Different Safety Profile of Risperidone and Paliperidone Extended-release
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): risperidone; paliperidone ER; placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): risperidone 3mg, PO, 3 times; paliperidone ER 6mg, PO,3 times; lactose PO, 3times
Other intervention name(s): Rispedal; Invega
Intervention MeSH terms: Risperidone; Paliperidone Palmitate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Keywords: cognitive function; subjective experiences; neuroleptic-induced deficit syndrome; paliperidone extended-release; risperidone