Jeffrey Rado, MD

In the 9 months since paliperidone extended-release was FDA-approved for schizophrenia, the 3 acute pivotal trials supporting its approval have been published.^1-3 They join a handful of post hoc analyses of this second-generation antipsychotic (SGA) in schizophrenia subgroups, including patients over age 65, recently diagnosed patients, and those with predominant negative symptoms.

This article discusses the evidence and paliperidone ER’s probable clinical benefits and adverse effects, with focus on its:

• pharmacodynamics and pharmacokinetics
  
• potential efficacy in schizophrenia and for specific patients and symptoms
  
• safety and tolerability.
  

How does paliperidone ER work?

Paliperidone ER was approved for schizophrenia treatment in December 2006 based on three 6-week, randomized, placebo-controlled trials. Paliperidone ER is the active metabolite of risperidone (9-OH risperidone) delivered in a once-daily, time-released formulation (Table 1).

Pharmacodynamics. Similar to risperidone, paliperidone ER has high binding affinity for dopamine (D₂) and serotonin (5-HT_2A) receptors, with additional affinity for histaminic (H₁) and adrenergic receptors (alpha1 and alpha2) but not for muscarinic-cholinergic receptors.

Pharmacokinetics. After oral administration, the medication is widely and rapidly distributed. The drug’s terminal half-life is about 23 hours, and steady-state concentration is reached in 4 to 5 days.^4,5

Approximately 60% of the medication is eliminated renally and 11% is eliminated in the feces unchanged, with very limited hepatic metabolism.⁶ As a result, paliperidone ER appears to lack enzyme-inducing or inhibiting properties and does not substantially affect drugs that undergo cytochrome P-450 metabolism in the liver.

Thus paliperidone ER—when compared with risperidone and other antipsychotics that are metabolized primarily in the liver—is less likely to be involved in hepatic drug-drug or drug-disease interactions. However, some drugs that can induce CYP-450 enzymes—such as carbamazepine—may affect paliperidone’s metabolism.⁷

Paliperidone has an osmotic controlled-release oral delivery system (OROS^®) for steady medication delivery across 24 hours⁸ (Table 2).^1-3 The tablet consists of an osmotically active tri-layer core surrounded by a semipermeable membrane. When the tablet is swallowed, the membrane controls the rate of water reaching the tablet core, which determines the rate of drug delivery.⁶ The result is less variation between peak and trough drug concentrations, compared with immediate-release formulations.

Table 1

How paliperidone ER compares with risperidone

Characteristic	Paliperidone ER	Risperidone
Formulation	OROS extended-release	Immediate release
Active moiety	9-OH risperidone	Risperidone plus 9-OH risperidone
Metabolism	Primarily renal	Primarily hepatic
Drug interactions	Minimal	Primarily through cytochrome P-450 enzyme 2D6
Dosing	Start at target dose	Titrate to target dose
OROS: osmotic controlled-release oral delivery system

Table 2

Paliperidone ER’s clinical characteristics

Second-generation antipsychotic approved for schizophrenia
9-OH active metabolite of risperidone
Osmotic controlled-release system provides steady-state drug delivery over 24 hours
Terminal half-life (time for 50% of drug to be eliminated from the body) ~23 hours
Available in 3-mg, 6-mg, and 9-mg tablets; recommended starting dose is 6 mg/d, and labeled dose range is 3 to 12 mg/d
Excreted primarily by the kidney; maximum recommended dose for patients with oderate to severe renal impairment is 3 mg/d
Source: References 1-3

Clinical use

Paliperidone ER offers potential therapeutic benefits in treating schizophrenia patients, although not without the risk of adverse events such as extrapyramidal symptoms (EPS) (Table 3).^1-3

Patient selection. Because of its slow-release formulation and relatively stable plasma concentrations, paliperidone ER might be useful for patients who are highly sensitive to antipsychotics’ side effects. In particular, paliperidone ER might be ideal for patients who respond to but may not tolerate risperidone.

Paliperidone ER appears to be safe in patients with liver disease. Its primary renal excretion should minimize the risk of hepatic-related drug interactions in patients taking multiple medications.

Dosage and titration. For treating schizophrenia, the suggested starting dose of paliperidone ER is 6 mg/d taken in the morning. In the 3 pivotal trials, 6 mg was the lowest dose to show broad efficacy with minimal adverse events.⁹

For many patients, the 6-mg starting dose will be the therapeutic dose. When needed, the dose may be increased in 3-mg increments every 1 to 2 weeks to a maximum 12 mg/d (a 15-mg dose was used in clinical trials, but the adverse effects out-weighed the benefits). Lower maximum doses are recommended for patients with renal impairment:

• 6 mg/d for those with creatinine clearance ≥50 to
• 3 mg/d for those with creatinine clearance 10 to 10
  

In the pivotal trials, differences in the terminal elimination half-life between hepatically impaired and healthy patients were minimal (26.5 hours vs 23.6 hours, respectively). Unbound paliperidone levels were slightly lower in patients with hepatic impairment¹¹ but not low enough to recommend dose adjustment.

Safety and tolerability. Pooled data from the 3 trials indicate that adverse events (AEs) occurred during treatment in 66% to 77% of patients receiving paliperidone ER vs 66% in placebo groups. The most common AEs were headache (11% to 18%), insomnia (4% to 12%), and anxiety (6% to 9%).⁹

 

EPS. Risk of EPS-related AEs (such as akathisia and parkinsonian symptoms) with 3-mg and 6-mg paliperidone ER doses (13% and 10%, respectively) was similar to placebo (11%) but increased with the 9-mg, 12-mg, and 15-mg doses (25%, 26%, and 24%, respectively). Should EPS occur, reduce the paliperidone ER dose or consider adding antiparkinsonian medications.

Lab values. No clinically relevant changes were noted in blood glucose, insulin, or lipids.¹² Similar to risperidone, paliperidone ER elevated prolactin levels.

Weight gain with paliperidone ER is dose-dependent; in the clinical trials, mean body weight change for all doses was ≤1.9 kg, which is similar to the weight gain seen with risperidone and in the moderate range compared with other SGAs. When using paliperidone ER, follow the American Diabetes Association/American Psychiatric Association guidelines¹³ for monitoring weight gain and metabolic parameters with antipsychotics. Also monitor patients for clinical symptoms of hyperprolactinemia, and—if intolerable—adjust the dose or switch to another SGA.

Tachycardia. Advise patients that they may experience a rapid heart rate while taking paliperidone ER. In clinical trials, tachycardia occurred in ≤14% of patients—twice the rate with placebo—but did not contribute to more serious cardiac rhythm disturbances or to discontinuation. Incidence of prolonged corrected QT interval (QTc) was 3% to 5% in the paliperidone ER group vs 3% in the placebo group.

