Different Safety Profile of Risperidone and Paliperidone Extended-release

NCT ID: NCT01284959

Last Updated: 2012-10-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-06-30
• Study Completion Date: 2010-12-31

Brief Summary

The main objective of this study was to assess subjective experiences related to secondary negative symptoms and cognitive performance in healthy volunteers in response to multiple doses of paliperidone ER and risperidone in a double-blind, placebo-controlled trial. Adverse events caused by these drugs were also evaluated.

Detailed Description

A new oral antipsychotic drug, paliperidone extended-release (ER), has recently been developed and might represent an innovative approach in the treatment of schizophrenia. Paliperidone is 9-hydroxyrisperidone, the chief active metabolite of risperidone. Although paliperidone possesses a pharmacological profile very similar to that of its parent compound, it has many different pharmacokinetic and pharmacodynamic characteristics compared with risperidone (Pani and Marchese, 2009). First, paliperidone ER utilizes an osmotic controlled-release oral delivery system (OROS), resulting in a more stable serum concentration and reduced likelihood of causing unexpected over- or under-dosages due to CYP2D6 genetic variability. Second, paliperidone does not undergo significant hepatic metabolism, and the drug is predominantly excreted by the kidney as an unchanged drug; whereas risperidone is extensively metabolized by the CYP2D6 hepatic enzyme. Third, the off-rate for dissociation from human cloned D2 receptors in tissue culture cells is faster for paliperidone (60 s) compared with risperidone (27 min) (Seeman, 2005). Due to its looser binding to D2 receptors, paliperidone should be associated with a reduced risk of extrapyramidal side effects compared with its parent drug. Fourth, ex vivo studies have indicated that paliperidone injections induce relatively smaller H1 occupancy levels in the brains of animals when compared with similar dosages of risperidone (Schotte, et al. 1995 and 1996). This may contribute to a reduced sedative effect and less weight gain secondary to paliperidone when compared with risperidone. Finally, paliperidone has no relevant affinity toward muscarinic receptors, resulting in the absence of anticholinergic side effects; this is another important benefit compared with risperidone (Schotte, et al. 1996). Therefore, paliperidone would be the drug of choice in young psychotic patients for whom preservation or improvement of cognitive function is critical. All of these properties might be associated with improved efficacy and better tolerability of paliperidone ER compared with risperidone. In support of this view, recent studies (Canuso, et al. 2008 and 2010) demonstrated that switching from risperidone to paliperidone ER resulted in improvements in medication satisfaction, Positive and Negative Syndrome Scale (PANSS) (Kay, et al. 1987) score, and abbreviated Extrapyramidal Symptoms Rating Scale (Chouinard and Margolese, 2005) score. However, to date, no clinical trials have investigated the relative superiority of paliperidone ER over risperidone in terms of effects on cognitive function. Recently, interest in the negative subjective experiences secondary to antipsychotic medications has been renewed, as these experiences are key factors in adherence and clinical outcomes (Awad, 1993; van Putten and May, 1978). Artaloytia et al. (2006) reported that risperidone induced negative symptoms in healthy volunteers, which might be termed secondary negative symptoms. Therefore, we hypothesized that paliperidone ER has a better safety profile in terms of subjective experiences and cognitive function compared with risperidone. Research on the effects of antipsychotic drugs on subjective experiences and cognitive function in patients with schizophrenia may be hampered by numerous confounding factors, such as pathological features of the illness, patient motivation, or concomitant medications. Investigating the effects of antipsychotic drugs in healthy subjects provides a method for controlling these variables. Therefore, the main objective of this study was to assess subjective experiences related to secondary negative symptoms and cognitive performance in healthy volunteers in response to multiple doses of paliperidone ER and risperidone in a double-blind, placebo-controlled trial. Adverse events caused by these drugs were also evaluated.

Conditions

Schizophrenia

Keywords

cognitive function; subjective experiences; neuroleptic-induced deficit syndrome; paliperidone extended-release; risperidone

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Blinding Strategy: DOUBLE

Study Groups

risperidone

Drug: risperidone 3mg, PO two times Groups: risperidone

Group Type: EXPERIMENTAL

risperidone

Intervention Type: DRUG

risperidone 3mg, PO, 3 times

placebo

drug: lactose, PO 3 times group: placebo

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

lactose PO, 3times

paliperidone ER

drug : Paliperidone ER 6mg PO, two times group: paliperidone ER

Group Type: EXPERIMENTAL

paliperidone ER

Intervention Type: DRUG

paliperidone ER 6mg, PO,3 times

Interventions

risperidone

risperidone 3mg, PO, 3 times

Intervention Type: DRUG

paliperidone ER

paliperidone ER 6mg, PO,3 times

Intervention Type: DRUG

placebo

lactose PO, 3times

Intervention Type: DRUG

Other Intervention Names

Rispedal; Invega

Eligibility Criteria

Inclusion Criteria

• Aged 18-38 years and meet no DSM-IV diagnostic criteria as assessed by using the Structured Clinical Interview for DSM-IV, research version

Exclusion Criteria

Anyone who:

• Participated in other clinical trials within 30 days from the start of this clinical trial or is currently participating in one
• Has progressive disease or in unstable medical condition unfit for the trial
• Has been diagnosed in psychiatric terms in the past, depends on psychotropic substance, or has overdosed or depended on the substance or alcohol (except for coffee or tobacco) within 1 month from the trial start
• Is suicidal or highly probable of suicides; OR
• Has test results considered clinically meaningful

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 38 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Janssen Korea, Ltd., Korea

INDUSTRY

Sponsor Role: collaborator

Korea Otsuka Pharmaceutical Co., Ltd.

INDUSTRY

Sponsor Role: collaborator

Sanofi-Synthelabo

INDUSTRY

Sponsor Role: collaborator

Chonbuk National University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Young Chul Chung

Professor of Psychiatry

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Young-chul Chung, M.D., Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Chonbuk National University Hospital

Locations

Chonbuk national university hospital

Jeonju, , South Korea

Countries

South Korea

Other Identifiers

CBIRB1005-58

Identifier Type: -

Identifier Source: org_study_id