Summary

• The release profile and dosing regimen of INVEGA TRINZA results in sustained therapeutic concentrations over 3 months while the release profile and dosing regimen of INVEGA SUSTENNA results in sustained therapeutic concentrations over 1 month.¹
• INVEGA TRINZA and INVEGA SUSTENNA are hydrolyzed to paliperidone. Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination of central dopamine Type 2 (D₂) and serotonin Type 2 (5HT_2A) receptor antagonism.²
• Paliperidone is also active as an antagonist at α₁ and α₂ adrenergic receptors and H₁ histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic, or β₁- and β₂-adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers is qualitatively and quantitatively similar in vitro.²
• Using a variety of experimental designs, the reported K_i/K_d ranges from 0.22-1.21 nM for the 5HT_2A receptor, 2.8-6.6 nM for the D₂ receptor, 1.3-11 nM for the α₁-adrenergic receptor, and 3.4-34 nM for the H₁ (histamine type 1) receptor.^3-5
• Arakawa et al (2007)⁶ proposed that 6-9 mg of paliperidone ER provides a dopamine D₂ receptor occupancy between 70-80%, a range that should provide efficacy (>70%) without associated extrapyramidal symptoms (EPS; <80%).

RECEPTOR BINDING

Published Literature

Smith et al (2006)⁷ conducted a series of experiments evaluating the receptor binding of risperidone and 9-hydroxyrisperidone to the h5-HT₇ serotonin receptor. In vitro experiments were performed with intact HEK293 cells (human embryonic kidney cells) transfected to stably express active mutant h5-HT₇ receptor. Risperidone (20 nM), 9-hydroxyrisperidone (100 nM), methiothepin (30 nM), and clozapine (300 nM) were added to cells for 30 minutes and then washed off.

After washout, risperidone, 9-hydroxyrisperidone, and methiothepin had a significant loss of 5HT-induced (10 μM) cyclic adenosine monophosphate (cAMP) production, relative to no drug treatment or clozapine (P<0.001). Several other compounds tested (amperozide, cinanserin, chlorpromazine, fluperlapine, fluphenazine, mesulergine, penfluridol, perphenazine, thioridazine, ziprasidone, zotepine), similar to clozapine, also did not produce this inhibition. When incubated with intact cells for 30 minutes and then washed off, risperidone (20 nM), 9-hydroxyrisperidone (100 nM), and methiothepin (30 nM), but not clozapine (300 nM), significantly blocked [³H]5-HT (2nM; radiolabeled serotonin) binding. Ability of risperidone, 9-hydroxyrisperidone, and methiothepin to block the h5-HT₇ receptor persisted, even after 24 hours, as measured with both the 5-HT-induced cAMP production assay and [³H] 5HT receptor binding assay (P<0.01 for both assays). Results indicate that risperidone, 9-hydroxyrisperidone, and methiothepin, irreversibly, or pseudo-irreversibly, inactivate the h5-HT₇ receptor.

Richelson et al (2000)⁵ conducted experiments to determine the equilibrium dissociation constant (K_d) for 13 antipsychotics at 9 different receptors. Investigators used postmortem human brain tissue obtained at autopsy. 9-hydroxyrisperidone demonstrated higher affinity for the 5HT_2A and dopamine D₂ receptors than any other receptors it was tested against.

Schotte et al (1996)⁸ conducted experiments to determine the equilibrium dissociation constant for a competitive inhibitor (K_i) for 12 compounds. Two in-vitro experiments (one using animal brains and one using cloned human receptors stably expressed in mammalian cell lines) were conducted to obtain K_i data for 9-hydroxyrisperidone. Rats and guinea pigs received subcutaneous injections of 9-hydroxyrisperidone, and ex vivo receptor occupancy was determined at two hours after injection.

In all three experiments, 9-hydroxyrisperidone demonstrated higher affinity for the 5HT_2A receptor than any other receptor tested. See Table: Ex Vivo Receptor Binding of 9-hydroxyrisperidone.⁸

Leysen et al (1994)³ conducted a series of experiments on four compounds, including 9-hydroxyrisperidone. K_i was determined in both animal brains and cells cloned to express human receptors. In addition, the dose of 9-hydroxyrisperidone that blocked 50% of receptors was determined by autoradiography in animals injected subcutaneously with 9-hydroxyrisperidone.

