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Newer Oral Atypical Antipsychotic Agents: A Review

Jonathan R. Scarff, MD; and David A. Casey, MD

Educational Objectives
After completing this program, readers should be able to: I Describe the newer oral antipsychotic agents and indicate the differences between them. I Compare and contrast the newer oral antipsychotic agents with the older atypical antipsychotic medications. I Review the appropriate use of these agents, including dosing, contraindications, side-effect profiles, and interactions. black-box warnings for all antipsychotic drugs.2 Antipsychotic agents may be classified in several ways. Commonly, they can be designated as older drugs (often called conventional or typical antipsychotics) and newer atypicals. The term atypical refers to the perceived lower likelihood of extrapyramidal symptoms, a sequela that had been deemed characteristic of the first generation of antipsychotic drugs. The atypicals are widely prescribed based on the perception that they are more effective and produce fewer side effects than the typicals, even though some atypicals are much more expensive. CATIE (Clinical Antipsychotic Trials in Intervention Effectiveness), a large study published in 2005, cast doubt on the relative overall effectiveness of the atypicals, which seemed to perform no better than perphenazine (formerly Trilafon, Schering-Plough), an older, less expensive typical antipsychotic medication.3 Some observers have suggested a return to the use of the less expensive typical medications. In this setting, the field is in need of better agents to bring about improved antipsychotic effects, a lower rate of refractory illness, and reduced both metabolic and neurological side effects. The atypical antipsychotics include risperidone (Risperdal, Janssen), olanzapine (Zyprexa, Eli Lilly), quetiapine (Seroquel, AstraZeneca), ziprasidone (Geodon, Pfizer), and aripiprazole (Abilify, Bristol-Myers Squibb/Otsuka). Clozapine (Clozaril, Novartis) is usually included in this list as the prototypical agent, although its potential for bone marrow suppression sets it apart. Since the introduction of aripiprazole in 2002, there has been a relative hiatus in the development of new atypical antipsychotic drugs. In this article, we review four oral atypical antipsychotic agents introduced since 2007: paliperidone (Invega, Ortho-McNeil-Janssen), iloperidone (Fanapt, Vanda), asenapine (Saphris, Organon), and lurasidone (Latuda, Sunovion). We discuss their classification, indications, mechanism of action, clinical trials, efficacy, adverse effects, comparisons with other antipsychotics, new indications being sought, dosing and administration, absorption, distribution, metabolism, excretion, contraindications, FDA warnings, and drugdrug interactions. We excluded antipsychotic agents that are currently under investigation and those that have not yet been approved by the FDA. We conducted a Medline search for the terms paliperidone, iloperidone, asenapine, and lurasidone to identify efficacy and tolerability trials for each drug. Product information and results from unpublished studies were obtained from the manufacturers.

Introduction
Antipsychotic drugs are commonly prescribed for a variety of psychiatric conditions. In addition to individuals with schizophrenia, the original target patient population, several antipsychotic medications are widely used for bipolar disorder, depression, anxiety, delirium, insomnia, agitation, and aggression in various patient types. Despite their important role in the treatment of psychotic and other illnesses, these medications have some shortcomings. Some patients with psychosis fail to respond to treatment, or they may respond incompletely. Some patients experience neurological events such as extrapyramidal side effects or, more rarely, tardive dyskinesia. Neuroleptic malignant syndrome is another rare but potentially life-threatening complication of treatment with antipsychotic drugs. Recently, the antipsychotic medications (particularly the atypical, second-generation antipsychotics) have come under scrutiny because of an increased risk of weight gain and metabolic adverse effects (AEs), such as glucose intolerance and lipid abnormalities. These AEs have the potential to increase the risk of type-2 diabetes mellitus and cardiovascular disease as well as morbidity and mortality rates related to these conditions.1 Antipsychotic drugs are often prescribed off-label for the management of agitation and psychosis in patients with dementia without an approved FDA indication. The use of these medications in elderly dementia patients has become controversial and has been reported by the FDA to increase the risk of cerebrovascular events as well as the all-cause death rate among these patients, leading to the advent of
Dr. Casey is Vice Chairman of the Department of Psychiatry at the University of Louisville, Kentucky. Dr. Scarff is a Resident in General Psychiatry at the university.

Accepted for CE credit on August 23, 2011, and for CME credit on October 20, 2011.

