Clinical trial NCT01284959: Different Safety Profile of Risperidone and Paliperidone Extended-release
Official title: Different Safety Profile of Risperidone and Paliperidone Extended-release: a Double-blind, Placebo-controlled Trial With Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Keywords: cognitive function
subjective experiences
neuroleptic-induced deficit syndrome
paliperidone extended-release
risperidone
Lead sponsor: Chonbuk National University Hospital
Sponsor class: OTHER
Collaborators: name: AstraZeneca
name: Janssen Korea, Ltd., Korea
name: Korea Otsuka Pharmaceutical Co., Ltd.
name: Sanofi-Synthelabo
First posted: 2011-01-27
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 38
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL

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.

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

Primary outcomes:
measure: Assessment of Negative Symptoms and Neuroleptic Induced Deficit Syndromes by Objective Rating Scales
timeFrame: baseline and 2hr after third medication
Secondary outcomes:
measure: Assessment of Adverse Events by Objective Rating Scales and Self Report Scales
timeFrame: baseline and 2hr after third medication
measure: Assessment of Adverse Events by Objective Rating Scales and Self Report Scales
timeFrame: baseline and 50hr after third medication
measure: Assessment of Cognitive Functioning-1
timeFrame: baseline and 50hr after third medication
measure: Symptoms Assessment by Objective Rating Scales
timeFrame: baseline and 50hr after third medication
measure: Assessment of Cognitive Functioning-2
timeFrame: baseline and 50hr after third medication
measure: Assessment of Cognitive Functioning-3
timeFrame: baseline and 50hr after third medication
Other outcomes:
Locations:
city: Chonju
country: Korea, Republic of
facility: Chonbuk national university hospital
Study officials:
affiliation: Chonbuk National University Hospital
name: Young-chul Chung, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: