Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania.
The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support.
Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213; e-mail: HowlandRH@upmc.edu.
Many types of antipsychotic drugs are currently available (“Drugs for Psychotic Disorders,” 2010). Although originally developed for the treatment of schizophrenia, many of them—especially the so-called atypical or second-generation antipsychotic (SGA) drugs—also are commonly used for treating bipolar disorder. Some are used for treatment-resistant depression. Regardless of the indication, many patients do not have a satisfactory response to available drugs because of limited efficacy, tolerability, or both. As a result, new drug therapies for schizophrenia, bipolar disorder, and other severe chronic mental disorders are always needed. Even though a new antipsychotic drug may not necessarily be more effective on average compared with other available drugs, it might be relatively more efficacious or better tolerated for certain patients. Since my review of the SGA drug paliperidone (Invega®) in 2007 (Howland, 2007), three other SGA drugs have been approved by the U.S. Food and Drug Administration (FDA). In this article, I will briefly review these three antipsychotic drugs.
Iloperidone (Fanapt®), structurally related to risperidone (Risperdal®) and paliperidone, was first approved by the FDA for the treatment of schizophrenia in 2009 (Albers, Musenga, & Raggi, 2008). It has not been studied in bipolar disorder or other psychiatric disorders. Similar to other SGA drugs, iloperidone blocks dopamine D-2 receptors and serotonin 5HT-2A receptors. It does not have significant anticholinergic effects but can block histamine receptors and alpha-adrenergic receptors. Sedation and weight gain can be related to the antihistamine effects. Alpha-receptor blockade can result in dizziness, orthostatic hypotension, and reflex tachycardia. Common adverse effects of iloperidone include dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight gain. A potential rare adverse effect is cardiac electrocardiogram changes (i.e., prolongation of the QTC interval), especially at high doses. Similar to risperidone and paliperidone, higher doses of iloperidone are somewhat more likely to cause extrapyramidal (parkinsonian) effects and hyperprolactinemia compared with other SGA drugs.
The recommended dose range for iloperidone is 12 to 24 mg per day. To avoid orthostatic hypotension, the drug should be given in two divided doses and started at a very low dosage (e.g., 2 to 4 mg per day) with daily dose increases. Iloperidone is metabolized primarily by the cytochrome P450-2D6 (CYP2D6) and CY-P3A4 enzymes in the liver. Hence, there is the potential for drug-drug interactions involving drugs that are inhibitors or inducers for these particular hepatic enzymes. Lower doses and careful clinical monitoring is especially prudent when patients are taking iloperidone together with other medications that inhibit these two enzymes. Iloperidone has metabolites, but their pharmacological activity has not been clearly characterized. The effect of impaired liver or renal function on the metabolism or clearance of iloperidone has been investigated in only one single-dose, low-dose study (Albers et al., 2008). Although the drug was well tolerated in this study, it should be used cautiously in patients with liver or kidney disease. According to the product label, iloperidone should not be used in patients with impaired liver function.
Asenapine (Saphris®) is a dibenzo-oxepino pyrrole drug that was developed by modifying the structure of mianserin (Tolvon®, Depnon®, Bolvidon®), a tetracyclic antidepressant drug that acts primarily at presynaptic alpha-2-adrenergic receptors (Leonard, 1978; Nickolson, Wieringa, & van Delft, 1982). Interestingly, the antidepressant drug mirtazapine (Remeron®) is also a derivative of mianserin. Asenapine was first approved in 2009 by the FDA for schizophrenia and for manic or mixed episodes in bipolar disorder (Citrome, 2009). Similar to other SGA drugs, asenapine blocks D-2 and 5HT-2A receptors. However, it also has a high affinity for other dopamine and serotonin receptors, histamine receptors, and alpha-adrenergic receptors, but it does not have significant anticholinergic effects. Sedation and weight gain can be related to the antihistamine effects. Alpha-receptor blockade can result in dizziness, orthostatic hypotension, and reflex tachycardia. Common adverse effects include somnolence, dizziness, decreased oral sensation, akathisia, parkinsonian symptoms, and weight gain. A potential rare adverse effect is prolongation of the QTC interval. Similar to risperidone, paliperidone, and iloperidone, asenapine is also more likely to cause hyperprolactinemia compared with other SGA drugs.
The dose range for asenapine is 10 to 20 mg per day. Based on the drug’s clinical trials, the recommended target dosage is 10 mg per day for schizophrenia (although 20 mg per day can be tried if needed) and 20 mg per day for bipolar disorder. To avoid orthostatic hypotension, the drug should be given in two divided doses. Asenapine is metabolized primarily by the CYP1A2 enzyme, and it is a weak inhibitor of CYP2D6. As a result, there is the potential for drug-drug interactions involving drugs that inhibit or induce the activity of these particular liver enzymes. Because asenapine has very low bioavailability when swallowed, it is available only as a sublingual tablet formulation. To maximize absorption, it should not be taken with food. Asenapine has inactive metabolites. The effect of impaired liver or renal function on the metabolism or clearance of asenapine has been investigated in single-dose, low-dose studies (Citrome, 2009). It should be used cautiously in patients with liver or kidney disease, and it should not be used in patients with severely impaired liver function.