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The Four New Atypicals

Paliperidone (Invega)
Paliperidone belongs to the benzisoxazole derivative class of atypical antipsychotic agents. It was approved by the FDA in December 2006 for the treatment of schizophrenia and for the maintenance treatment of schizophrenia in April 2007. In July 2009, it received an indication for the acute treatment of schizoaffective disorder, both as monotherapy and as an adjunct to mood stabilizers or antidepressants. Paliperidone is the major active metabolite of risperidone (9-hydroxy risperidone). It is an antagonist at D2-dopaminergic receptors, alpha1-adrenergic and alpha2-adrenergic receptors, and H1-histaminergic receptors.2 Paliperidone demonstrates serotonin (5-HT2A) agonist activity and displays no affinity for muscarinic cholinergic or beta-adrenergic receptors.4 Compared with risperidone, paliperidone exhibits easier dissociation from the D2 receptors; this is thought to make it less likely to induce extrapyramidal symptoms when compared with the parent compound.5 In three six-week, double-blind, placebo-controlled studies, paliperidone was effective as monotherapy for the acute exacerbations of schizophrenia; it also demonstrated efficacy as a maintenance therapy in 14-week and 52-week clinical trials.611 In two six-week clinical trials, paliperidone demonstrated efficacy either as monotherapy or as an adjunct to mood stabilizers or antidepressants in patients with schizoaffective disorder.1215 In another 6-week study, paliperidone showed greater efficacy than a comparable dose of quetiapine for symptom control in patients with acute exacerbations of schizophrenia who required hospitalization.15 Patients with schizophrenia who were suboptimally responsive to risperidone reported improved satisfaction with paliperidone after 4 to 6 weeks of treatment.16,17 Although paliperidone is not currently indicated for the treatment of bipolar disorder, two studies of 6 and 9 weeks in duration found it effective as monotherapy in reducing acute manic or mixed symptoms in patients with bipolar disorder.18,19 However, in another 6-week trial, paliperidone did not show greater efficacy as an adjunct to lithium or valproate (e.g., Depakene, Abbott) when it was compared with mood-stabilizer monotherapy in patients with acute mania.20 In a pooled analysis of three six-week trials, the most serious AE associated with paliperidone was worsening psychosis or schizophrenia.21 The most common treatment-emergent AEs were headache, akathisia, insomnia, somnolence, and orthostatic hypotension. In the treatment group, weight gain was less than 2 kg, and there was a minimal, clinically insignificant change (less than 0.1 mmol/L) in the lipid profile. No information was available to determine whether additional treatment indications are currently being sought for paliperidone. Paliperidone is sold in 1.5-mg, 3-mg, 6-mg, and 9-mg extended-release (ER) formulation tablets as well as in a longacting injection formulation known as Invega Sustena. It is administered whole, with liquid, and without regard to food intake.4 For patients with schizophrenia and schizoaffective disorder, the recommended dosage is 6 mg once daily in the morning. The maximum recommended dosage is 12 mg/day. Because of its extended-release delivery system, the tablets

should not be chewed, divided, or crushed. Following ingestion, paliperidone absorption occurs through an osmotic, controlled-release mechanism that delivers paliperidone at a controlled rate.4 In the aqueous environment of the gastrointestinal (GI) tract, the tablet overcoat erodes quickly and water enters the tablet core at a controlled rate through a semipermeable membrane. Hydrophilic polymers in the core hydrate and swell to create a paliperidonecontaining gel that is then pushed out through laser-drilled orifices on the dome of the tablet. Biologically inert components of the tablet remain intact during transit through the GI tract and are eliminated in the stool as a tablet shell. Patients should be informed that it is normal to occasionally find the tablet shell eliminated in feces. The absolute oral bioavailability of paliperidone following administration is 28%, and steady-state concentrations are attained within 4 or 5 days of administration in most subjects.4 As a result of the extended delivery system, the elimination half-life of paliperidone is approximately 23 hours.4 Paliperidone undergoes primarily renal metabolism. Although four hepatic metabolic pathways have been identified in vivo, none of these could be shown to account for more than 10% of the metabolized dose. Similarly, in vitro studies showed that paliperidone does not substantially inhibit the metabolism of drugs by cytochrome P450 (CYP) isozymes.2 Therefore, paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by CYP isozymes, and no dosage adjustment is required in patients with mild-to-moderate hepatic impairment. For patients with mild renal impairment (a creatinine clearance [CrCl] of 50 to 80 mL/minute), the recommended initial dosage of paliperidone is 3 mg once daily. The dosage may then be increased to a maximum of 6 mg once daily according to the patients clinical response and tolerance.4 For patients with moderate-to-severe renal impairment (CrCl, 1050 mL/ minute), the recommended initial dosage of paliperidone is 1.5 mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment. Paliperidone is not recommended in patients with a CrCl below 10 mL/minute, and it is contraindicated in patients with hypersensitivity to this drug or to risperidone. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.2 Because of its potential to induce orthostatic hypotension, paliperidone may have an additive effect if it is given with antihypertensive agents. Coadministration of 6 mg of paliperidone daily with carbamazepine (Carbatrol, Shire) 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state concentration of paliperidone, largely as a result of increased renal clearance (35%) of paliperidone.4 Conversely, administration of paliperidone with divalproex sodium extended-release tablets (Depakote, Abbott) resulted in an increase of approximately 50% in the peak concentration (Cmax) of paliperidone.4 A reduced dosage of paliperidone should be considered if it is administered with valproate. The renal metabolism of paliperidone and lithium is through separate mechanisms, which allows for coadministration without the risk of adverse drug interactions. Like other antipsychotic agents, paliperi-

