The molecular evolution of schizophrenia treatment

In recent decades, schizophrenia treatment has evolved thanks to significant molecular advances. As a result, long-acting treatments today ensure longer sustained plasma levels, which can reduce the risk of relapse due to missed doses or discontinuation.1

Over the years, antipsychotic treatment for people living with schizophrenia has developed to accommodate the need for treatment that reduces the risk of relapse if the patient is non-adherent.

From first- to second-generation antipsychotics: potent therapeutic actions and reduced side effects

Back in the 1960s, the first-generation of antipsychotic (FGA) treatments were developed.2 They are characterised by predominant dopaminergic blockade. However, they all have potent antidopaminergic actions and hence show parkinsonism and often cardiovascular side effects along with their primary antipsychotic actions.3

It took until the 1990s until the second-generation antipsychotic (SGA) treatments arrived. The first second-generation antipsychotic was clozapine, which has uniquely potent antipsychotic actions and no motor side effects, yet it has the serious side effect of agranulocytosis. Though clozapine was an old drug (developed in the 1960s), its drug effects became targets for drug development, that is referred to as SGAs.3


"The size of the paliperidone palmitate particles determines the release of paliperidone and allows for the extended administration of once-monthly paliperidone palmitate and four-per-year paliperidone palmitate"


The new generation of antipsychotic treatments has potent therapeutic actions on the positive symptoms of psychosis with far fewer side effects, especially motor effects. However, each of the new drugs has its own characteristic clinical and pharmacological features that affect individual patient response.3

In 1993, the first newer SGA, risperidone, was developed.2 Risperidone was designed on the basis of the clinical observation that haloperidol (one of the first FGAs) combined with a pure serotonin antagonist showed fewer motor side effects than haloperidol alone.3 Risperidone contains both the antidopaminergic and the antiserotonergic components of the two distinct test drugs.3 Risperidone was the first drug rationally designed to affect both the dopamine and the serotonin systems, where the antiserotonergic actions are more potent than the antidopaminergic actions.3

Introducing long-acting antipsychotics

Even though risperidone was launched in a long acting formulation risperidone in 1993, there was still a need for a treatment that could reduce the risk of relapse. In 2011, the major active metabolite of risperidone, paliperidone palmitate, was launched.2 The two molecules share a similar

pharmacological profile, but structural differences may influence the receptor binding.4 Both bind strongly to serotonergic 5-HT2- and antagonise dopaminergic D2-receptors. They also block alpha 1-adrenergic receptors and, to a slightly lesser extent, H1-histaminergic and alpha 2-adrenergic receptors.4-6 As it is the difference in receptor binding profiles that largely determines the individual efficacy and tolerability profiles of antipsychotics, paliperidone palmitate has shown non-inferiority to risperidone as well as a similar tolerability profile.7,8

The size of the paliperidone palmitate particles determines the release of paliperidone and allows for the extended administration of once-monthly paliperidone palmitate and four-per-year paliperidone palmitate.9

A study has shown that the longer half-life of paliperidone palmitate (25–49 days) ensures longer sustained therapeutic plasma concentrations compared with risperidone (136 days vs 32.9 days).10 The continued exposure to paliperidone palmitate beyond the point of medication discontinuation may potentially delay relapse.1



Real-world evidence study with 29,823 patients compared the effectiveness of antipsychotic treatment


What is your view on first and
second generation drugs?

Contact your
Janssen Account Manager