Introduction

Schizophrenia is devastating illness with significant psychological, physical, social and economic impact, affecting about 1% of the population. [₁] Disease course is variable and mostly chronic, characterized by ongoing functional impairment and the frequent recurrence of acute psychotic symptoms. Thus, the general goals of the treatment are to quickly reduce symptoms severity, improve patient functioning, prevent recurrences of the symptomatic episodes and associated deterioration of the functioning. Atypical antipsychotics are currently the most frequently prescribed class of drugs for schizophrenia, as they have good efficacy with lower risk of extra pyramidal side effects. [₂] These agents are associated with varying degrees of metabolic adverse effects like weight gain, impaired glucose metabolism, dyslipidemia and in some cases serious morbidity, such as cardiovascular diseases. Paliperidone is new molecule in list of atypical antipsychotics, which has low propensity to interfere with metabolic parameters. In addition, receptor antagonism profile is favorable, leading to very few adverse effects.

Figure 1

Figure 1: Molecular structure of paliperidone ER []

Indications

Paliperidone ER (Extended Release) received its FDA approval for use in schizophrenia on December 20, 2006, but subsequently it was also used for bipolar mania. [₃]

In 3 week randomized, placebo and active controlled study, Participants were randomized to receive paliperidone ER 3 to 12 mg QD (n = 190), quetiapine 400 to 800 mg QD (n = 192), or placebo (n = 104) for 3 weeks. The primary endpoint was change in the Young Mania Rating Scale (YMRS) score from baseline to 3 weeks. Paliperidone ER was shown to be superior to placebo as well as active in meeting primary endpoint, with a mean change in YMRS score of -13.2, compared with -11.7 for quetiapine and -7.4 for placebo (paliperidone vs placebo; P =0.001). Hence, it was concluded that paliperidone ER is efficacious in acute mania. [₄]

Paliperidone is also useful in schizoaffective disorder based on a 6-week, randomized, double blind, placebo controlled trial on 316 patients with an established diagnosis of schizoaffective disorder experiencing acute symptoms. They received either 6 mg/day or 12 mg/day paliperidone ER or a placebo. The results showed that patients in the higher dose group (11.6 mg/day) paliperidone ER had significantly improved symptoms, based on the primary outcome parameter of total change in mean positive and negative syndrome scale (PANSS) scores, compared to patients on placebo (p = 0.003). [₅] Its off-label use for other conditions like autism and Asperger's syndrome may be studied. [₃]

Pharmacokinetic Profile

Paliperidone is formulated using osmotically released oral (OROS) delivery system, which make it sustained release and avoids peak to trough variation. [₃₆] Steady state concentrations occur after 4 to 5 days of dosing in most patients. Peak plasma concentrations occur at 23.1 to 29 hours after the oral administration of a paliperidone ER tablet. [₇]

Absorption And Distribution

The bioavailability of paliperidone ER is more than 28%. [₈₃] Four healthy volunteers were given a 6 mg dose of paliperidone ER, mean Cmax was 11.7 ng/ml, Tmax was 25.1 hours and AUC from 0 to 48 was 302 ng.h/mL. Following administration of paliperidone ER 9 mg, mean steady state peak to trough ratio is 1.7. [₉₁₀]

Paliperidone can be taken with or without food. It has been seen that plasma concentration of paliperidone was increased by 50 to 60% when given along with food. Plasma protein binding of paliperidone is 74%. [₉₁₁₇]

Paliperidone exists in two interconvertible enantiomers (+) and (-). At steady state, AUC of (+) enantiomer is 1.6 fold greater than (-) enantiomer. [₉₁₀] Drug is detected in human milk but not in breast fed infant. But still paliperidone can be used in pregnancy if benefits are justifiable than risk to the fetus. [₈₉] Pharmacokinetic parameters of various atypical antipsychotics are compared in table 1.