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done carries an FDA boxed warning that mentions increased mortality rates in elderly patients with dementia-related psychosis. duction, hydroxylation (mediated by CYP2D6), and O-demethylation (mediated by CYP3A4).22 Inhibitors of either isozyme, such as ketoconazole (Nizoral, Janssen), paroxetine (Paxil, GlaxoSmithKline), and fluoxetine (Prozac, Eli Lilly), demonstrated a serum increase in iloperidone. Inhibitors or inducers of other CYP isozymes are unlikely to affect the metabolism of iloperidone. Iloperidone has not been shown to significantly affect metabolism and bioavailability of other drugs. The renal clearance of iloperidone is 47 to 102 L/hour, with a volume of distribution of 1,340 to 2,800 L. The mean elimination half-life of iloperidone is 18 to 31 hours, depending on whether the patient is a normal, poor, or extensive metabolizer. Steady-state concentrations are attained within 3 to 4 four days after administration. The bulk of iloperidone metabolites are recovered in urine. Iloperidone is available in tablet strengths of 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg, and an injectable depot formulation is under development.22,28 The medication is administered without regard to food intake, with twice-daily dosing starting at 1 mg. The dosage may be titrated to efficacy (624 mg/day total) over 1 to 2 weeks. The maximum dosage is 24 mg/day.22 To prevent hypotension, iloperidone is initiated at a dosage of 1 mg twice daily and is then increased to 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg twice daily on each subsequent day to reach the target dosage of 12 to 24 mg/day.22 Iloperidone is not recommended for patients with hepatic impairment.22 In addition to an FDA boxed warning regarding increased mortality rates in elderly patients with dementia-related psychosis, iloperidone is contraindicated in patients with hypersensitivity to iloperidone or to its formulation components. Iloperidone should not be used with other drugs that prolong the QT interval.22 The dose should be reduced in patients who are receiving a strong CYP2D6 or CYP3A4 inhibitor.

Iloperidone (Fanapt)
Iloperidone belongs to the piperidinylbenzisoxazole derivative class of antipsychotic drugs. Introduced in May 2009, iloperidone was approved by the FDA for the treatment of schizophrenia.22 Its mechanism of action involves high-affinity antagonism of serotonergic (5-HT2A), alpha1- and alpha2cadrenergic, and D2- and D3-dopaminergic receptors.23 The Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS) were used to evaluate iloperidone in two randomized, placebo-controlled, doubleblind trials (one lasting 4 weeks and one lasting 6 weeks).24,25 The drug was found to reduce symptoms in individuals experiencing acute exacerbations of schizophrenia or schizoaffective disorder. In a 52-week trial, a pooled analysis of the active-treatment group showed the efficacy of iloperidone as maintenance therapy in reducing positive and negative symptoms of schizophrenia.26 The safety of iloperidone in individuals with schizophrenia or schizoaffective disorder has also been demonstrated. In 1,044 patients who were randomly assigned to receive iloperidone during three 6-week clinical trials, the most common AEs were dizziness, dry mouth, dyspepsia, and somnolence.27 Extrapyramidal Symptom Rating Scale (ESRS) scores improved with all iloperidone doses. Akathisia scores were reduced significantly from baseline in groups receiving iloperidone at a dosage of either 10 to 16 mg/day or 20 to 24 mg/day. The incidence of akathisia in treated patients was comparable to that in patients receiving placebo, according to the Barnes Akathisia Scale. Statistically significant changes in vital signs, particularly hypotension, orthostatic hypotension, and tachycardia, were noted in all iloperidone-treated groups. 27 Such changes occurred most frequently with iloperidone therapy, but they were generally short-lived and occurred in the first week of treatment. Although the corrected QT interval (QTc, Fridericia) increased in all treatment groups, no deaths or arrhythmias attributed to QTc prolongation occurred during the studies. Minimal weight gain occurred in all patient groups receiving iloperidone. Additional laborator y studies showed no changes in glucose and lipid profiles, and a decrease in triglyceride levels was noted in all iloperidone-treated groups.27 Although efficacy and safety trials evaluated iloperidone simultaneously with haloperidol (Haldol, Ortho-McNeilJanssen), ziprasidone, and risperidone, the other antipsychotic agents were used to assess study validity and did not serve as direct comparators with iloperidone. No information was accessible to determine whether additional indications were being sought for iloperidone from the FDA. Iloperidone is well absorbed after administration, and the Cmax occurs within 2 to 4 hours. The relative bioavailability of the tablet formulation, compared with an oral solution, is 96% and is not significantly affected by a concurrent high-fat meal.22 The drug is metabolized hepatically through carbonyl re-

Asenapine (Saphris)
Asenapine belongs to the dibenzo-oxepino pyrrole class of atypical antipsychotic agents. It was approved by the FDA in August 2009 for the treatment of schizophrenia in adults and as acute therapy (either as monotherapy or adjunctive therapy) for manic or mixed episodes associated with bipolar I disorder.29 Asenapine is a high-affinity antagonist at 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT57 serotonergic receptors; at D1- to D4-dopaminergic receptors; at alpha1- and alpha2-adrenergic receptors; and at H1-histaminergic receptors.29 It demonstrates moderate antagonist affinity for histamine H2 receptors and no appreciable affinity for muscarinic cholinergic receptors.29 In 6-week and 1-year clinical trials, asenapine reduced both positive and negative symptoms in acute exacerbations of schizophrenia, and it was effective as a maintenance therapy.30,31 In acute (6-week) and maintenance (12- and 40-week) trials, asenapine reduced symptoms of acute manic or mixed states as monotherapy or in combination with valproate or lithium in individuals with bipolar disorder type I.3134 In clinical trials, the most common AEs were sedation, dizziness, somnolence, fatigue, oral hypoesthesia, dry mouth, and increased weight. Extrapyramidal symptoms occurred in fewer than 5% of patients; the most common AEs were dystonia,