Cost. Paliperidone ER costs approximately $12 to $18 per daily dose, which is similar to risperidone. Cost may be a greater consideration for patients next year, when generic risperidone becomes available (see Related Resources).

Patient education. Because of paliperidone ER’s pharmacokinetic properties, counsel patients to:

• take 1 tablet each day in the morning
  
• not chew, split, or crush the tablets but swallow whole to preserve the controlled-release delivery.
  

Also inform patients that they may see the tablet’s nonabsorbable shell in their stool as undigested residue.

Table 3

Paliperidone ER’s potential benefits and risks in clinical practice

Potential benefits	Details
Efficacy	Data support acute (6 weeks) and chronic (up to 24 weeks) improvement in schizophrenia symptoms, patient function, and quality of life
Pharmacokinetics	Primarily renal excretion decreases risk of hepatic drug-drug or drug-disease interactions
Long-acting formulation	Once-daily dosing simplifies treatment and may improve adherence
EPS	Risk similar to placebo at 3-mg and 6-mg doses, but increased at higher doses
Weight gain	Similar to risperidone
Hyperprolactinemia	Similar to risperidone
Tachycardia	Occurred in up to 14% of patients in clinical trials (twice the rate of placebo [7%])
QTc prolongation	Increase up to 12 msec on average, with no patients exceeding 500 msec and no clinically adverse events during trials; use paliperidone with caution in patients with arrhythmias or cardiovascular disease or who are taking other medication that can prolong the QT interval
EPS: extrapyramidal symptoms
Source: References 1-3

Efficacy trials in schizophrenia

Three 6-week trials^1-3 examined paliperidone ER’s efficacy in a total of 1,692 patients with chronic schizophrenia who were hospitalized ≥14 days with acute exacerbations. The trials were double-blind, randomized, fixed-dose, parallel-group, and placebo- and active-controlled (compared with olanzapine, 10 mg/d). Patients showed no significant differences in demographic or baseline characteristics or in the use of rescue medications.

The primary outcome measure was mean change in Positive and Negative Syndrome Scale (PANSS) total score, which quantifies positive, negative, and global psychopathologic symptom severity. Secondary outcome measures included:

• PANSS Marder factor scores¹⁴ (derived from PANSS items that reflect positive and negative symptoms, anxiety and depression, hostility, and thought disorganization).
  
• Clinical Global Impressions-Severity (CGI-S) score, which measures overall illness severity.¹⁵
  
• Personal and Social Performance (PSP) scores, which rate socially useful activities, relationships, self-care, and disturbing and aggressive behaviors; improvement by 1 category (10 points) reflects a clinically meaningful change.^16,17
  

The first study¹ was conducted at 74 U.S. centers and enrolled 444 subjects (PANSS mean baseline score 94 ± 12). Patients were randomly assigned to fixed doses of paliperidone ER, 6 mg or 12 mg; placebo; or olanzapine, 10 mg/d. The olanzapine arm confirmed assay sensitivity and was not included in the efficacy analyses. Clinical response was defined as ≥30% improvement from baseline in total PANSS score.

A total of 43% of patients completed the study—34% taking placebo; 46% taking paliperidone ER, 6 mg; 48% taking paliperidone ER, 12 mg; and 45% taking olanzapine. Demographic and baseline characteristics of the 432 patients who received ≥1 dose were similar across all groups. Approximately 75% of patients in each group used rescue medications—primarily lorazepam—for agitation, restlessness, or insomnia for a mean of 8 days.

 

Patients taking either paliperidone ER dose showed statistically significant greater improvement in PANSS total score compared with those taking placebo (6 mg, P = 0.006; 12 mg, P

Clinical response rates were similar with the 6-mg and 12-mg paliperidone ER doses—50% and 51%, respectively—and greater than with placebo (34%). The higher response rates with paliperidone ER were statistically significant compared with placebo (6 mg, P

Discontinuation rates for lack of efficacy were lower with paliperidone ER (6 mg, 23%; 12 mg, 14%) than with placebo (35%). A substantially lower percentage of patients taking this agent remained classified as “marked/severe/extremely severe” on the CGI-S score from baseline to endpoint, compared with the placebo group;

• 6 mg paliperidone ER, 58% to 26%
  
• 12 mg paliperidone ER, 64% to 21%
  
• placebo, 60% to 45%.
  

PSP scores improved in both paliperidone ER groups, but the difference compared with placebo was statistically significant only for the 6-mg dose (P

The second study² included U.S. and international sites and compared 3 fixed doses of paliperidone ER (6-, 9-, and 12-mg) with placebo. Among the 630 patients enrolled, 66% completed the study. Patients were randomly assigned to 6 mg, 9 mg, or 12 mg of paliperidone ER; 10 mg of olanzapine; or placebo. The number of patients who dropped out because of adverse events was comparable across the groups.

Patient groups assigned to paliperidone ER showed significant improvement when compared with placebo (P 30% reduction in PANSS total score from baseline to endpoint included:

• 6 mg paliperidone ER, 56%
  
• 9 mg paliperidone ER, 51%
  
• 12 mg paliperidone ER, 61%
  
• placebo, 30%.
  

Discontinuation rates for lack of efficacy also were lower in the paliperidone ER groups vs placebo (6 mg, 16%; 9 mg, 16%; 12 mg, 10%; placebo, 40%). A substantially lower percentage of patients taking the drug remained classified as “marked/severe/extremely severe” by CGI-S score, compared with placebo:

• 6 mg paliperidone ER, 63% at baseline to 22% at endpoint
  
• 9 mg paliperidone ER, 58% to 23%
  
• 12 mg paliperidone ER, 64% to 16%
  
• placebo, 60% to 51%.
  

PSP scores improved significantly for all 3 paliperidone ER doses vs placebo.

The third study³ was a multicenter international trial that compared 3 fixed doses of paliperidone ER (3, 9, and 15 mg) with placebo. Among the 618 randomized patients, 365 (59%) completed the study: 70 of 127 (55%) on 3-mg paliperidone ER, 78 of 125 (62%) on 9-mg paliperidone ER, 82 of 115 (71%) on 15-mg paliperidone ER, and 47 of 123 (38%) on placebo.

All 3 paliperidone ER doses were associated with statistically significant improvements in PANSS total and Marder factor scores at endpoint compared with placebo (P

• 3 mg paliperidone ER, 40%
  
• 9 mg paliperidone ER, 46%
  
• 15 mg paliperidone ER, 53%
  
• placebo, 18% (P ≤0.005).
  

