Iloperidone, asenapine, and lurasidone: a brief overview of 3 new second-generation antipsychotics.
ABSTRACT Three new second-generation antipsychotics were approved by the US Food and Drug Administration in 2009 and 2010: iloperidone, asenapine, and lurasidone. All 3 agents are approved for the treatment of acute schizophrenia in adults, and asenapine is also approved for the maintenance treatment of schizophrenia and as a monotherapy or as an adjunct to lithium or valproate for the treatment of bipolar manic or mixed episodes. The expectation is that these new agents will be less problematic regarding treatment-emergent weight gain and metabolic disturbances, which unfortunately can occur with several other second-generation antipsychotics. Asenapine is a sublingual preparation, in contrast to iloperidone and lurasidone, which are swallowed. Iloperidone and asenapine are dosed twice daily, in contrast to lurasidone, which is dosed once daily with food. Both asenapine and lurasidone can be initiated at a dose that is possibly therapeutic, but iloperidone requires 4 days of titration to reach its recommended target dose range. Although both asenapine and lurasidone can be associated with dose-related treatment-emergent akathisia, iloperidone is essentially free of extrapyramidal adverse effects or akathisia throughout its recommended dose range. Sedation and/or somnolence have been reported with each medication. They are the most common adverse events associated with asenapine treatment, and are clearly dose-related for lurasidone. In contrast, no therapeutic dose response for iloperidone, asenapine, or lurasidone is clearly evident from short-term clinical trials. Longer-term and naturalistic studies will be helpful in evaluating these agents and their role in the psychiatric armamentarium.
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ABSTRACT: INTRODUCTION: Pharmacokinetic and pharmacodynamic drug interactions (DIs) can occur between antiepileptics (AEDs) and second-generation antipsychotics (SGAPs). Some AED and SGAP pharmacodynamic mechanisms are poorly understood. AED-SGAP combinations are used for treating comorbid illnesses or increasing efficacy, particularly in bipolar disorder. AREAS COVERED: This article provides a comprehensive review of the interactions between antiepileptics and second-generation antipsychotics. The authors cover pharmacokinetic AED-SGAP DI studies, the newest drug pharmacokinetics in addition to the limited pharmacodynamic DI studies. EXPERT OPINION: Dosing correction factors and measuring SGAP levels can help to compensate for the inductive properties of carbamazepine, phenytoin, phenobarbital and primidone. Further studies are needed to establish the clinical relevance of combining: i) AED strong inducers with amisulpride, asenapine, iloperidone, lurasidone and paliperidone; ii) valproate with aripiprazole, asenapine, clozapine and olanzapine; iii) high doses of oxcarbazepine (≥ 1500 mg/day) or topiramate (≥ 400 mg/day) with aripiprazole, lurasidone, quetiapine, risperidone, asenapine and olanzapine. Two pharmacodynamic DIs are beneficial: i) valproate-SGAP combinations may have additive effects in bipolar disorder, ii) combining topiramate or zonisamide with SGAPs may decrease weight gain. Three pharmacodynamic DIs contributing to decreased safety are common: sedation, weight gain and swallowing disturbances. A few AED-SGAP combinations may increase risk for osteoporosis or nausea. Three potentially lethal but rare pharmacodynamic DIs include pancreatitis, agranulocytosis/leukopenia and heat stroke. The authors believe that collaboration is needed from drug agencies and pharmaceutical companies, the clinicians using these combinations, researchers with expertise in meta-analyses, grant agencies, pharmacoepidemiologists and DI pharmacologists for future progression in this field.Expert Opinion on Drug Metabolism & Toxicology 03/2012; 8(3):311-34. · 2.94 Impact Factor