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akathisia, parkinsonism, and dyskinesia. No published studies have compared the efficacy of asenapine with that of other atypicals, and no information is available regarding possible future indications. Asenapine is available in 5- and 10-mg unflavored and black cherryflavored tablets for sublingual administration.29 The drug is rapidly absorbed, and the Cmax occurs within 30 to 90 minutes.29 To ensure optimal absorption, patients should be instructed not to crush, chew, or swallow the tablets. The tablets should be placed under the tongue and should be allowed to dissolve completely. Patients should also be instructed not to eat or drink for 10 minutes after taking asenapine; in efficacy studies, water intake 2 to 5 minutes after administration resulted in decreased asenapine exposure. The mean terminal half-life of asenapine is approximately 24 hours, and the absolute bioavailability of a 5-mg tablet is 35%; however, bioavailability is only 2% if the tablet is swallowed instead of being dissolved.29 With multiple-dose twice-daily dosing, steady state is attained within 3 days.29 About 90% of the dose is eliminated; approximately 50% was recovered in urine and 40% was recovered in feces.29 Asenapine is cleared primarily through glucuronidation by UDP-glucuronosyltransferase (UGT) 1A4 and through oxidative metabolism by CYP isoenzymes (predominantly CYP1A2 and, to a lesser extent, CYP3A4 and CYP2D6).29 Asenapine is a weak inhibitor of CYP2D6 and does not cause induction of CYP1A2 or CYP3A4 activities.29 Inhibitors and inducers of other CYP pathwaysparoxetine, imipramine (Tofranil, Mallinckrodt), cimetidine (Tagamet, GlaxoSmithKline), carbamazepine, and valproic acidhave not been found to significantly affect the Cmax of asenapine and do not warrant dosage adjustments for asenapine. A population analysis indicated that the concomitant administration of lithium had no effect on the pharmacokinetics of asenapine.29 Coadministration of fluvoxamine (Luvox, Solvay/Jazz/Abbott), a CYP1A2 inhibitor, at a dosage of 25 mg twice daily for 8 days and one dose of asenapine 5 mg increased the Cmax of asenapine by 13%; therefore, the manufacturer recommends coadministration with caution.29 As a result of alpha1-adrenergic antagonism, asenapine may enhance the effects of some antihypertensive agents. Asenapine is not recommended for patients with severe hepatic impairment; however, no dosage adjustments are required based on the degree of renal impairment.29 Although no contraindications are listed in the prescribing information, a boxed warning mentions an increased mortality rate in older patients with dementia-related psychosis. In adults with acute schizophrenia, the recommended starting and target dosage of asenapine is 5 mg twice daily. In a maintenance trial in patients with schizophrenia, the starting dosage was 5 mg twice daily, with an increase to 10 mg twice daily after one week, based on the patients tolerance. As an acute therapy for manic or mixed episodes, the recommended starting dosage of asenapine is 10 mg twice daily. This dosage can be decreased to 5 mg twice daily if warranted by adverse effects or individual tolerance.29 When administered as an adjunctive therapy with lithium or valproate, the recommended starting dosage of asenapine is 5 mg twice daily; this dosage can be increased to 10 mg twice daily, depending on the clinical response and patient tolerance. There is no recommendation for the duration or dose of maintenance therapy with asenapine in patients with schizophrenia or bipolar disorder.

Lurasidone (Latuda)
Lurasidone belongs to the benzisothiazol class of atypical antipsychotic drugs and was approved for the treatment of schizophrenia in October 2010. It acts as an antagonist at dopamine (D2) and serotonin (5-HT2A and 5-HT7) receptors, as a partial agonist at 5-HT1A receptors, as a moderate agonist at alpha2C receptors, and as a minimal agonist at alpha 1noradrenergic receptors.35 In 6-week, double-blind, placebo-controlled studies that evaluated the safety and efficacy of lurasidone in reducing psychotic symptoms in individuals with schizophrenia, lurasidone was found to be as efficacious as haloperidol and olanzapine.3639 Although lurasidone did not demonstrate efficacy in a fifth clinical trial, the data were included in a pooled safety analysis.40 In the pooled analysis, 78.9% of individuals receiving lurasidone experienced at least one treatment-emergent AE.39 Those AEs leading to discontinuation of lurasidone were worsening of schizophrenia, akathisia, psychotic disorders, dystonia, and agitation. Other AEs included nausea, vomiting, dyspepsia, salivar y hypersecretion, fatigue, somnolence, dizziness, insomnia, agitation, anxiety, and restlessness. No information was available about future indications being sought for lurasidone, although studies of patients with bipolar disorder are under way.41,42 A boxed warning mentions increased mortality rates in older patients with dementiarelated psychosis. Lurasidone is available in tablet strengths of 40 and 80 mg. The tablets should be administered orally with food (an intake of at least 350 calories), because food affects the drugs bioavailability.35 The initial dosage, 40 mg once daily, can be increased to 80 mg once daily if indicated.35 Following ingestion, lurasidone is rapidly absorbed and reaches the Cmax within 1 to 3 hours. Approximately 9% to 19% of the administered dose is absorbed. The mean half-life varies from 29 to 37 hours, but it may last nearly 40 hours in patients with schizophrenia when given at a dosage of 120 to 160 mg/day.35 The volume of distribution is approximately 6,173 L, and the apparent CrCl is 3,902 mL/minute.35 Lurasidone undergoes hepatic metabolism, primarily by the CYP3A4 isozyme. It undergoes biotransformation pathways through N-dealkylation, hydroxylation, and S-oxidation, which in turn produces pharmacologically active metabolites.35 Lurasidone is eliminated primarily in feces, with the remainder excreted in the urine.35 When lurasidone was administered with ketoconazole (a potent CYP3A4 inhibitor), there was a seven-fold increase in the serum concentration of lurasidone; administration with diltiazem (Cardizem, Biovail/Valeant/Abbott), a moderate CYP3A4 inhibitor, nearly doubled the serum concentration of lurasidone.35 With coadministration of rifampin, a potent CYP3A4 inducer, serum lurasidone concentrations were decreased by more than 80%. Therefore, lurasidone is contraindicated in patients receiving CYP3A4 inducers or inhibitors

