countries) Arms, completion rate, NNT for completion vs. placebo Placebo, 45.6% Paliperidone 6 mg, 65.0%, NNT 6 Paliperidone 9 mg, 70.5%, NNT 4 Paliperidone 12 mg, 77.7%, NNT 4 Olanzapine 10 mg, 70.3%, NNT 4 Timing of improvement over placebo Paliperidone 6 mg: day 8 Paliperidone 9 mg: day 8 Response by at least 30% improvement in the PANSS total score from baseline to end-point, NNT vs. placebo Treatment-related adverse events leading to discontinuation Paliperidone 12 mg: day 4 Placebo, 30% Paliperidone 6 mg, 56%, NNT 4 Paliperidone 9 mg, 51%, NNT 5 Paliperidone 12 mg, 61%, NNT 4 Olanzapine 10 mg, 52%, NNT 5 Placebo, 7% Paliperidone 6 mg, 7% Paliperidone 9 mg, 3% Paliperidone 12 mg, 6% Olanzapine 10 mg, 7% Extra-pyramidal adverse events Frequency similar between paliperidone 6 mg and placebo, but more patients in the 9 and 12 mg groups reported these than patients in the placebo group. Change in SAS global scores similar in the paliperidone 6 mg and placebo groups, but higher in the 9 and 12 mg groups. At end-point the use of anticholinergic medication was 6% in the placebo group, 11%, 17% and 22% in the paliperidone 6, 9 and 12 mg groups respectively, and 8% in the olanzapine group Mean plasma prolactin Increased among patients receiving paliperidone (from a baseline of 17.4 to 45.3 ng/ml for the men, and from 38.0 to ng/ml for the women). Decreased from baseline to end-point in both men and women in the placebo and olanzapine groups Placebo, 33.6% Paliperidone 6 mg, 45.5%, NNT 9 Paliperidone 12 mg, 48.2%, NNT 7 Olanzapine 10 mg, 45.4%, NNT 9 Paliperidone 6 mg: day 4 Paliperidone 12 mg: day 15 Placebo, 34% Paliperidone 6 mg, 50%, NNT 7 Paliperidone 12 mg, 51%, NNT 6 Olanzapine 10 mg, 46%, NNT 9 Placebo, 5% Paliperidone 6 mg, 7% Paliperidone 12 mg, 5% Olanzapine 10 mg, 7% Frequency in the 6 mg group similar to placebo and olanzapine. More common in the paliperidone 12 mg group than in the 6 mg group. No statistically significant differences observed between the paliperidone groups and placebo in terms of changes in the SAS global score, AIMS total or BAS global score. The percentage receiving anticholinergic medications was not reported Increased from baseline to end-point in the paliperidone groups (from 14.5 to 38.1 ng/ml in men, and from 29.2 to ng/ml in women), but did not appreciably change in the placebo or olanzapine groups Glucose-related adverse events None Two patients in the paliperidone 6 mg group and in 2 patients in the olanzapine group Placebo, 38.2% Paliperidone 3 mg, 55.1%, NNT 6 Paliperidone 9 mg, 62.4%, NNT 5 Paliperidone 15 mg, 71.3%, NNT 3 Olanzapine 10 mg, 68.8%, NNT 4 Paliperidone 3 mg: day 4 Paliperidone 9 mg: day 4 Paliperidone 15 mg: day 4 Placebo, 18% Paliperidone 3 mg, 40%, NNT 5 Paliperidone 9 mg, 46%, NNT 4 Paliperidone 15 mg, 53%, NNT 3 Olanzapine 10 mg, 52%, NNT 3 Placebo, 4% Paliperidone 3 mg, 2% Paliperidone 9 mg, 5% Paliperidone 15 mg, 3% Olanzapine 10 mg, 4% Frequency of hypertonia, dystonia and tremor were similar for paliperidone 3 and 15 mg, placebo and olanzapine, but higher incidences were reported in the paliperidone 9 mg group. Extra-pyramidal disorder (not otherwise specified) and hyperkinesias similar for paliperidone 3 mg, placebo and olanzapine, while a higher incidence was reported in the paliperidone 9 and 15 mg groups. No statistically significant differences were observed between the paliperidone groups and placebo in terms of changes in the SAS global score, AIMS total or BAS global score, except for the SAS global score for paliperidone 9 mg. The percentage receiving anticholinergic medications was not reported Mean plasma prolactin levels increased from baseline to end-point in the paliperidone groups but the actual values were not included in the poster Two patients in the placebo group, and 2, 1 and 1 in the paliperidone 3, 9 and 15 mg groups respectively, and none in the olanzapine group AIMS, Abnormal Involuntary Movement Scale; BAS, Barnes Akathisia Scale; NNT, number needed to treat; PANSS, Positive and Negative Syndrome Scale; SAS, Simpson Angus Scale.