See Table: In Vitro Receptor Binding of 9-hydroxyrisperidone in Animal Brains, Table: In Vitro Receptor Binding of 9-hydroxyrisperidone in Cloned Human Receptors, and Table: Ex Vivo Receptor Binding of 9-hydroxyrisperidone.³

van Beijsterveldt et al (1994)⁴ conducted a series of experiments testing the receptor binding of 9-hydroxyrisperidone and its ability to block the reuptake of neurotransmitters in animal brains.⁹ In addition, the pharmacological properties of subcutaneously administered 9-hydroxyrisperidone were analyzed in rats challenged with apomorphine, tryptamine, and noradrenaline.

9-hydroxyrisperidone bound most tightly to 5HT₂, α₁-adrenergic, and D₂ receptors. See Table: Receptor Binding of 9-hydroxyrisperidone and Table: Neurotransmitter Uptake Inhibition Profile of 9-hydroxyrisperidone.⁴

RECEPTOR OCCUPANCY

Published Literature

Arakawa et al (2007)⁶ conducted an open-label phase 2 trial conducted in Japan measuring dopamine D₂ receptor occupancy in adult male patients (mean age, 29.4 years) with schizophrenia. Patients were included if they had a Positive and Negative Syndrome Scale (PANSS) score <120 and good symptom control with one oral antipsychotic during the 4 weeks prior to the study. Patients received 3 mg/day (n=6), 9 mg/day (n=4), or 15 mg/day (n=3) of paliperidone ER for 6 weeks. After 2 to 6 weeks, patients received a positron emission tomography (PET) scan with [¹¹C]raclopride and [¹¹C]FLB 457 to measure striatal and extrastriatal dopamine D₂ receptor occupancy, respectively.

With [11C]raclopride, the mean dopamine D2 receptor occupancies in the striatum (occupancy(%)=(BP_base-BP_drug)/BP_base•100 where BP_base=binding potential without drug and BP_drug=binding potential with paliperidone ER) were 57.9%, 77.4%, and 80.4% in patients receiving 3, 9, and 15 mg/day of paliperidone ER, respectively. ED₅₀ in the striatum corresponded to a dose of 2.38 mg/day and a plasma concentration of 6.65 ng/mL.

With [11C]FLB 457, the mean dopamine D2 receptor occupancies in the temporal cortex with 3, 9, and 15 mg/day of paliperidone ER were 53.1%, 76.2%, and 77.7%, respectively. ED₅₀ of paliperidone ER was 2.84 mg/day, or a plasma level of 7.73 ng/mL paliperidone.

Receptor occupancy did not significantly differ between the striatum or temporal cortex. Investigators calculated the dopamine D₂ receptor occupancy of 6 mg/day paliperidone ER as 72%, an occupancy rate that should provide therapeutic efficacy (>70% occupancy) without associated extrapyramidal symptoms (<80% occupancy). Clinically, average PANSS scores of all patients changed from 62.9 at baseline to 58.5 after 6 weeks, and three patients showed EPS.

Muly et al (2012)¹⁰ conducted a study evaluating the regional variation in D₂ receptor occupancy for risperidone and paliperidone (each drug given at 1 mg doses intravenously).  The investigators examined 7 brain regions of interests using a within-subject design in macaque monkeys.  The results indicated a dose-dependent D₂ receptor occupancy of risperidone and paliperidone in the basal ganglia (the caudate, putamen, ventral striatum) and four cortical regions (3 prefrontal and 1 temporal).  The caudate and putamen had the highest D₂ receptor binding potential followed by the ventral striatum (one-third the caudate and putamen) and the cortical regions (2% of the caudate and putamen). D₂ receptor occupancy of 60-80% was obtained with serum drug concentrations of 60-80 ng/mL of risperidone and 45-80 ng/mL of paliperidone.  The investigators did not find evidence to support regional variation in D₂ receptor occupancy for either drug.  