Figure 2

Table1. Comparison of pharmacokinetic parameters of atypical antipsychotics []

Metabolism And Excretion

Paliperidone undergoes limited hepatic metabolism. in vitro metabolism of paliperidone involves CYP 2D6 and 3A4, but in vivo, paliperidone does not inhibit any of the cytochrome isoenzymes. [₈₁₀₇₁₁] In five healthy volunteers administered with 1 mg ¹⁴ C] paliperidone, 91% of the radioactivity was recovered, 80% in urine and 11% in faeces. [₇₁₇] In urine most of the dose was excreted unchanged, remainder was eliminated as dealkylation, hydroxylation, dehydrogenation and benzisoxazole scission pathways. After single 1 mg dose of paliperidone, clearance for (+) and (-) enantiomer was 1.41 L/hr and 8.15 L/hr respectively. [₉]

Dosage, Administration And Formulation

Paliperidone ER is available in 3 mg, 6 mg, 9 mg and 12 mg tablet. Daily and maximum recommended dose is 6 mg and 12 mg once daily respectively administered in the morning. [₁₈] Initial dose titration is not recommended in the product labeling, which also recommends that dose increases generally should occur at intervals of more than 5 days in increments of 3 mg/day if considered necessary. Paliperidone must be swallowed whole and should not be chewed, divided, or crushed. The tablet shell, along with insoluble core components, is eliminated from the body in the stool. [₁₉]

Special Populations

Renal Impairment As paliperidone has maximum elimination by renal route; definitely renal impairment mandates decrease its dosage in moderate to severe renal impairment. Its plasma clearance decreases with decreasing creatinine clearance as shown in the table 2.

Figure 3

Table 2: Dose adjustment of paliperidone in renal failure []

Age The age itself doesn’t make in any difference in dosing but in old age renal clearance may decrease, in that case dose should be reduced. There has been positive correlation found between steady state plasma concentration of 9-hydroxy-risperidone and age. [₂₁]

Gender, hepatic impairment and race have no impact on dose adjustment of paliperidone ER. [10.7 ]

Pharmacodynamic Profile

Receptor occupation

Paliperidone is known antagonist of dopamine D₂, serotonin 5HT_2A, histamine H₁, α₁ and α₂ adrenergic receptors. It has no affinity for cholinergic muscarinic or β₁ or β₂ receptors. Due to non-occupancy of muscarinic receptor, it does not have side effects like dry mouth, constipation and dysuria. The precise mechanism is still not known, but it has been proposed that therapeutic activity of paliperidone is mediated through antagonism of D2 and 5HT_2A. [₁₀₈₁₉₃] Receptor antagonism and its positive impact in schizophrenic patients is shown in table 3.

Figure 4

Table 3. Inference of paliperidone receptor antagonism []

Paliperidone has higher affinity towards 5HT_2A and D₂ receptor than olanzapine, quetiapine and risperidone enhancing its efficacy and potency.

A single dose of paliperidone ER 6 mg was given to four healthy volunteers. In them D₂ receptor occupancy at 22 hrs was 64 % and at 46 hrs, it was 53 %. [₉]

Figure 5

Table 4. Comparative Receptor antagonism of antipsychotics []

Drug Interactions

Due to minimal liver metabolism and lack of interaction with cytochrome enzymes, paliperidone is not a culprit in interfering clearance of drugs metabolized by this route. A study was carried out on a large group of 616 schizophrenic patients to check the incidence of adverse effects in CYP2D6 poor metabolizers and found no adverse effects in CYP2D6 poor metabolizer phenotype as compared to normal CYP2D6 phenotype. [₁₀]

At standard dosage, paliperidone do not inhibit P-glycoprotein transporter, making it a safer option to use in a patient on drugs using P-glycoprotein. [₈₁₀]

In a study, 3 mg risperidone was given twice daily to 66 schizophrenic patients. Samples were collected after 12 hours and plasma concentration of 9-hydroxy-risperidone was estimated. Also, MDR-1 (C3435T and G2677T/A) genotype was identified using PCR-RFLP method. There was no difference between steady state plasma concentration of 9-hydroxy-risperidone between C3435T genotypes or 2677T/A genotypes. [₂₁]

Paliperidone ER 6 mg along with trimethoprim 200 mg twice daily for 5 days, inhibitor of organic cation transport were administered in 30 healthy male subjects. It resulted in insignificant increase in paliperidone unbound fraction (29.7% vs 25.7%), renal clearance (59.2 vs 52.4 mL/min), total exposure (356 vs 391 ng/mL.h), and terminal half-life (21.8 vs 26.8 hours). [₈₁₀]

Paliperidone should be used with caution along with centrally acting drugs, alcohol and, agents causing orthostatic hypotension. It has antagonistic action on levodopa and other dopaminergic agonists.