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Table 1 A Comparison of Four Recently FDA-Approved Oral Atypical Antipsychotic Agents FDA Indication Paliperidone (Invega) Schizophrenia, schizoaffective disorder Starting Dose 6 mg once daily Effective Dose 312 mg once daily Clinical Caveats Inform patients that tablets should not be chewed or broken and that the tablet shell might be eliminated intact in feces

Iloperidone (Fanapt)

Schizophrenia

1 mg twice daily

612 mg twice daily Titrate slowly to avoid orthostatic hypotension; potential for significant QTc prolongation 10 mg twice daily Advise patients not to chew or swallow tablets; administer cautiously with drugs that inhibit CYP 450 2D6 and 1A2 isozymes Administer with food (350 calories or more)

Asenapine (Saphris)

Schizophrenia, bipolar disorder I

5 mg twice daily (10 mg twice daily if monotherapy for bipolar disorder) 40 mg once daily

Lurasidone (Latuda)

Schizophrenia

80 mg once daily

CYP 450 = cytochrome P450; QTc = corrected QT interval.

and in patients with a hypersensitivity to the drug or its formulation components.35 Although lurasidone demonstrates some CYP3A4 inhibition, no decrease in the dosage was required when the drug was coadministered with midazolam (Versed, Roche), a CYP3A4 substrate. No clinically significant metabolic interactions were noted when lurasidone was given with lithium.35

Discussion
Paliperidone, iloperidone, asenapine, and lurasidone are the newest oral atypical antipsychotic medications to be introduced since the approval of aripiprazole in 2002. Important characteristics of these drugs are summarized in Table 1. Except for paliperidone, all of these medications undergo hepatic metabolism and can be altered by CYP450 inducers or inhibitors. Mechanisms of action (a combination of dopamine blockade and various serotonin effects) are similar to those of other atypical antipsychotic drugs. Clinical trials suggest that the antipsychotic effects of these agents are generally similar to those of other atypicals, although direct comparisons are difficult, given the dearth of head-to-head trials. In comparison to the typical (older) and atypical antipsychotic agents, the newer atypicals have the potential advantages of a favorable metabolic profile; an apparently lower risk of extrapyramidal AEs; and, in the case of asenapine, sublingual administration, which may be useful for patients with dysphagia or a history of noncompliance by cheeking medications. Disadvantages of the newer oral atypicals include the class effects of possible orthostatic hypotension, prolongation of the QTc interval, sedation, and weight gain. Despite claims of minimal weight gain and metabolic abnormalities with the newest atypicals, many patients in clinical trials were probably not treatment-naive. Patients may have experienced the greatest changes in weight or metabolic profile when they received a previous antipsychotic medication; this makes it difficult to

determine causality when a subsequent switch to a newer atypical antipsychotic drug seems to lead to relative improvements in the metabolic profile or in weight. In addition, 6-week trial durations might have been insufficient to observe significant changes in the metabolic profile or emerging extrapyramidal symptoms. Given the short duration of published trials and the relatively brief period that these drugs have been on the market, it is difficult to state the possible risks of tardive dyskinesia or neuroleptic malignant syndrome. Paliperidones close relationship with the parent compound, risperidone, is worthy of consideration. Financial constraints may make it difficult to justify prescribing paliperidone in place of its less expensive, and apparently equally efficacious, mother compound. However, the cost of prescribing paliperidone may be considered reasonable for three groups of patients: those with hepatic impairment who previously responded to risperidone, those with limited compliance who previously responded to risperidone but declined depot risperidone, and those who responded to risperidone but could not tolerate the drugs extrapyramidal effects.43 The need for a slow titration to efficacy may limit the usefulness of iloperidone in an acute setting. Studies of iloperidone have included the comparators haloperidol, ziprasidone, and risperidone for assay sensitivity, and they were not designed or powered to be viewed as head-to-head trials of comparative effectiveness. Nevertheless, the apparent trend toward lower efficacy for iloperidone is not reassuring. The sublingual formulation of asenapine can pose a potential disadvantage for some patients, because no alternative administration option exists for those who experience unpleasant taste or tongue sensations. Twice-a-day dosing, as recommended in the package insert despite asenapines relatively long half-life, may have a negative impact on adherence, especially for those who find the drugs taste unpleasant. Patients who swallow the tablet, instead of allowing it to dissolve in the mouth, may experience poor absorption.