Discontinuation rates for lack of efficacy were lower in the paliperidone ER groups vs placebo and were dose-related (3 mg, 24%; 9 mg, 18%; 15 mg, 12%; placebo, 44%). Among patients taking olanzapine, 10 mg, 13% discontinued for lack of efficacy. Substantially fewer patients in the active drug groups were classified as “marked/severe/extremely severe” from baseline to end-point on the CGI-S scale vs the placebo group:

• 3 mg paliperidone ER, 54% to 32%
  
• 9 mg paliperidone ER, 52% to 23%
  
• 15 mg paliperidone ER, 57% to 17%
  
• placebo, 56% to 50%.
  

Finally, a statistically significant improvement in mean PSP scores from baseline to endpoint was seen for all 3 paliperidone ER doses vs placebo (3 mg, 8.3 ± 17 points; 9 mg, 7.6 ± 14 points; 15 mg, 12 ± 15.7 points; placebo, 1.5 ± 16 points [P

Additional trial evidence

Schizophrenia subpopulations. Post hoc analyses of data reported from the 3 pivotal trials suggest that paliperidone ER may be useful for specific groups of schizophrenia patients, including those who are recently diagnosed, age >65, or severely ill or have predominant negative symptoms or sleep problems (Table 4).^18-23

So far, these analyses have been presented as posters at meetings or in sponsored supplements but have not been published in peer-reviewed publications.

Efficacy in delaying recurrence. Paliperidone ER’s efficacy in delaying symptom recurrence was examined in a randomized, double-blind, placebo-controlled study of 207 patients who had been stabilized on open-label, flexible-dosed paliperidone ER.²⁴ Time to first recurrence of schizophrenia symptoms was the primary efficacy measure. Starting dose was 9 mg/d (flexible dose range 3 to 15 mg/d).

 

The study was halted at a planned interim analysis because time-to-recurrence was significantly longer for patients receiving paliperidone ER compared with placebo (P

Final analysis of the 179 patients who completed the study confirmed the interim findings. Ongoing treatment maintained improvement in patients’ acute symptoms, functioning, and quality-of-life measures.

Table 4

Studies of paliperidone ER in schizophrenia subpopulations

Patient population	Study design	Findings
Recently diagnosed	413 patients diagnosed within 5 years of study entry compared with 893 patients who had been ill ≥5 years*18,19	Tolerability was similar, but recently diagnosed patients were more likely to experience movement disorders and somnolence
Age ≥65 years	114 schizophrenia patients age ≥65 given paliperidone ER, 3 to 12 mg/d, or placebo in 6-week, double-blind, randomized, placebo-controlled trial20	Rates of cardiovascular, cerebrovascular, neuromotor, and metabolic changes similar to placebo, except for tachycardia (16% with paliperidone vs 0% with placebo)
Severely ill	217 patients with marked to severe symptoms (baseline total PANSS score ≥105)*21	Patients treated with paliperidone showed significantly greater improvement vs placebo in mean total PANSS score (–26.7 vs –5.7) and other measures
Substantial negative symptoms	299 patients with predominant negative symptoms from 3 acute efficacy trials*22	Patients treated with paliperidone showed significant improvements vs placebo on primary and secondary measures of negative symptoms
Sleep problems	36 patients age 18 to 45 diagnosed with schizophrenia and schizophrenia-related insomnia*23	In stable patients, paliperidone improved sleep architecture, continuity, and patient-rated sleep quality without producing or worsening daytime sleepiness
* Studies marked with asterisks represent post hoc analyses of data from the 3 clinical trials on which the FDA based its approval of paliperidone ER.
PANSS: Positive and Negative Syndrome Scale

Related resources

• Paliperidone extended release. Prescribing information. www.invega.com.
  
• Johnson & Johnson. U.S. District Court upholds Risperdal^® (risperidone) patent (press release). October 16, 2006. www.jnj.com/news/jnj_news/20061016_094453.htm.
  

Drug brand names

• Carbamazepine • Tegretol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Paliperidone ER • Invega
  
• Risperidone • Risperdal
  

Disclosures

Dr. Rado and Dr. Dowd receive research support from Neuronetics, sanofi-aventis, Janssen Pharmaceutica, and Solvay.

Dr. Janicak receives research support from Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, Solvay, and sanofi-aventis. He is a consultant to Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, and Solvay, and a speaker for Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, and Pfizer.

In the 9 months since paliperidone extended-release was FDA-approved for schizophrenia, the 3 acute pivotal trials supporting its approval have been published.^1-3 They join a handful of post hoc analyses of this second-generation antipsychotic (SGA) in schizophrenia subgroups, including patients over age 65, recently diagnosed patients, and those with predominant negative symptoms.

This article discusses the evidence and paliperidone ER’s probable clinical benefits and adverse effects, with focus on its:

• pharmacodynamics and pharmacokinetics
  
• potential efficacy in schizophrenia and for specific patients and symptoms
  
• safety and tolerability.
  

How does paliperidone ER work?

Paliperidone ER was approved for schizophrenia treatment in December 2006 based on three 6-week, randomized, placebo-controlled trials. Paliperidone ER is the active metabolite of risperidone (9-OH risperidone) delivered in a once-daily, time-released formulation (Table 1).

Pharmacodynamics. Similar to risperidone, paliperidone ER has high binding affinity for dopamine (D₂) and serotonin (5-HT_2A) receptors, with additional affinity for histaminic (H₁) and adrenergic receptors (alpha1 and alpha2) but not for muscarinic-cholinergic receptors.

Pharmacokinetics. After oral administration, the medication is widely and rapidly distributed. The drug’s terminal half-life is about 23 hours, and steady-state concentration is reached in 4 to 5 days.^4,5

Approximately 60% of the medication is eliminated renally and 11% is eliminated in the feces unchanged, with very limited hepatic metabolism.⁶ As a result, paliperidone ER appears to lack enzyme-inducing or inhibiting properties and does not substantially affect drugs that undergo cytochrome P-450 metabolism in the liver.

Thus paliperidone ER—when compared with risperidone and other antipsychotics that are metabolized primarily in the liver—is less likely to be involved in hepatic drug-drug or drug-disease interactions. However, some drugs that can induce CYP-450 enzymes—such as carbamazepine—may affect paliperidone’s metabolism.⁷

Paliperidone has an osmotic controlled-release oral delivery system (OROS^®) for steady medication delivery across 24 hours⁸ (Table 2).^1-3 The tablet consists of an osmotically active tri-layer core surrounded by a semipermeable membrane. When the tablet is swallowed, the membrane controls the rate of water reaching the tablet core, which determines the rate of drug delivery.⁶ The result is less variation between peak and trough drug concentrations, compared with immediate-release formulations.