Lurasidone (Latuda®) is a benzoisothiazol derivative drug that is also structurally related to azapirone derivatives. Buspirone (Buspar®), an azapirone drug indicated for the treatment of generalized anxiety disorder, is a partial agonist at postsynaptic serotonin 5HT-1A receptors. Lurasidone was first approved in 2010 by the FDA for schizophrenia (Citrome, 2011). It has not been studied in bipolar disorder or in other psychiatric disorders. Similar to other SGA drugs, lurasidone blocks D-2 and 5HT-2A receptors. It also has high affinity for serotonin 5HT-7 receptors and moderate affinity for alpha-2-adrenergic receptors (but not alpha-1-adrenergic receptors). It does not have significant antihistamine or anticholinergic effects. Similar to buspirone and vilazodone (Viibryd™) (Howland, 2011), lurasidone is a partial agonist at 5HT-1A receptors. Common adverse effects include akathisia, parkinsonian symptoms, nausea, agitation, and somnolence. Because it does not have alpha-2-receptor effects, dizziness, orthostatic hypotension, and syncope are rare.
The recommended dose range for lurasidone is 40 to 80 mg per day, given once per day. Doses up to 120 mg per day were used in some of the clinical trials, without additional benefit and with more side effects compared with the lower doses. Lurasidone is metabolized primarily by the CYP3A4 hepatic enzyme; hence, drug-drug interactions may occur with drugs that are strong inhibitors or inducers for this enzyme. Lurasidone has active and inactive metabolites but their clinical significance is not known. Lower doses (i.e., 40 mg per day) should be used in patients with impaired liver or renal function.
Iloperidone, asenapine, and lurasidone are all novel SGA drugs. Based on the clinical trials, there is no evidence that any one of these drugs is superior to the others or to other available antipsychotic drugs with respect to efficacy. The side effect profiles of these drugs are somewhat different, but there is no evidence to suggest that any or all of them are necessarily safer or better tolerated than other antipsychotic drugs. Although an increased risk for hyperglycemia or diabetes is not well established with these drugs, clinical monitoring is recommended, and they each carry the same FDA-mandated warning regarding metabolic issues that applies to all antipsychotic drugs. There is a small elevated risk of death associated with the use of antipsychotic agents in elderly patients with dementia-related psychosis on the basis of placebo-controlled studies with several other agents, and this FDA-mandated warning also applies to these three drugs. Monitoring for tardive dyskinesia and neuroleptic malignant syndrome is recommended. There is very little information about the tolerability or safety of these three drugs in pediatric or geriatric patients and during pregnancy or breastfeeding. Because of their unique pharmacologies and different tolerability profiles, they may be an appropriate alternative for patients who do not respond to or cannot tolerate other available antipsychotic drugs. Nurses should therefore be familiar with the pharmacology and clinical profile of these newer drugs.
- Albers, L.J., Musenga, A. & Raggi, M.A. (2008). Iloperidone: A new benzisoxazole atypical antipsychotic drug. Is it novel enough to impact the crowded atypical antipsychotic market?Expert Opinion on Investigational Drugs, 17, 61–75. doi:10.1517/135437220.127.116.11 [CrossRef]
- Citrome, L. (2009). Asenapine for schizophrenia and bipolar disorder: A review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic. International Journal of Clinical Practice, 63, 1762–1784. doi:10.1111/j.1742-1241.2009.02228.x [CrossRef]
- Citrome, L. (2011). Lurasidone for schizophrenia: A review of the efficacy and safety profile for this newly approved second-generation antipsychotic. International Journal of Clinical Practice, 65, 189–210. doi:10.1111/j.1742-1241.2010.02587.x [CrossRef]
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- Howland, R.H. (2011). Vilazodone: Another novel atypical antidepressant drug. Journal of Psychosocial Nursing and Mental Health Services, 49(3), 19–22.
- Leonard, B.E. (1978). Mianserin, an antidepressant with a unique neuropharmacological profile. Acta Psychiatrica Belgica, 78, 770–780.
- Nickolson, V.J., Wieringa, J.H. & van Delft, A.M. (1982). Comparative pharmacology of mianserin, its main metabolites and 6-azamianserin. Naunyn-Schmiedeberg’s Archives of Pharmacology, 319, 48–55. doi:10.1007/BF00491478 [CrossRef]