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ABSTRACT: To describe the efficacy, safety and tolerability of lurasidone for the acute treatment of schizophrenia using the metrics number needed to treat (NNT) and number needed to harm (NNH). Study data were pooled from six Phase II and III, 6-week, randomized, placebo-controlled trials that were conducted to test the efficacy and safety of lurasidone for the acute treatment of schizophrenia. Included were the following interventions: fixed doses of lurasidone 20, 40, 80, 120 and 160 mg/d; haloperidol 10 mg/d; olanzapine 15 mg/d; quetiapine extended-release 600 mg/d; placebo. The following outcomes were assessed: responder rates as defined by a reduction of ≥20, 30, 40 or 50% from baseline on the Positive and Negative Syndrome Scale (PANSS) total score; study completion; discontinuation due to an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; incidence of total cholesterol ≥240 mg/dL, low-density lipoprotein cholesterol ≥160 mg/dL, fasting triglycerides ≥200 mg/dL and glucose ≥126 mg/dL at endpoint. NNT for the efficacy outcomes were calculated after excluding one failed study. NNH for the safety/tolerability outcomes were calculated using all six studies. Likelihood of being helped or harmed (LHH) was also calculated to illustrate trade-offs between outcomes of improvement ≥30% on the PANSS vs. incidence of akathisia, nausea, sedation, somnolence and parkinsonism. NNT vs. placebo for PANSS reductions ≥30% were 6, 6, 7 and 4 for lurasidone doses of 40, 80, 120 and 160 mg/d, respectively, and 4 and 3 for olanzapine 15 mg/d and quetiapine extended-release 600 mg/d, respectively. Lurasidone was not associated with any statistically significant disadvantages over placebo for weight gain or metabolic abnormalities; NNH vs. placebo for weight gain ≥7% from baseline was 4 for olanzapine and 9 for quetiapine extended-release in contrast to a NNH for this outcome ranging from 43 to 150 for lurasidone 40-160 mg/d. The 5 most consistently encountered adverse events attributable to lurasidone were akathisia, nausea, sedation, somnolence and parkinsonism, with NNH vs. placebo for lurasidone 40-120 mg/d ranging from 6 (akathisia with 120 mg/d) to 30 (parkinsonism with 80 mg/d). Lurasidone 160 mg/d appeared better tolerated than doses of 40, 80 or 120 mg/d for akathisia, nausea, sedation or somnolence, with no NNH values for these adverse events for 160 mg/d vs. placebo being statistically significant. LHH was favorable for lurasidone when contrasting PANSS reductions vs. adverse events. NNT and NNH can help quantify efficacy, safety and tolerability outcomes and place lurasidone into clinical perspective. Advantages for lurasidone include a low propensity for weight gain and metabolic abnormalities. More commonly encountered adverse events include akathisia, nausea, sedation, somnolence and parkinsonism, but NNH values are generally in the double digits, reflecting an overall tolerable profile. Individual patient characteristics, values and preferences will need to be considered when selecting lurasidone over other antipsychotics.Clinical Schizophrenia & Related Psychoses 07/2012; 6(2):76-85.
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ABSTRACT: Major depression is a common psychiatric disorder associated with high symptomatic and functional burdens. Pharmacological treatment is often effective, but there remain substantial unmet needs in the form of non-responders, delayed onset of clinical effect, and side effects. Recent studies have positioned the serotonin 5-HT7 receptor as a new target for the treatment of depression. Preclinical studies have shown that antagonists induce an antidepressant-like response, a phenotype that can also be observed in mice lacking the receptor. Lurasidone is a new atypical antipsychotic agent with very high affinity for the 5-HT7 receptor. Patients in clinical trials have reported improved scores in depression ratings. We have tested lurasidone in both acute and chronic mouse models of depression. In the tail suspension and forced swim tests lurasidone decreased immobility, an antidepressant-like response. The effect required functional 5-HT7 receptors as it was absent in mice lacking the receptor. In the repeated open-space swim test lurasidone was able to reverse the despair induced by repeated swims in a manner similar to the commonly used antidepressant citalopram. The results provide evidence that lurasidone can act as a 5-HT7 receptor antagonist and provide a possible explanation for the antidepressant effect data currently emerging from lurasidone clinical trials. Additionally, the results give further support for targeting the 5-HT7 receptor in the treatment of depression. It will be of interest to clinically evaluate lurasidone as an antidepressant either as monotherapy or as an adjunctive therapy to available drugs.Neuropharmacology 02/2013; 70C:211-217. · 4.11 Impact Factor