Table 1

How paliperidone ER compares with risperidone

Characteristic	Paliperidone ER	Risperidone
Formulation	OROS extended-release	Immediate release
Active moiety	9-OH risperidone	Risperidone plus 9-OH risperidone
Metabolism	Primarily renal	Primarily hepatic
Drug interactions	Minimal	Primarily through cytochrome P-450 enzyme 2D6
Dosing	Start at target dose	Titrate to target dose
OROS: osmotic controlled-release oral delivery system

Table 2

Paliperidone ER’s clinical characteristics

Second-generation antipsychotic approved for schizophrenia
9-OH active metabolite of risperidone
Osmotic controlled-release system provides steady-state drug delivery over 24 hours
Terminal half-life (time for 50% of drug to be eliminated from the body) ~23 hours
Available in 3-mg, 6-mg, and 9-mg tablets; recommended starting dose is 6 mg/d, and labeled dose range is 3 to 12 mg/d
Excreted primarily by the kidney; maximum recommended dose for patients with oderate to severe renal impairment is 3 mg/d
Source: References 1-3

Clinical use

Paliperidone ER offers potential therapeutic benefits in treating schizophrenia patients, although not without the risk of adverse events such as extrapyramidal symptoms (EPS) (Table 3).^1-3

Patient selection. Because of its slow-release formulation and relatively stable plasma concentrations, paliperidone ER might be useful for patients who are highly sensitive to antipsychotics’ side effects. In particular, paliperidone ER might be ideal for patients who respond to but may not tolerate risperidone.

Paliperidone ER appears to be safe in patients with liver disease. Its primary renal excretion should minimize the risk of hepatic-related drug interactions in patients taking multiple medications.

Dosage and titration. For treating schizophrenia, the suggested starting dose of paliperidone ER is 6 mg/d taken in the morning. In the 3 pivotal trials, 6 mg was the lowest dose to show broad efficacy with minimal adverse events.⁹

For many patients, the 6-mg starting dose will be the therapeutic dose. When needed, the dose may be increased in 3-mg increments every 1 to 2 weeks to a maximum 12 mg/d (a 15-mg dose was used in clinical trials, but the adverse effects out-weighed the benefits). Lower maximum doses are recommended for patients with renal impairment:

• 6 mg/d for those with creatinine clearance ≥50 to
• 3 mg/d for those with creatinine clearance 10 to 10
  

In the pivotal trials, differences in the terminal elimination half-life between hepatically impaired and healthy patients were minimal (26.5 hours vs 23.6 hours, respectively). Unbound paliperidone levels were slightly lower in patients with hepatic impairment¹¹ but not low enough to recommend dose adjustment.

Safety and tolerability. Pooled data from the 3 trials indicate that adverse events (AEs) occurred during treatment in 66% to 77% of patients receiving paliperidone ER vs 66% in placebo groups. The most common AEs were headache (11% to 18%), insomnia (4% to 12%), and anxiety (6% to 9%).⁹

 

EPS. Risk of EPS-related AEs (such as akathisia and parkinsonian symptoms) with 3-mg and 6-mg paliperidone ER doses (13% and 10%, respectively) was similar to placebo (11%) but increased with the 9-mg, 12-mg, and 15-mg doses (25%, 26%, and 24%, respectively). Should EPS occur, reduce the paliperidone ER dose or consider adding antiparkinsonian medications.

Lab values. No clinically relevant changes were noted in blood glucose, insulin, or lipids.¹² Similar to risperidone, paliperidone ER elevated prolactin levels.

Weight gain with paliperidone ER is dose-dependent; in the clinical trials, mean body weight change for all doses was ≤1.9 kg, which is similar to the weight gain seen with risperidone and in the moderate range compared with other SGAs. When using paliperidone ER, follow the American Diabetes Association/American Psychiatric Association guidelines¹³ for monitoring weight gain and metabolic parameters with antipsychotics. Also monitor patients for clinical symptoms of hyperprolactinemia, and—if intolerable—adjust the dose or switch to another SGA.

Tachycardia. Advise patients that they may experience a rapid heart rate while taking paliperidone ER. In clinical trials, tachycardia occurred in ≤14% of patients—twice the rate with placebo—but did not contribute to more serious cardiac rhythm disturbances or to discontinuation. Incidence of prolonged corrected QT interval (QTc) was 3% to 5% in the paliperidone ER group vs 3% in the placebo group.

Cost. Paliperidone ER costs approximately $12 to $18 per daily dose, which is similar to risperidone. Cost may be a greater consideration for patients next year, when generic risperidone becomes available (see Related Resources).

Patient education. Because of paliperidone ER’s pharmacokinetic properties, counsel patients to:

• take 1 tablet each day in the morning
  
• not chew, split, or crush the tablets but swallow whole to preserve the controlled-release delivery.
  

Also inform patients that they may see the tablet’s nonabsorbable shell in their stool as undigested residue.

Table 3

Paliperidone ER’s potential benefits and risks in clinical practice

Potential benefits	Details
Efficacy	Data support acute (6 weeks) and chronic (up to 24 weeks) improvement in schizophrenia symptoms, patient function, and quality of life
Pharmacokinetics	Primarily renal excretion decreases risk of hepatic drug-drug or drug-disease interactions
Long-acting formulation	Once-daily dosing simplifies treatment and may improve adherence
EPS	Risk similar to placebo at 3-mg and 6-mg doses, but increased at higher doses
Weight gain	Similar to risperidone
Hyperprolactinemia	Similar to risperidone
Tachycardia	Occurred in up to 14% of patients in clinical trials (twice the rate of placebo [7%])
QTc prolongation	Increase up to 12 msec on average, with no patients exceeding 500 msec and no clinically adverse events during trials; use paliperidone with caution in patients with arrhythmias or cardiovascular disease or who are taking other medication that can prolong the QT interval
EPS: extrapyramidal symptoms
Source: References 1-3

Efficacy trials in schizophrenia

Three 6-week trials^1-3 examined paliperidone ER’s efficacy in a total of 1,692 patients with chronic schizophrenia who were hospitalized ≥14 days with acute exacerbations. The trials were double-blind, randomized, fixed-dose, parallel-group, and placebo- and active-controlled (compared with olanzapine, 10 mg/d). Patients showed no significant differences in demographic or baseline characteristics or in the use of rescue medications.