Paroxetine, an antidepressant with potent CYP2D6 inhibiting property, was given in 20 mg dose for 13 days along with paliperidone ER 3 mg. This was associated with a slight increase in systemic exposure to paliperidone given on day 10, with ratios of 1.16 (CI 1.04 to 1.30) for AUC and 1.09 (CI, 0.98 to 1.22) for Cmax which were not clinically significant. So it was concluded that there is no clinically significant interaction between paroxetine and paliperidone ER. [₈₁₀₂₅]

Therapeutic Efficacy

Three multicentric, randomised, double blind, placebo controlled trials were conducted the efficacy and safety of paliperidone in patients of schizophrenia. Paliperidone doses varied from range 3 mg to 15 mg once daily. The primary endpoint was decrease in total Positive and Negative Syndrome Scale (PANSS) score from baseline assessment, for which ≥ 30% reduction is defined as clinically significant. Secondary endpoints included the Personal and Social Performance (PSP) scale and the Clinical Global Impression Severity (GCI-S) scale. [₁₁]

A 6-week study assessed the efficacy and safety of once daily paliperidone (6 mg, 9 mg and 12 mg) versus placebo or olanzapine 10 mg in 630 patients. At all doses of paliperidone, significant improvement in total PANSS score, with significantly more patients attaining ≥ 30% reduction in PANSS total score (51 to 61%) compared with placebo (30%; p < 0.001). [₁₁₂₆]

Another 6-week study randomised 618 patients to once daily paliperidone (3 mg, 9 mg and 15 mg), placebo or olanzapine 10 mg. Only 59% of patients completed the study. All doses of paliperidone demonstrated significant improvement in total PANSS score (p < 0.001), with 40 to 53% of the treatment groups achieving ≥ 30% reduction in total PANSS score compared with 18% of the placebo group (p ≤ 0.005). Significant improvements in PSP scale was also demonstrated compared with placebo. [₁₁₂₇]

A further 6-week study randomised 444 patients to once daily paliperidone (6 mg and 12 mg), placebo and olanzapine 10 mg, with 43% of patients completing the study. Both doses of paliperidone demonstrated significant improvement in total PANSS score from baseline, when compared with placebo (p = 0.006 and p < 0.001, respectively). Lack of efficacy was the most commonly reported reason for withdrawal from each of these studies (19 to 24% of total study population). [₁₁₂₈]

All three studies included an active treatment group receiving olanzapine 10 mg. This was to provide a concurrent active control group to confirm that the studies were adequate to detect a drug effect in the event of negative findings for paliperidone compared with placebo. [₂₆₂₇₂₈]

Apart from the above studies, a fourth study evaluated the efficacy and safety of paliperidone in delaying symptom recurrence in patients who had been stabilized after an acute episode of schizophrenia. In this randomised, double blind, placebo controlled study 530 patients were stabilized during an 8 week run in phase using open label, flexibly dosed once daily paliperidone (3 mg to 15 mg, starting dose 9 mg) and a 6 week stabilization phase. The study was terminated early at the pre planned interim analysis when 43 patients from the intention to treat population (n = 113) experienced a relapse [14 patients (25%) in the paliperidone group and 29 patients (53%) in the placebo group]. At final analysis, a recurrence event occurred in 22% of the paliperidone ER recipient and 52% of the placebo recipient (p<0.001). [₈₉₂₉]