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Conclusion
With daily or twice-daily administration and generally favorable metabolic profiles, paliperidone, iloperidone, asenapine, and lurasidone offer new treatment options for schizophrenia, schizoaffective disorder, bipolar disorder, or antidepressant augmentation. Given the number of patients who fail to respond or to tolerate existing antipsychotic medications, it is likely that some patients will find one of more of these newer oral drugs useful. However, at present they appear to represent an evolution of existing therapeutic approaches rather than a paradigm shift in the effectiveness and safety of antipsychotic medications. The brief (6-week) duration of most clinical trials, as well as the relatively short time on the market for these drugs, limits an overall analysis of their value relative to that of pre-existing drugs. If any or all of these products prove to offer improved efficacy or a reduced risk of neurological and metabolic side effects over a period of time, the additional costs incurred in prescribing them might be a good value.

14.

15.

16.

17.

18.

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of paliperidone extended release in the treatment of subjects with schizoaffective disorder. Poster, presented at the U.S. Psychiatric and Mental Health Congress, San Diego, Calif., October 30 November 2, 2008. Canuso CM, Lindenmayer JP, Kosik-Gonzalez C, et al. A randomized, double-blind, placebo-controlled study of paliperidone extended-release in the treatment of subjects with schizoaffective disorder. J Clin Psychiatry 2010;71(5):587596. Canuso CM, Dirks B, Carothers J, et al. Randomized, doubleblind, placebo-controlled study of paliperidone extended-release and quetiapine in inpatients with recently exacerbated schizophrenia. Am J Psychiatry 2009;166(6):691701. Canuso C, Grinspan A, Merriman C, et al. Medication satisfaction in subjects with schizophrenia treated with paliperidone extendedrelease after suboptimal response to oral risperidone. Poster, presented at the College of Psychiatric and Neurologic Pharmacists, annual meeting; Jacksonville, Fla., April 1922, 2009. Canuso CM, Grinspan A, Kalali A, et al. Medication satisfaction in schizophrenia: A blinded-initiation study of paliperidone extended release in patients suboptimally responsive to risperidone. Int Clin Psychopharmacol 2010;25(3):155164. Berwaerts J, Xu H, Nuamah I, et al. Evaluation of the efficacy and safety of paliperidone extended-release in the treatment of acute mania: A randomized, double-blind, doseresponse study. J Affect Disord, July 10, 2010 (online). Vieta E, Nuamah I, Lim P, et al. A randomized, placebo- and activecontrolled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord 2010;12:230243. Berwaerts J, Lane R, Nuamah IF, et al. Paliperidone extendedrelease as adjunctive therapy to lithium or valproate in the treatment of acute mania: A randomized, placebo-controlled study. J Affect Disord 2011;129(13):252260. Meltzer HY, Bobo WV, Nuamah IF, et al. Efficacy and tolerability of oral paliperidone extended-release tablets in the treatment of acute schizophrenia: Pooled data from three 6-week, placebocontrolled studies. J Clin Psychiatry 2008;69(5):817829. Fanapt (iloperidone), prescribing information. Rockville, Md.: Vanda Pharmaceuticals, Inc.; August 2010. Kalkman HO, Feuerbach D, Ltscher E, Schoeffter P. Functional characterization of the novel antipsychotic iloperidone at human D2, D3, alpha 2C, 5-HT6, and 5-HT1A receptors. Life Sci 2003; 73(9):11511159. Potkin SG, Litman RE, Torres R, Wolfgang CD. Efficacy of iloperidone in the treatment of schizophrenia: Initial phase 3 studies. J Clin Psychopharmacol 2008;28(2 Suppl 1):S4S11. Cutler AJ, Kalali AH, Weiden PJ, et al. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol 2008;28(2 Suppl 1):S20S28. Kane JM, Lauriello J, Laska E, et al. Long-term efficacy and safety of iloperidone: Results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol 2008;28(2 Suppl 1):S29 S35. Weiden PJ, Cutler AJ, Polymeropoulos MH, Wolfgang CD. Safety profile of iloperidone: A pooled analysis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol 2008;28(2 Suppl 1):S12S19. Hill CL, Phadke D, Boyce KM. Four-week iloperidone depot injectable: Safety and pharmacokinetic profile in patients with schizophrenia and schizoaffective disorder. Poster NR4-022, 169170 (New Research Abstract), presented at the American Psychiatric Association annual meeting, Washington, D.C., May 38, 2008. Saphris (asenapine maleate) sublingual tablets, prescribing information. Kenilworth, N.J.; Organon; August 2009. Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: A placebo- and risperidonecontrolled trial. J Clin Psychiatry 2007;68(10):1492500. Data on file. Study 7501012. Kenilworth, N.J.: Schering-Plough. Data on file. Study A7501008. Kenilworth, N.J.: Schering-Plough. Data on file. Study A7501009. Kenilworth, N.J.: Schering-Plough. McIntyre RS, Cohen M, Zhao J, et al. A 3-week, randomized,