7 Paliperidone 659 on metabolic outcomes (24), recently diagnosed patients (25), young adults (26), negative symptoms (27) and speed of onset of action (28). In the poster examining metabolic outcomes, mean increases in bodyweight at end-point increased in a dose-related manner (24). Weight gain 7% of baseline was observed in 5% of patients receiving placebo and in 7%, 6%, 9%, 9% and 18% of the patients receiving paliperidone 3, 6, 9, 12 and 15 mg respectively. No clinically relevant changes were observed in terms of glucose, insulin, cholesterol or triglycerides. This is consistent with risperidone s metabolic profile. In patients diagnosed with schizophrenia within the prior 5 years, outcomes were similar to patients diagnosed >5 years prior, except for a small but statistically significant worsening of the SAS score for patients receiving paliperidone 3 12 mg daily (25). Patients receiving paliperidone 15 mg daily were not included in the primary analysis. The results of this analysis suggest that patients early on in their disease course may be more sensitive to extra-pyramidal side effects. In patients aged years, paliperidone 3 15 mg resulted in statistically significant decreases in PANSS total scores (26). Responder analysis (response defined as an improvement in the total PANSS score by at least 30% from baseline to endpoint), revealed rates of 22%, 42%, 52%, 54%, 49% and 59% for placebo, paliperidone 3, 6, 9, 12 or 15 mg respectively (corresponding NNTs vs. placebo are 5, 4, 4, 4 and 3 for paliperidone 3, 6, 9, 12 and 15 mg respectively). Extra-pyramidal-related adverse events occurring most frequently with paliperidone were akathisia and tremor (8% each event). In contrast to the analysis of recently diagnosed patients, no changes were seen in the movement-related rating scales. A dose-dependent increase in bodyweight was observed. The hypothesis that paliperidone has effects on negative symptoms of schizophrenia was tested in another report (27). A path analysis revealed that 33% of the negative symptom improvement was a direct effect of paliperidone. The indirect effects on negative symptoms were modulated through changes in positive symptoms (51%) and depressive symptoms (18%). Changes in movement disorders accounted for a 2.1% inverse effect on negative symptoms. Inconsistent results were observed in the pivotal trials (17,19,20) with regard to time of onset when paliperidone statistically separates from placebo in terms of the reduction in the PANSS total score. In one, superiority over placebo was evident at day 4 for paliperidone 12 mg, and at day 8 for the 6 mg and 9 mg doses (17). In another, improvement vs. placebo occurred as early as day 4 for paliperidone 6 mg, and at day 15 for paliperidone 12 mg (19). In the third study, improvement vs. placebo occurred as early as day 4 for all three paliperidone arms: 3, 9 and 15 mg (20). In a pooled analysis, a significant improvement was observed on day 4 for paliperidone 3, 6, 9 and 12 mg (the data for paliperidone 15 mg was not included in this analysis) (28). Clinical response, as defined by a decrease of at least 30% on the PANSS total score, was achieved by week 2, except for the paliperidone 6 mg dose group where this degree of response was achieved by week 3. Optimal dose So far it appears that paliperidone within the dose range of 3 15 mg given once daily can reduce the symptoms of acute schizophrenia, as measured by the PANSS. According to product labelling (6), the recommended dose is 6 mg once daily, administered in the morning. Initial dose titration is not required. There may be a dose-response relationship the studies generally describe more robust improvements in the PANSS for the higher doses in terms of magnitude of the reduction in the PANSS and in the percentage of responders. The label advises that dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days, in increments of 3 mg/day, to a maximum daily dose of 12 mg. However, higher doses in this range are associated with a greater risk for adverse events, in particular extrapyramidal symptoms. Of additional concern is the possible effect of dose on prolactin levels. According to a brief clinical review (29) by one of the investigators involved in the relapse prevention study (23), it was noted in the long-term study that when paliperidone was compared with placebo, mean prolactin values were four times as high among men (40 vs. 10 ng/ml) and five times as high among women (100 vs. 20 ng/ml) receiving paliperidone at any dosage. It was recommended that during paliperidone therapy patients should be asked if they are experiencing abnormal movements, sexual dysfunction, breast enlargement or irregular menstruation (women). If so, one possible remedy is to decrease the dosage by 3 mg and monitor for side effects and clinical efficacy (29). The pattern of dose response for paliperidone may resemble that for risperidone, in that for most patients moderate doses (4 8 mg/day) may be adequate in controlling symptoms while minimising liability for extra-pyramidal side effects (30,31). However, what constitutes a moderate dose of paliperidone may not be immediately apparent, given