Improvement in mean scores from baseline values at final analysis in the following scales were greater with paliperidone ER 3 to 15 mg/day than with placebo: PANSS (6.0 vs 15.1; p ≤ 0.003), CGI-S (0.0 vs 1.0; p ≤ 0.003), PSP (-3.0 vs -8.0; p ≤ 0.003), SQL (2.0 vs 6.1; p = 0.04) and sleep quality visual analogue (-6.4 vs -15.3; p ≤ 0.003). [₉]

One international 6 week, double blind study included recently and acutely exacerbated inpatients with schizophrenia randomized to paliperidone ER, quetiapine or placebo in a 2:2:1 ratio. The study consisted of a 2 week monotherapy phase followed by a 4 week additive-therapy phase. Paliperidone ER was given in 9 to 12 mg dose and quetiapine in 600 or 800 mg/day. Outcomes included the PANSS total and factor scores.

Randomization was done on 399 patients. There was a significant improvement with paliperidone ER compared to quetiapine in the mean (SEM) PANSS total change score from day 5 (–11.4 [1.1] vs –8.2 [1.1]; P = 0.011) through the 2 week monotherapy endpoint (–23.4 [1.8] vs –17.1 [1.8]; P < 0.001). There was significant improvement with paliperidone ER compared to quetiapine for the positive, negative, disorganized thoughts. [₆]

During the 4 week additive therapy phase, 53% of paliperidone ER, 55% of quetiapine and 67% of placebo, subjects used additional psychotropic therapies. Despite optional additive therapy, the paliperidone ER group continued to show significant improvement compared to the quetiapine group in the mean (SE) PANSS total change score at study endpoint (–31.2 [1.9] vs –26.6 [1.9]; P = 0.023). [₆]

Paliperidone ER was also assessed in a 6 week, double blind, placebo controlled study enrolling 114 patients 65 years of age and older (mean, 69.7 years of age) with a mean PANSS total score of 70 to 120 (mean, 92.6). Patients received paliperidone extended release 6 mg or placebo. If tolerated, the paliperidone dose was increased to 9 mg/day after 7 days and then adjusted in 3 mg increments over the range of 3 to 12 mg. The mean paliperidone dose was 8.3 mg/day. The mean change in PANSS total score was –14.6 in the paliperidone group and –9.9 in the placebo group. The response rate was 38% among paliperidone ER recipients and 29% among placebo recipients. [₈₉]

In a pooled virtual analysis of three comparative studies, paliperidone and risperidone were compared. Patients were of 18 to 65 years of age and received either paliperidone ER 6 to 12 mg/day (n = 275), risperidone 2 to 4 mg/day (n = 173), risperidone 4 to 6 mg/day (n = 174), or placebo (n = 360). The PANSS score reductions were not that much significant for the paliperidone ER and risperidone groups, 19.0 and 19.7 respectively (P = 0.825). The paliperidone ER group had a superior mean PANSS reduction of 19 compared to the risperidone 2 to 4 mg/day reduction of 11.4 (P = 0.003). The risperidone 4 to 6 mg/day group was associated with higher rates of akathisia, restlessness, anxiety, insomnia, somnolence, dizziness, and gastrointestinal side effects than the paliperidone ER group. [₃₀]

Figure 6

Figure 2. Change from baseline in PANSS score after treatment with paliperidone ER versus placebo. []

Tolerability

Paliperidone ER in 3 to 12 mg/day is well tolerated in adult schizophrenic patients including those with old age. [₉] The most common side effects of paliperidone ER 3 to 12 mg/day were akathisia (3 to 10% vs 4%) and extra pyramidal disorders (2 to 7% vs 2%). Another study noted common adverse effect of headache. [₁₁] Other less commonly reported adverse reactions with paliperidone use include insomnia, somnolence, headache, dry mouth, hyperkinesia, hypertonia, tachycardia, postural hypotension, dizziness, electrocardiogram abnormalities (QTc prolongation), and elevated prolactin levels [Prolactin related side effects were more common with paliperidone ER than placebo (4% vs 0%)] [₈₉₃₁]