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placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord 2009; 11(7):673686. Latuda (lurasidone HCl) tablets, prescribing information. Marlborough, Mass.: Sunovion Pharmaceuticals: October 2010. Data on file. Lurasidone HCl, NDA 200603, Clinical Study Report D1050006. Fort Lee, N.J.: Sunovion Pharmaceuticals. Nakamura M, Ogasa M, Guarino J, etal. Lurasidone in the treatment of acute schizophrenia: A double-blind, placebo-controlled trial. J Clin Psychiatry 2009;70:829836. Data on file. Lurasidone HCl, NDA 200603, Clinical Study Report D1050229. Fort Lee, N.J.: Sunovion Pharmaceuticals. Data on file. Lurasidone HCl, NDA 200603, Clinical Study Report D1050231. Fort Lee, N.J.: Sunovion Pharmaceuticals. Data on file. Lurasidone HCl, NDA 200603, Clinical Study Report D1050049. Fort Lee, N.J.: Sunovion Pharmaceuticals. Bipolar Maintenance Study of Lurasidone Adjunctive to Lithium or Divalproex (PERSIST). Available at: http://clinicaltrials.gov/ ct2/show/NCT01358357. Accessed October 31, 2011. Data on file. Lurasidone HCl, NDA 200603, Integrated Summary of Safety. Fort Lee, N.J.: Sunovion Pharmaceuticals. Gahr M, Klle MA, Schnfeldt-Lecuona C, Lepping P, Freudenmann RW. Paliperidone extended-release: Does it have a place in antipsychotic therapy? Drug Des Devel Ther 2011;5:125146. I

Conflict-of-Interest Statement (COI Policy)

Disclosure: Jefferson Medical College endorses the Standards of the Accreditation Council for Continuing Medical Education and the Guidelines for Commercial Support. Every effort has been made to encourage individuals to disclose any commercial relationships or personal benefit with commercial companies whose products are discussed in the educational presentation. Disclosure of a relationship is not intended to suggest or condone bias in any presentations but is made to provide participants with information that might be of potential importance to their evaluation of a presentation. Drs. Casey and Scarff have no relationships to disclose.The article contains discussion of commercial products/services and investigative/off-label uses.

35. 36. 37. 38. 39. 40. 41. 42. 43.

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Continuing Education Credit for Physicians and Pharmacists

P&T 2011;36(12):832838 ACPE Program #0079-9999-11-014-H01-P Expiration Date: December 31, 2012 TOPIC: Newer Oral Atypical Antipsychotic Agents: A Review

CME Accreditation
This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Jefferson Medical College and MediMedia USA, Inc. Jefferson Medical College of Thomas Jefferson University is accredited by the ACCME to provide medical education for physicians. This CME activity is designed to assist physicians and other health care professionals who are P&T committee members in making formulary decisions. Its goal is to increase participants ability to recognize and treat important medical problems. Jefferson Medical College of Thomas Jefferson University designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit.TM Physicians should claim only the credit commensurate with the extent of their participation in the activity. This credit is available for the period of one year from the date of publication. Although forms will be processed when received, certificates for CME credits will be issued every six months, in February and August. Interim requests for certificates can be made by contacting the Jefferson Office of Continuing Medical Education at (215) 955-6992 or by going online to http://jeffline.jefferson.edu/jeffcme/JeffETC.

Continuing Pharmacy Education Credit

The Jefferson School of Population Health, Thomas Jefferson University, is approved by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education and complies with the Criteria for Quality for continuing pharmacy education programming. This program (0079-9999-11-014-H01-P) is acceptable for 1.0 hour of continuing education credit (0.1 CEUs) in states that recognize ACPE-approved providers. Statements of Credit indicating hours/CEUs will be mailed within six to eight weeks to participants who completed this activity and submitted a completed evaluation with payment.

How to Apply for CE Credit

Review learning objectives to determine whether the article is relevant to your individual learning needs. Read the article carefully, paying particular attention to the tables and other illustrative materials. Complete the CE Registration: Type or print your full name, address, and e-mail address in the space provided. In order for the form to be processed, all information must be complete and legible. Pharmacists: Please be sure to provide your NABP e-Profile ID# and date of birth (MM/DD) in order to receive credit. NABP e-Profile ID numbers can be obtained by going to www.MyCPEmonitor.net. This information must be provided to obtain credit. (CPE Monitor is a national collaborative effort by NABP and ACPE.) Physicians and others: Please be sure to provide the last four digits of your Social Security Number (or four other numbers you will remember). This number, combined with your last name, will be the tracking number for retrieving your CME certificate online. Complete the CE Evaluation Form by answering all questions. Payment of $15 per exam is required for processing and maintenance of records. Make checks payable to P&T. This processing fee is non-refundable. Send the completed form, answer sheet, and $15 payment to: Jefferson School of Population Health Attn: Continuing Education Credit 1015 Walnut Street, Suite 115 Philadelphia, PA 19107 Mail your completed CE Registration and Evaluation Form with your $15 payment within one year of the date of publication. After that date, this article will no longer be designated for CE Credit and forms cannot be processed.
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Continuing Education Questions for Physicians and Pharmacists

TOPIC: Newer Oral Atypical Antipsychotic Agents: A Review ACPE Program # 0079-9999-11-014-H01-P

CE Evaluation: Select the one best answer to each of the following questions, and record your response on the examination answer sheet. Complete the additional requested information. Forward the answer sheet, with appropriate payment, to The Jefferson School of Population Health, Thomas Jefferson University, at the address indicated. A certificate of completion will be mailed within six to eight weeks of receipt of your exam/payment. (A minimum test score of 70% is required.)

