The preclinical discovery and development of paliperidone for the treatment of schizophrenia

ABSTRACT

Introduction: Paliperidone is approved in the United States and Europe for the short- and long-term treatment of schizophrenia in adults and adolescents as well as for the acute treatment of schizoaffective disorder either as monotherapy or adjunctive therapy to mood stabilizers and/or antidepressants. It is recommended in patients with hepatic impairment and evokes less drug–drug interactions.

Areas covered: This review article focuses on the preclinical discovery of paliperidone, the major active metabolite of risperidone. It provides details regarding paliperidone’s pharmacological and neurochemical mechanisms, and their contribution to therapeutic benefits and adverse effects, based on the available literature with respect to the preclinical and clinical findings and product labels.

Expert opinion: Paliperidone exhibits a high affinity and antagonistic activity toward D₂ and 5-HT_2A receptors, followed by 5-HT₇, H₁, α_1, and α₂ receptors. In preclinical studies, paliperidone produces antidepressant, anxiolytic, mood-stabilizing, analgesic actions, and affects the endocannabinoid system. It is also known to evoke procognitive, antioxidant, and anti-inflammatory activities. Its positive activity on neurogenesis, neuronal, and synaptic plasticity deserves to be emphasized. The clinical superiority of paliperidone is based primarily on the available formulations of the drug rather than in the subtle differences in its pharmacokinetic/pharmacodynamic properties compared to risperidone.

KEYWORDS:

• Antioxidant/anti-inflammatory activity
• analgesic activity
• mood-stabilizing action
• neurodevelopment model
• paliperidone
• rodent models
• schizophrenia

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Article highlights

• Paliperidone (9-hydroxyrisperidone) is approved in the United States and Europe for the short- and long-term treatment of schizophrenia in adults and adolescents as well as for the acute treatment of schizoaffective disorder either as monotherapy or adjunctive therapy to mood stabilizers and/or antidepressants.

• Paliperidone is recommended for patients with hepatic impairment due to limited hepatic metabolism and a low hepatic extraction ratio, and evokes less drug–drug interactions.

• Paliperidone is available in long-acting forms that may enhance therapeutic adherence, i.e. extended-release tablets, and once-monthly or 3-monthly injection that has been licensed for maintenance treatment in adults diagnosed with schizophrenia.

• Paliperidone shows highest affinity toward 5-HT_2A and D₂ receptors. It also shows significant affinity toward 5-HT₇, H₁, and α₁ and α₂ receptors; moderate affinity toward remained dopaminergic D₁–D₅ receptors, 5-HT_1D, 5-HT_1E, 5-HT_2C, and H₂; and negligible affinity toward cholinergic muscarinic, β₁- and β₂-adrenergic, and peptidergic receptors. It is a 5-HT_2A/D₂ receptor antagonist with clinically relevant antagonistic activity toward 5-HT₇, H₁, and α₁ receptors.

• Studies indicate that paliperidone is active in in vitro and in vivo models predictive of antipsychotic, antidepressant, anxiolytic, and mood-stabilizing activities. It also displays procognitive, antioxidant, and anti-inflammatory effects, which are studied in the neurodevelopmental models of schizophrenia. Positive effects of paliperidone on neurogenesis, neuronal and synaptic plasticity deserve to be mentioned.

Reviewer Disclosures

One referee is an employee of In Silico Biosciences. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by funds for statutory activity from the Jagiellonian University Medical College [K/ZDS/006133].