8 660 Paliperidone the historical pattern of dosing of risperidone that witnessed a decrease in both mean daily dose and percentage of patients receiving a high daily dose over a period of several years among patients hospitalised in public psychiatric centres (32). However, a major difference between paliperidone and risperidone is the recommended starting dose, which for paliperidone ER (6 mg/day) is potentially therapeutic, whereas for risperidone (2 mg/day for schizophrenia) is likely not (30,31). Is paliperidone worth using? We can calculate the NNT for the numbers of patients who experienced a percentage improvement in PANSS, and the number needed to harm (NNH) for adverse events for which dichotomous outcomes are reported (Table 3). Ideally, an intervention should have a small NNT to show that the benefit is large and a large NNH to show that the risk of harm is small. These comparisons of paliperidone vs. placebo demonstrate that paliperidone is reasonably efficacious and tolerable. There are no head-to-head studies currently available comparing paliperidone directly with other second-generation antipsychotics (the studies of paliperidone that have been reported so far that include an active comparator such as olanzapine were not designed to compare the two second-generation antipsychotics). We can turn to studies of risperidone and extrapolate how paliperidone will likely perform, especially as a substantial percentage of patients receiving risperidone have non-detectable plasma levels of risperidone but have measurable amounts of paliperidone (8). These studies of risperidone generally place it on par with olanzapine in superiority in efficacy to first-generation antipsychotics, but inferior to clozapine on this measure (1). A large effectiveness trial recently conducted in the USA essentially demonstrated that risperidone had superior tolerability, but poorer efficacy, compared with olanzapine (2,18,33,34). There are no head-to-head studies available comparing paliperidone to risperidone. Pragmatic advantages for paliperidone include its potentially therapeutic starting dose vs. the need to titrate dose for risperidone. There are also hypothesised advantages of paliperidone in terms of tolerability because of the ER formulation, but these need to be tested under controlled conditions. A potential disadvantage of paliperidone is its association with elevation in plasma prolactin levels that may be greater than what is observed with risperidone. In the meantime, cost may become a substantial consideration (35). Cost of a paliperidone 3 or 6 mg tablet is $9.54, and that for a 9 mg tablet is $14.31 (Rockland Psychiatric Center Pharmacy, Orangeburg, NY, 2 January, 2007). In contrast, risperidone 4 mg has an acquisition cost at our institution of $9.12 and will no doubt be lower when risperidone is scheduled to go off patent in December 2007 and generic preparations become available. In Canada, where risperidone has been available as a generic medication since July 2006, the generic 4 mg tablet is now available for $CDN1.92 compared with $CDN4.40 for the branded product (see program/drugs/odbf_eformulary.html). The depot intramuscular preparation of paliperidone holds greater promise if it can be demonstrated that it can be administered less frequently than risperidone intramuscular microspheres and that there is little lag time prior to the development of adequate blood levels, thus eliminating the need for concurrent oral administration of an antipsychotic upon the initiation of the depot. At present little information about paliperidone palmitate is publicly available other than the list of clinical trials registered on Table 3 Paliperidone number needed to treat (NNT) and number needed to harm (NNH)* NNT NNH Comparison vs. placebo 30% improvement in PANSS 50% improvement in PANSS Tachycardia Use of anticholinergic medication Weight increase 7% Paliperidone 6 mg/day Paliperidone 9 mg/day Paliperidone 12 mg/day Olanzapine 10 mg/day *Calculated from Kane et al. (17). PANSS, Positive and Negative Syndrome Scale.

9 Paliperidone 661 Conclusions Paliperidone, the 9-hydroxy metabolite of risperidone, has been evaluated in several double-blind placebo-controlled clinical trials. The ER oral formulation has demonstrated efficacy in reducing the symptoms of acute schizophrenia at fixed daily doses ranging from 3 to 15 mg. A relapse prevention study also provided evidence of superiority of paliperidone over placebo in the maintenance of response. There appears to be a dose response in terms of extra-pyramidal effects, and possibly efficacy. Prolactin elevation can occur, with mean plasma prolactin levels rising several fold. 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. References 1 Davis JM, Chen N, Glick ID. 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