There were no clinically relevant changes in mean fasting serum glucose, insulin or serum lipid levels (low-density lipoprotein, high-density lipoprotein and triglycerides). Nevertheless, a dose related increase in body weight is found with paliperidone ER. [₁₉]

In one 6 weeks placebo and olanzapine controlled comparative trial, more than 7% weight gain was occurred in 2% of the placebo treated patients, 5% of patients taking 6 mg of paliperidone, 7% with paliperidone 9 mg compared to 13% with olanzapine 10 mg. In another 6 week study, body weight was increased 0.4 kg with placebo, 1 kg with paliperidone 6 mg, 2 kg with paliperidone 12 mg, and a significant of 2.7 kg with olanzapine.

Overall, in a pooled analysis from these three 6-week studies of paliperidone in acute schizophrenia body weight was increased by 1 kg in the combined paliperidone group compared with a reduction of 0.4 kg in the placebo group. Weight gain was dose-related (0.6 kg with 3 mg, 0.6 kg with 6 mg, 1 kg with 9 mg, 1.1 kg with 12 mg, and 1.9 kg with 15 mg). Weight gain of 7% or more occurred in 5% of patients in the placebo group, 7% in the 3 mg group, 6% in the 6 mg group, 9% in the 9 mg group, and 9% in the 12 mg Group. [₈]

A rare case report of neuroleptic malignant syndrome with paliperidone was published. One woman had no improvement in schizophrenic symptoms for 8 days after admission; paliperidone was started at 6 mg/day. At the same time quetiapine taper was begun and it was discontinued over the next 5 days, while paliperidone was increased to 9 mg/day. Two days after starting paliperidone, trifluoperazine was discontinued. She started complaining of increased stiffness. She had cogwheel rigidity and dysarthria on examination. Though started with benztropine, her rigidity worsened over the next 2 days (After 8 days of starting paliperidone). Only after suspending paliperidone and resuming quetiapine and trifluoperazine, symptoms of neuroleptic malignant syndrome resolved. [₃₂]

Risk of death in elderly patient with dementia related psychosis is remained same with paliperidone as compared to other atypical antipsychotics. [₇]

Figure 7

Table 5. Comparison of Adverse Effects of Atypical Antipsychotics []

Cost Effectiveness

In one cost and effect study, paliperidone ER was compared with other atypical antipsychotics like risperidone, olanzapine, quetiapine, aripiprazole and ziprasidone over 1 year period. The study population was patients who suffered from acute exacerbation of schizophrenia. Therapeutic effectiveness was defined as the annual number of stable days and cost (in euro) per atypical antipsychotic over one year. Official retail prices are used for comparison. The data indicates that paliperidone ER might offer an increased number of stable days (272.5 compared to 272.2 for olanzapine, 265.5 for risperidone, 260.7 for quetiapine, 260.5 for ziprasidone and 258.6 for aripiprazole) with a lower cost compared to the other therapies examined (€7,030 compared to €7,034 for olanzapine, €7,082 for risperidone, €8,321 for quetiapine, €7,713 for ziprasidone and €7,807 for aripiprazole). [₃₄] But single trial should not mislead us to any conclusion, better we wait for more such trials comparing other antipsychotics.

Conclusion

Paliperidone ER is novel atypical antipsychotic, which has definite advantages over other atypicals and placebo. Its high bioavailability and sustained release formulation improves safety, reduces dosing frequency and provides uniform drug action. It does not undergo hepatic metabolism. It is excreted entirely by renal route with minimal hepatic biotransformation. Due to low CYP450 enzyme modulation and moderate plasma protein binding drug-drug interactions risk is very low. Tolerability profile of paliperidone is almost same as risperidone. The advantage of paliperidone over risperidone is still oblivious and need further research. Paliperidone has proved its cost effectiveness in Greek market but future research should focus on 'real-world' effectiveness data and the conduction of additional economic evaluation studies in other countries. This would enable data collection on clinical practice, economic outcomes and eventually cross-country comparisons. Still, the safety and efficacy of Paliperidone ER is not established in age younger than 18 years.