A publication by De Ridder and Vermeulen (2011)¹¹ highlights the integrated PK/PD modeling approach that was employed during the clinical development program for paliperidone ER. The citation for this publication is included in the reference list.

ELECTROPHYSIOLOGY

Published Literature

Dremencov et al (2007)¹² conducted a series of in vivo experiments comparing the firing rate of the 5HT neurons in the dorsal raphe nucleus and the norepinephrine (NE) neurons in the locus coeruleus of risperidone- or paliperidone-treated rats. Rats were treated with risperidone or paliperidone and then treated with the NE reuptake inhibitor desipramine, the 5HT_1A antagonist WAY 100635, the selective serotonin reuptake inhibitor (SSRI) escitalopram, or a combination of these drugs to evaluate their effects on 5HT firing.

5HT neuronal firing rate decreased in risperidone-treated rats (0.2-0.4 mg/kg, IV; P<0.05 for 0.4 mg/kg dose) but did not decrease after paliperidone treatment (up to 1.0 mg/kg, IV). Administration of the NE reuptake inhibitor desipramine (5 mg/kg, IV) or WAY 100635

(0.1-0.2 mg/kg, IV) after risperidone treatment partially reversed this risperidone-induced firing inhibition, and the combination of desipramine (5 mg/kg, IV) and WAY 100635 (0.05 mg/kg, IV) totally reversed the inhibition (P<0.05 vs. risperidone 0.4 mg/kg dose). Administration of the SSRI escitalopram (10 mg/kg per day for 2 days infused by a subcutaneous osmotic pump) decreased the firing rate of 5-HT neurons (P<0.001 vs control treatment) on day 2. Risperidone (1.0 mg/kg per day subcutaneously for 2 days), but not identically dosed paliperidone, also decreased the firing rate in these neurons (P<0.01 for risperidone). Furthermore, the combination of escitalopram and paliperidone/risperidone decreased the firing rate of 5HT neurons (P<0.01). After 14 days of treatment, the neuronal firing rate remained low in rats treated with escitalopram and risperidone (P<0.01) or risperidone alone (P<0.001); however, escitalopram or the combination of paliperidone and escitalopram no longer decreased 5HT neuronal firing rate. Escitalopram alone (10 mg/kg per day infused by a subcutaneous osmotic pump), unlike paliperidone alone (1.0 mg/kg per day subcutaneously), significantly decreased NE neuronal firing rate when administered for 2 (P<0.001) or 14 days (P<0.01); however, paliperidone treatment significantly increased NE neuronal firing rate in rats treated with escitalopram for 2 (P<0.01 vs. escitalopram alone) or 14 days (P<0.001 vs. escitalopram alone).

The authors concluded that SSRIs may inhibit NE neuronal firing in the locus coeruleus, which could explain some patients’ lack of optimal response to these drugs. Atypical antipsychotics that block 5HT_2A could restore normal firing rates to this region. Paliperidone can reverse the escitalopram-induced inhibition of NE neuronal firing rate at 14 days, without altering 5HT neuronal firing on day 14.

NEUROPROTECTIVE/NEUROTOXIC ACTIVITY

Mechanisms of Neuronal Protection

Zhu et al (2016)¹³ evaluated potential mechanisms of neuronal protection by paliperidone. The team created a neuronal injury model of psychosis by utilizing SH-SY5Y cells to study the neuroprotective effects of paliperidone against simulated neurotoxicity induced by various concentrations of MK-801 (dizocilpine), an N-methyl-D-aspartate receptor antagonist. They further evaluated cell viability, cell death, and explored the ability of paliperidone to regulate calcium channel activity. Finally, they evaluated expression of SIRT1 (sirtuin 1) and miR-134 (microRNA-134).  Nicotinamide (a SIRT1 inhibitor) was used to study the roles of SIRT1 and miR-134 in paliperidone’s neuroprotection against MK- 801-induced cell damage.

The results demonstrated that paliperidone protects SH-SY5Y cells against MK-801 induced neurotoxicity through inhibition of Ca²⁺ influx and regulation of the SIRT1/miR-134 pathway.