Multiple Choice
Select the one correct answer.
1. The main finding of the CATIE trial was that the

atypical class of antipsychotics was observed to be: a. as effective as chlorpromazine. b. as effective as haloperidol. c. less effective than haloperidol. d. less effective than perphenazine. 2. Paliperidone is the major active metabolite of: a. quetiapine. b. aripiprazole. c. olanzapine. d. risperidone. 3. All of the following are mechanisms of action of paliperidone except: a. antagonist at D2 receptors. b. antagonist of alpha1 and alpha 2 receptors. c. antagonist of 5-HT2A receptors. d. antagonist of H1 receptors. 4. According to the article, the most serious adverse effect of paliperidone is: a. worsening psychosis. b. akathisia. c. tardive dyskinesia. d. prolongation of the QT interval. 5. All of the following statements about the administration of iloperidone are true except: a. Patients should be instructed to not eat or drink for 10 minutes after taking iloperidone. b. Dosing should be titrated over 1 to 2 weeks to avoid hypotension. c. The starting dose of iloperidone is 1 mg twice daily. d. Iloperidone is not recommended for patients with hepatic impairment.

6. Which of the following atypical antipsychotics is available in a sublingual form, which may prevent cheeking in some patients? a. paliperidone b. iloperidone c. asenapine d. lurasidone 7. Which of the following does not interact with lurasidone via the CYP3A4 pathway? a. ketoconazole b. diltiazem c. rifampin d. midazolam 8. Common side effects seen among the atypical antipsychotics include the following except: a. tardive dyskinesia. b. somnolence. c. orthostatic hypotension. d. akathisia. 9. Which of the following antipsychotic medications must be taken with at least 350 calories because of bioavailability? a. paliperidone b. iloperidone c. asenapine d. lurasidone
10.Which of the following is an advantage that the

newer atypical antipsychotics may have over older atypicals? a. a decreased risk of extrapyramidal side effects b. a favorable metabolic profile c. less expense d. no need to titrate the dose e. both a. and b.

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CE Registration and Evaluation Form

Date of publication: December 2011 Title: Newer Oral Antipsychotic Agents: A Review Authors: Jonathan R. Scarff, MD; and David A. Casey, MD Submission deadline: December 31, 2012 ACPE Program # 0079-9999-11-014-H01-P

Pharmacy and Therapeutics

A Peer-Reviewed Journal for Managed Care and Hospital Formulary Management

Registration
Name: ____________________________________________________________ Degree: ____________________________________ Street address: ______________________________________________ Last 4 Digits of Social Security No. (Web ID): __________ City: ___________________________________ State: _________ Zip:__________ Telephone: _____________________________ E-mail address: _______________________________________ Check one: I Physician I Pharmacist I Other Time needed to complete this CE activity in hours: I 0.5 hr I 1 hr I 1.5 hr NABP ID # (required for pharmacists only): _________________ I 2 hr I Other _________________________ Date of birth (MM/DD): ______________________

Certification: I attest to having completed this CE activity. ___________________________________________________________ Signature (required) Date _______________

Answer Sheet
Please fill in the box next to the letter corresponding to the correct answer

1. 2. 3. 4. 5.

a a a a a

I I I I I

b b b b b

I I I I I

c c c c c

I I I I I

d d d d d

I I I I I

6. 7. 8. 9. 10.

a a a a a

I I I I I

b b b b b

I I I I I

c c c c c

I I I I I

d d d d d

I I I I I

e I

Evaluation
Rate the extent to which: 1. Objectives of this activity were met 2. You were satisfied with the overall quality of this activity 3. Content was relevant to your practice needs Very High I I High I I Moderate I I Low I I Very Low I I

I I I I I 4. Participation in this activity changed your I I I I I knowledge/attitudes I I I I I 5. You will make a change in your practice as a result I I I I I of participation in this activity. Specify the changes you plan to make. _________________________________________________________________________________________ 6. This activity presented scientifically rigorous, I I I I I unbiased, and balanced information 7. Individual presentations were free of commercial bias I I I I I 8. Adequate time was available for Q&A I I I I I 9. Which ONE of the following best describes the impact of this activity on your performance: I This program will not change my behavior because my current practice is consistent with what was taught. I This activity will not change my behavior because I do not agree with the information presented. I I need more information before I can change my practice behavior. I I will immediately implement the information into my practice. 10. Will you take any of the following actions as a result of participating in this educational activity (check all that apply) I Discuss new information with other professionals I Consult the literature I Discuss with industry representative(s) I Participate in another educational activity I Other _____________________________________________ I None
Send the completed form and $15 payment (make checks payable to P&T) to: The Jefferson School of Population Health, Attn: Continuing Education Credit, 1015 Walnut Street, Suite 115, Philadelphia, PA 19107.
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