The primary outcome measure was mean change in Positive and Negative Syndrome Scale (PANSS) total score, which quantifies positive, negative, and global psychopathologic symptom severity. Secondary outcome measures included:

• PANSS Marder factor scores¹⁴ (derived from PANSS items that reflect positive and negative symptoms, anxiety and depression, hostility, and thought disorganization).
  
• Clinical Global Impressions-Severity (CGI-S) score, which measures overall illness severity.¹⁵
  
• Personal and Social Performance (PSP) scores, which rate socially useful activities, relationships, self-care, and disturbing and aggressive behaviors; improvement by 1 category (10 points) reflects a clinically meaningful change.^16,17
  

The first study¹ was conducted at 74 U.S. centers and enrolled 444 subjects (PANSS mean baseline score 94 ± 12). Patients were randomly assigned to fixed doses of paliperidone ER, 6 mg or 12 mg; placebo; or olanzapine, 10 mg/d. The olanzapine arm confirmed assay sensitivity and was not included in the efficacy analyses. Clinical response was defined as ≥30% improvement from baseline in total PANSS score.

A total of 43% of patients completed the study—34% taking placebo; 46% taking paliperidone ER, 6 mg; 48% taking paliperidone ER, 12 mg; and 45% taking olanzapine. Demographic and baseline characteristics of the 432 patients who received ≥1 dose were similar across all groups. Approximately 75% of patients in each group used rescue medications—primarily lorazepam—for agitation, restlessness, or insomnia for a mean of 8 days.

 

Patients taking either paliperidone ER dose showed statistically significant greater improvement in PANSS total score compared with those taking placebo (6 mg, P = 0.006; 12 mg, P

Clinical response rates were similar with the 6-mg and 12-mg paliperidone ER doses—50% and 51%, respectively—and greater than with placebo (34%). The higher response rates with paliperidone ER were statistically significant compared with placebo (6 mg, P

Discontinuation rates for lack of efficacy were lower with paliperidone ER (6 mg, 23%; 12 mg, 14%) than with placebo (35%). A substantially lower percentage of patients taking this agent remained classified as “marked/severe/extremely severe” on the CGI-S score from baseline to endpoint, compared with the placebo group;

• 6 mg paliperidone ER, 58% to 26%
  
• 12 mg paliperidone ER, 64% to 21%
  
• placebo, 60% to 45%.
  

PSP scores improved in both paliperidone ER groups, but the difference compared with placebo was statistically significant only for the 6-mg dose (P

The second study² included U.S. and international sites and compared 3 fixed doses of paliperidone ER (6-, 9-, and 12-mg) with placebo. Among the 630 patients enrolled, 66% completed the study. Patients were randomly assigned to 6 mg, 9 mg, or 12 mg of paliperidone ER; 10 mg of olanzapine; or placebo. The number of patients who dropped out because of adverse events was comparable across the groups.

Patient groups assigned to paliperidone ER showed significant improvement when compared with placebo (P 30% reduction in PANSS total score from baseline to endpoint included:

• 6 mg paliperidone ER, 56%
  
• 9 mg paliperidone ER, 51%
  
• 12 mg paliperidone ER, 61%
  
• placebo, 30%.
  

Discontinuation rates for lack of efficacy also were lower in the paliperidone ER groups vs placebo (6 mg, 16%; 9 mg, 16%; 12 mg, 10%; placebo, 40%). A substantially lower percentage of patients taking the drug remained classified as “marked/severe/extremely severe” by CGI-S score, compared with placebo:

• 6 mg paliperidone ER, 63% at baseline to 22% at endpoint
  
• 9 mg paliperidone ER, 58% to 23%
  
• 12 mg paliperidone ER, 64% to 16%
  
• placebo, 60% to 51%.
  

PSP scores improved significantly for all 3 paliperidone ER doses vs placebo.

The third study³ was a multicenter international trial that compared 3 fixed doses of paliperidone ER (3, 9, and 15 mg) with placebo. Among the 618 randomized patients, 365 (59%) completed the study: 70 of 127 (55%) on 3-mg paliperidone ER, 78 of 125 (62%) on 9-mg paliperidone ER, 82 of 115 (71%) on 15-mg paliperidone ER, and 47 of 123 (38%) on placebo.

All 3 paliperidone ER doses were associated with statistically significant improvements in PANSS total and Marder factor scores at endpoint compared with placebo (P

• 3 mg paliperidone ER, 40%
  
• 9 mg paliperidone ER, 46%
  
• 15 mg paliperidone ER, 53%
  
• placebo, 18% (P ≤0.005).
  

Discontinuation rates for lack of efficacy were lower in the paliperidone ER groups vs placebo and were dose-related (3 mg, 24%; 9 mg, 18%; 15 mg, 12%; placebo, 44%). Among patients taking olanzapine, 10 mg, 13% discontinued for lack of efficacy. Substantially fewer patients in the active drug groups were classified as “marked/severe/extremely severe” from baseline to end-point on the CGI-S scale vs the placebo group:

• 3 mg paliperidone ER, 54% to 32%
  
• 9 mg paliperidone ER, 52% to 23%
  
• 15 mg paliperidone ER, 57% to 17%
  
• placebo, 56% to 50%.
  

Finally, a statistically significant improvement in mean PSP scores from baseline to endpoint was seen for all 3 paliperidone ER doses vs placebo (3 mg, 8.3 ± 17 points; 9 mg, 7.6 ± 14 points; 15 mg, 12 ± 15.7 points; placebo, 1.5 ± 16 points [P

Additional trial evidence

Schizophrenia subpopulations. Post hoc analyses of data reported from the 3 pivotal trials suggest that paliperidone ER may be useful for specific groups of schizophrenia patients, including those who are recently diagnosed, age >65, or severely ill or have predominant negative symptoms or sleep problems (Table 4).^18-23

So far, these analyses have been presented as posters at meetings or in sponsored supplements but have not been published in peer-reviewed publications.

Efficacy in delaying recurrence. Paliperidone ER’s efficacy in delaying symptom recurrence was examined in a randomized, double-blind, placebo-controlled study of 207 patients who had been stabilized on open-label, flexible-dosed paliperidone ER.²⁴ Time to first recurrence of schizophrenia symptoms was the primary efficacy measure. Starting dose was 9 mg/d (flexible dose range 3 to 15 mg/d).

 

The study was halted at a planned interim analysis because time-to-recurrence was significantly longer for patients receiving paliperidone ER compared with placebo (P

Final analysis of the 179 patients who completed the study confirmed the interim findings. Ongoing treatment maintained improvement in patients’ acute symptoms, functioning, and quality-of-life measures.