Cell Viability, Caspase-3 Activity, and Cell Death

Gassó et al (2012)¹⁴ compared the neurotoxic (e.g. EPS and tardive dyskinesia) and neuroprotective (e.g. prevention of disease progression/cognitive enhancement) activity of haloperidol, risperidone and paliperidone. Changes in viability, Caspase-3 Activity and Cell Death, produced by antipsychotics alone and in combination with a high dopamine (DA) concentration (100 μM), were measured using a dopaminergic cell model (neuroblastoma cells SK-N-SH). Due to differences in D₂ receptor affinities (haloperidol> risperidone and paliperidone), a wide range of antipsychotic concentrations (10, 50 and 100 μM) were evaluated for each product.

Cell Viability

• Antipsychotics Alone: Cell viability significantly decreased in a dose-dependent manner with haloperidol. Only the 100 μM concentration of risperidone and paliperidone affected Cell Viability (P<0.01).
• Antipsychotics with DA DA toxicity was enhanced by all three concentrations of haloperidol. Risperidone increased DA toxicity at 50 and 100 μM concentrations. At the 100 μM concentration, paliperidone enhanced DA toxicity.

Caspase-3 Activity

• Antipsychotics Alone: At all three concentrations, risperidone and paliperidone significantly decreased Caspase-3 Activity (P<0.01).
• Antipsychotics with DA: When compared to cells treated with DA alone, haloperidol 10 and 50 μM induced a greater increase in Caspase-3 Activity while risperidone and paliperidone reduced this activity.

Cell Death

• Antipsychotics Alone - 50 μM Concentrations: Compared to the control, few live cells were observed with haloperidol.
• Antipsychotics with DA: While all three antipsychotics enhanced DA toxicity, haloperidol produced the most Cell Deaths while paliperidone produced the least.

The authors concluded that haloperidol appears to induce apoptosis while risperidone and paliperidone may protect against it. Overall, the strongest neuroprotective effect was observed with paliperidone.

OTHER RELEVANT LITERATURE

By analyzing longitudinal EPS data from 2,630 patients with acute schizophrenia treated with haloperidol, paliperidone, ziprasidone, olanzapine, JNJ-37822681 or placebo, Reddy et al (2012)¹⁵ developed a continuous time, population-based Markov model to describe the probability of EPS incidence/severity as a function of dose, steady-state drug exposure or predicted dopamine receptor activity. Individual steady-state concentrations and D₂ occupancy levels were observed as predictors of EPS. Increased EPS occurrence rates occurred at D₂ occupancy levels above 80%.

Using a cross-sectional design, Prossen et al (2013)¹⁶ investigated the potential role of tumor necrosis factor-α (TNF-α) in the indirect relationship between atypical antipsychotic treatment (olanzapine; quetiapine; risperidone; paliperidone; clozapine) of bipolar disorder and metabolic syndrome (MetS). Overall, patients with MetS had higher levels of TNF-α then those without MetS. Atypical antipsychotic monotherapy was found to be associated with higher TNF-α levels (P=0.008) and a trend toward a greater likelihood of MetS (P=0.036). Due to sample size, metabolic associations of specific atypical antipsychotics could not be determined.

Roenker et al (2011)¹⁷ investigated the NMDA glutamate hypofunction model of schizophrenia and the effects of risperidone and paliperidone on extracellular glutamate in the prefrontal cortex of rats. Prefrontal cortical basal extracellular glutamate was normalized following pretreatment with low-dose risperidone and paliperidone. In addition, the acute MK-801 induced increase in extracellular glutamate was prevented.

Following an investigation determining the effects of risperidone and paliperidone on vascular function of diabetic rats, Aboul-Fotouh and Elgayar (2013)¹⁸ suggested that risperidone, but not paliperidone, aggravates the metabolic abnormalities and vascular dysfunction associated with diabetes possibly mediated by VCAM-1, ICAM-1 and E-selectin upregulation.

Additional articles, discussing pharmacokinetic-pharmacodynamic modeling^19,20, mitochondrial function/movement²¹ and signaling pathways^22-24, have been referenced for your review.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 23 December 2024.