Table 4

Studies of paliperidone ER in schizophrenia subpopulations

Patient population	Study design	Findings
Recently diagnosed	413 patients diagnosed within 5 years of study entry compared with 893 patients who had been ill ≥5 years*18,19	Tolerability was similar, but recently diagnosed patients were more likely to experience movement disorders and somnolence
Age ≥65 years	114 schizophrenia patients age ≥65 given paliperidone ER, 3 to 12 mg/d, or placebo in 6-week, double-blind, randomized, placebo-controlled trial20	Rates of cardiovascular, cerebrovascular, neuromotor, and metabolic changes similar to placebo, except for tachycardia (16% with paliperidone vs 0% with placebo)
Severely ill	217 patients with marked to severe symptoms (baseline total PANSS score ≥105)*21	Patients treated with paliperidone showed significantly greater improvement vs placebo in mean total PANSS score (–26.7 vs –5.7) and other measures
Substantial negative symptoms	299 patients with predominant negative symptoms from 3 acute efficacy trials*22	Patients treated with paliperidone showed significant improvements vs placebo on primary and secondary measures of negative symptoms
Sleep problems	36 patients age 18 to 45 diagnosed with schizophrenia and schizophrenia-related insomnia*23	In stable patients, paliperidone improved sleep architecture, continuity, and patient-rated sleep quality without producing or worsening daytime sleepiness
* Studies marked with asterisks represent post hoc analyses of data from the 3 clinical trials on which the FDA based its approval of paliperidone ER.
PANSS: Positive and Negative Syndrome Scale

Related resources

• Paliperidone extended release. Prescribing information. www.invega.com.
  
• Johnson & Johnson. U.S. District Court upholds Risperdal^® (risperidone) patent (press release). October 16, 2006. www.jnj.com/news/jnj_news/20061016_094453.htm.
  

Drug brand names

• Carbamazepine • Tegretol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Paliperidone ER • Invega
  
• Risperidone • Risperdal
  

Disclosures

Dr. Rado and Dr. Dowd receive research support from Neuronetics, sanofi-aventis, Janssen Pharmaceutica, and Solvay.

Dr. Janicak receives research support from Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, Solvay, and sanofi-aventis. He is a consultant to Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, and Solvay, and a speaker for Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, and Pfizer.

In the 9 months since paliperidone extended-release was FDA-approved for schizophrenia, the 3 acute pivotal trials supporting its approval have been published.^1-3 They join a handful of post hoc analyses of this second-generation antipsychotic (SGA) in schizophrenia subgroups, including patients over age 65, recently diagnosed patients, and those with predominant negative symptoms.

This article discusses the evidence and paliperidone ER’s probable clinical benefits and adverse effects, with focus on its:

• pharmacodynamics and pharmacokinetics
  
• potential efficacy in schizophrenia and for specific patients and symptoms
  
• safety and tolerability.
  

How does paliperidone ER work?

Paliperidone ER was approved for schizophrenia treatment in December 2006 based on three 6-week, randomized, placebo-controlled trials. Paliperidone ER is the active metabolite of risperidone (9-OH risperidone) delivered in a once-daily, time-released formulation (Table 1).

Pharmacodynamics. Similar to risperidone, paliperidone ER has high binding affinity for dopamine (D₂) and serotonin (5-HT_2A) receptors, with additional affinity for histaminic (H₁) and adrenergic receptors (alpha1 and alpha2) but not for muscarinic-cholinergic receptors.

Pharmacokinetics. After oral administration, the medication is widely and rapidly distributed. The drug’s terminal half-life is about 23 hours, and steady-state concentration is reached in 4 to 5 days.^4,5

Approximately 60% of the medication is eliminated renally and 11% is eliminated in the feces unchanged, with very limited hepatic metabolism.⁶ As a result, paliperidone ER appears to lack enzyme-inducing or inhibiting properties and does not substantially affect drugs that undergo cytochrome P-450 metabolism in the liver.

Thus paliperidone ER—when compared with risperidone and other antipsychotics that are metabolized primarily in the liver—is less likely to be involved in hepatic drug-drug or drug-disease interactions. However, some drugs that can induce CYP-450 enzymes—such as carbamazepine—may affect paliperidone’s metabolism.⁷

Paliperidone has an osmotic controlled-release oral delivery system (OROS^®) for steady medication delivery across 24 hours⁸ (Table 2).^1-3 The tablet consists of an osmotically active tri-layer core surrounded by a semipermeable membrane. When the tablet is swallowed, the membrane controls the rate of water reaching the tablet core, which determines the rate of drug delivery.⁶ The result is less variation between peak and trough drug concentrations, compared with immediate-release formulations.

Table 1

How paliperidone ER compares with risperidone

Characteristic	Paliperidone ER	Risperidone
Formulation	OROS extended-release	Immediate release
Active moiety	9-OH risperidone	Risperidone plus 9-OH risperidone
Metabolism	Primarily renal	Primarily hepatic
Drug interactions	Minimal	Primarily through cytochrome P-450 enzyme 2D6
Dosing	Start at target dose	Titrate to target dose
OROS: osmotic controlled-release oral delivery system

Table 2

Paliperidone ER’s clinical characteristics

Second-generation antipsychotic approved for schizophrenia
9-OH active metabolite of risperidone
Osmotic controlled-release system provides steady-state drug delivery over 24 hours
Terminal half-life (time for 50% of drug to be eliminated from the body) ~23 hours
Available in 3-mg, 6-mg, and 9-mg tablets; recommended starting dose is 6 mg/d, and labeled dose range is 3 to 12 mg/d
Excreted primarily by the kidney; maximum recommended dose for patients with oderate to severe renal impairment is 3 mg/d
Source: References 1-3

Clinical use

Paliperidone ER offers potential therapeutic benefits in treating schizophrenia patients, although not without the risk of adverse events such as extrapyramidal symptoms (EPS) (Table 3).^1-3

Patient selection. Because of its slow-release formulation and relatively stable plasma concentrations, paliperidone ER might be useful for patients who are highly sensitive to antipsychotics’ side effects. In particular, paliperidone ER might be ideal for patients who respond to but may not tolerate risperidone.

Paliperidone ER appears to be safe in patients with liver disease. Its primary renal excretion should minimize the risk of hepatic-related drug interactions in patients taking multiple medications.

Dosage and titration. For treating schizophrenia, the suggested starting dose of paliperidone ER is 6 mg/d taken in the morning. In the 3 pivotal trials, 6 mg was the lowest dose to show broad efficacy with minimal adverse events.⁹

For many patients, the 6-mg starting dose will be the therapeutic dose. When needed, the dose may be increased in 3-mg increments every 1 to 2 weeks to a maximum 12 mg/d (a 15-mg dose was used in clinical trials, but the adverse effects out-weighed the benefits). Lower maximum doses are recommended for patients with renal impairment:

• 6 mg/d for those with creatinine clearance ≥50 to
• 3 mg/d for those with creatinine clearance 10 to 10
  

In the pivotal trials, differences in the terminal elimination half-life between hepatically impaired and healthy patients were minimal (26.5 hours vs 23.6 hours, respectively). Unbound paliperidone levels were slightly lower in patients with hepatic impairment¹¹ but not low enough to recommend dose adjustment.

Safety and tolerability. Pooled data from the 3 trials indicate that adverse events (AEs) occurred during treatment in 66% to 77% of patients receiving paliperidone ER vs 66% in placebo groups. The most common AEs were headache (11% to 18%), insomnia (4% to 12%), and anxiety (6% to 9%).⁹

 

EPS. Risk of EPS-related AEs (such as akathisia and parkinsonian symptoms) with 3-mg and 6-mg paliperidone ER doses (13% and 10%, respectively) was similar to placebo (11%) but increased with the 9-mg, 12-mg, and 15-mg doses (25%, 26%, and 24%, respectively). Should EPS occur, reduce the paliperidone ER dose or consider adding antiparkinsonian medications.

Lab values. No clinically relevant changes were noted in blood glucose, insulin, or lipids.¹² Similar to risperidone, paliperidone ER elevated prolactin levels.

Weight gain with paliperidone ER is dose-dependent; in the clinical trials, mean body weight change for all doses was ≤1.9 kg, which is similar to the weight gain seen with risperidone and in the moderate range compared with other SGAs. When using paliperidone ER, follow the American Diabetes Association/American Psychiatric Association guidelines¹³ for monitoring weight gain and metabolic parameters with antipsychotics. Also monitor patients for clinical symptoms of hyperprolactinemia, and—if intolerable—adjust the dose or switch to another SGA.

Tachycardia. Advise patients that they may experience a rapid heart rate while taking paliperidone ER. In clinical trials, tachycardia occurred in ≤14% of patients—twice the rate with placebo—but did not contribute to more serious cardiac rhythm disturbances or to discontinuation. Incidence of prolonged corrected QT interval (QTc) was 3% to 5% in the paliperidone ER group vs 3% in the placebo group.

Cost. Paliperidone ER costs approximately $12 to $18 per daily dose, which is similar to risperidone. Cost may be a greater consideration for patients next year, when generic risperidone becomes available (see Related Resources).

Patient education. Because of paliperidone ER’s pharmacokinetic properties, counsel patients to:

• take 1 tablet each day in the morning
  
• not chew, split, or crush the tablets but swallow whole to preserve the controlled-release delivery.
  

Also inform patients that they may see the tablet’s nonabsorbable shell in their stool as undigested residue.

Table 3

Paliperidone ER’s potential benefits and risks in clinical practice

Potential benefits	Details
Efficacy	Data support acute (6 weeks) and chronic (up to 24 weeks) improvement in schizophrenia symptoms, patient function, and quality of life
Pharmacokinetics	Primarily renal excretion decreases risk of hepatic drug-drug or drug-disease interactions
Long-acting formulation	Once-daily dosing simplifies treatment and may improve adherence
EPS	Risk similar to placebo at 3-mg and 6-mg doses, but increased at higher doses
Weight gain	Similar to risperidone
Hyperprolactinemia	Similar to risperidone
Tachycardia	Occurred in up to 14% of patients in clinical trials (twice the rate of placebo [7%])
QTc prolongation	Increase up to 12 msec on average, with no patients exceeding 500 msec and no clinically adverse events during trials; use paliperidone with caution in patients with arrhythmias or cardiovascular disease or who are taking other medication that can prolong the QT interval
EPS: extrapyramidal symptoms
Source: References 1-3

Efficacy trials in schizophrenia

Three 6-week trials^1-3 examined paliperidone ER’s efficacy in a total of 1,692 patients with chronic schizophrenia who were hospitalized ≥14 days with acute exacerbations. The trials were double-blind, randomized, fixed-dose, parallel-group, and placebo- and active-controlled (compared with olanzapine, 10 mg/d). Patients showed no significant differences in demographic or baseline characteristics or in the use of rescue medications.

The primary outcome measure was mean change in Positive and Negative Syndrome Scale (PANSS) total score, which quantifies positive, negative, and global psychopathologic symptom severity. Secondary outcome measures included:

• PANSS Marder factor scores¹⁴ (derived from PANSS items that reflect positive and negative symptoms, anxiety and depression, hostility, and thought disorganization).
  
• Clinical Global Impressions-Severity (CGI-S) score, which measures overall illness severity.¹⁵
  
• Personal and Social Performance (PSP) scores, which rate socially useful activities, relationships, self-care, and disturbing and aggressive behaviors; improvement by 1 category (10 points) reflects a clinically meaningful change.^16,17
  

The first study¹ was conducted at 74 U.S. centers and enrolled 444 subjects (PANSS mean baseline score 94 ± 12). Patients were randomly assigned to fixed doses of paliperidone ER, 6 mg or 12 mg; placebo; or olanzapine, 10 mg/d. The olanzapine arm confirmed assay sensitivity and was not included in the efficacy analyses. Clinical response was defined as ≥30% improvement from baseline in total PANSS score.

A total of 43% of patients completed the study—34% taking placebo; 46% taking paliperidone ER, 6 mg; 48% taking paliperidone ER, 12 mg; and 45% taking olanzapine. Demographic and baseline characteristics of the 432 patients who received ≥1 dose were similar across all groups. Approximately 75% of patients in each group used rescue medications—primarily lorazepam—for agitation, restlessness, or insomnia for a mean of 8 days.

 

Patients taking either paliperidone ER dose showed statistically significant greater improvement in PANSS total score compared with those taking placebo (6 mg, P = 0.006; 12 mg, P

Clinical response rates were similar with the 6-mg and 12-mg paliperidone ER doses—50% and 51%, respectively—and greater than with placebo (34%). The higher response rates with paliperidone ER were statistically significant compared with placebo (6 mg, P

Discontinuation rates for lack of efficacy were lower with paliperidone ER (6 mg, 23%; 12 mg, 14%) than with placebo (35%). A substantially lower percentage of patients taking this agent remained classified as “marked/severe/extremely severe” on the CGI-S score from baseline to endpoint, compared with the placebo group;

• 6 mg paliperidone ER, 58% to 26%
  
• 12 mg paliperidone ER, 64% to 21%
  
• placebo, 60% to 45%.
  

PSP scores improved in both paliperidone ER groups, but the difference compared with placebo was statistically significant only for the 6-mg dose (P

The second study² included U.S. and international sites and compared 3 fixed doses of paliperidone ER (6-, 9-, and 12-mg) with placebo. Among the 630 patients enrolled, 66% completed the study. Patients were randomly assigned to 6 mg, 9 mg, or 12 mg of paliperidone ER; 10 mg of olanzapine; or placebo. The number of patients who dropped out because of adverse events was comparable across the groups.

Patient groups assigned to paliperidone ER showed significant improvement when compared with placebo (P 30% reduction in PANSS total score from baseline to endpoint included:

• 6 mg paliperidone ER, 56%
  
• 9 mg paliperidone ER, 51%
  
• 12 mg paliperidone ER, 61%
  
• placebo, 30%.
  

Discontinuation rates for lack of efficacy also were lower in the paliperidone ER groups vs placebo (6 mg, 16%; 9 mg, 16%; 12 mg, 10%; placebo, 40%). A substantially lower percentage of patients taking the drug remained classified as “marked/severe/extremely severe” by CGI-S score, compared with placebo:

• 6 mg paliperidone ER, 63% at baseline to 22% at endpoint
  
• 9 mg paliperidone ER, 58% to 23%
  
• 12 mg paliperidone ER, 64% to 16%
  
• placebo, 60% to 51%.
  

PSP scores improved significantly for all 3 paliperidone ER doses vs placebo.

The third study³ was a multicenter international trial that compared 3 fixed doses of paliperidone ER (3, 9, and 15 mg) with placebo. Among the 618 randomized patients, 365 (59%) completed the study: 70 of 127 (55%) on 3-mg paliperidone ER, 78 of 125 (62%) on 9-mg paliperidone ER, 82 of 115 (71%) on 15-mg paliperidone ER, and 47 of 123 (38%) on placebo.

All 3 paliperidone ER doses were associated with statistically significant improvements in PANSS total and Marder factor scores at endpoint compared with placebo (P

• 3 mg paliperidone ER, 40%
  
• 9 mg paliperidone ER, 46%
  
• 15 mg paliperidone ER, 53%
  
• placebo, 18% (P ≤0.005).
  

Discontinuation rates for lack of efficacy were lower in the paliperidone ER groups vs placebo and were dose-related (3 mg, 24%; 9 mg, 18%; 15 mg, 12%; placebo, 44%). Among patients taking olanzapine, 10 mg, 13% discontinued for lack of efficacy. Substantially fewer patients in the active drug groups were classified as “marked/severe/extremely severe” from baseline to end-point on the CGI-S scale vs the placebo group:

• 3 mg paliperidone ER, 54% to 32%
  
• 9 mg paliperidone ER, 52% to 23%
  
• 15 mg paliperidone ER, 57% to 17%
  
• placebo, 56% to 50%.
  

Finally, a statistically significant improvement in mean PSP scores from baseline to endpoint was seen for all 3 paliperidone ER doses vs placebo (3 mg, 8.3 ± 17 points; 9 mg, 7.6 ± 14 points; 15 mg, 12 ± 15.7 points; placebo, 1.5 ± 16 points [P

Additional trial evidence

Schizophrenia subpopulations. Post hoc analyses of data reported from the 3 pivotal trials suggest that paliperidone ER may be useful for specific groups of schizophrenia patients, including those who are recently diagnosed, age >65, or severely ill or have predominant negative symptoms or sleep problems (Table 4).^18-23

So far, these analyses have been presented as posters at meetings or in sponsored supplements but have not been published in peer-reviewed publications.

Efficacy in delaying recurrence. Paliperidone ER’s efficacy in delaying symptom recurrence was examined in a randomized, double-blind, placebo-controlled study of 207 patients who had been stabilized on open-label, flexible-dosed paliperidone ER.²⁴ Time to first recurrence of schizophrenia symptoms was the primary efficacy measure. Starting dose was 9 mg/d (flexible dose range 3 to 15 mg/d).

 

The study was halted at a planned interim analysis because time-to-recurrence was significantly longer for patients receiving paliperidone ER compared with placebo (P

Final analysis of the 179 patients who completed the study confirmed the interim findings. Ongoing treatment maintained improvement in patients’ acute symptoms, functioning, and quality-of-life measures.

Table 4

Studies of paliperidone ER in schizophrenia subpopulations

Patient population	Study design	Findings
Recently diagnosed	413 patients diagnosed within 5 years of study entry compared with 893 patients who had been ill ≥5 years*18,19	Tolerability was similar, but recently diagnosed patients were more likely to experience movement disorders and somnolence
Age ≥65 years	114 schizophrenia patients age ≥65 given paliperidone ER, 3 to 12 mg/d, or placebo in 6-week, double-blind, randomized, placebo-controlled trial20	Rates of cardiovascular, cerebrovascular, neuromotor, and metabolic changes similar to placebo, except for tachycardia (16% with paliperidone vs 0% with placebo)
Severely ill	217 patients with marked to severe symptoms (baseline total PANSS score ≥105)*21	Patients treated with paliperidone showed significantly greater improvement vs placebo in mean total PANSS score (–26.7 vs –5.7) and other measures
Substantial negative symptoms	299 patients with predominant negative symptoms from 3 acute efficacy trials*22	Patients treated with paliperidone showed significant improvements vs placebo on primary and secondary measures of negative symptoms
Sleep problems	36 patients age 18 to 45 diagnosed with schizophrenia and schizophrenia-related insomnia*23	In stable patients, paliperidone improved sleep architecture, continuity, and patient-rated sleep quality without producing or worsening daytime sleepiness
* Studies marked with asterisks represent post hoc analyses of data from the 3 clinical trials on which the FDA based its approval of paliperidone ER.
PANSS: Positive and Negative Syndrome Scale

Related resources

• Paliperidone extended release. Prescribing information. www.invega.com.
  
• Johnson & Johnson. U.S. District Court upholds Risperdal^® (risperidone) patent (press release). October 16, 2006. www.jnj.com/news/jnj_news/20061016_094453.htm.
  

Drug brand names

• Carbamazepine • Tegretol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Paliperidone ER • Invega
  
• Risperidone • Risperdal
  

Disclosures

Dr. Rado and Dr. Dowd receive research support from Neuronetics, sanofi-aventis, Janssen Pharmaceutica, and Solvay.

Dr. Janicak receives research support from Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, Solvay, and sanofi-aventis. He is a consultant to Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Neuronetics, and Solvay, and a speaker for Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, and Pfizer.