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Treatment with antipsychotics increases life expectancy for patients with schizophrenia.
On to 2010!
Dr. Alan Gelenberg reviews biological interventions approved during the past year, including new antipsychotics and a device to deliver repeated transcranial magnetic stimulation (rTMS).
Iloperidone, an antipsychotic recently approved by the U.S. Food and Drug Administration (FDA), is comparable in efficacy to other second-generation agents.
A new second-generation antipsychotic was recently approved by the U.S. Food and Drug Administration (FDA): the piperidinyl-benzisoxazole derivative iloperidone (Fanapt). Originally, iloperidone was not approved, but after reviewing additional information from the manufacturer, the FDA reversed its decision. Several short- and long-term clinical trials have compared iloperidone with other antipsychotics.
Potkin and coauthors reviewed efficacy results from three 6-week, randomized, double-blind, placebo- and active comparator-controlled studies of iloperidone in patients with schizophrenia or schizoaffective disorder.1 Almost 2000 patients were randomly assigned to iloperidone, 4 to 24 mg daily; haloperidol (Haldol and others), 15 mg daily; or risperidone (Risperdal and others), 4 to 8 mg daily. At least one iloperidone group in each study demonstrated statistical superiority to placebo. Extrapyramidal effects were comparatively infrequent.
Cutler and others report on a randomized, multicenter, 4-week, double-blind trial of iloperidone, 24 mg/day; ziprasidone (Geodon), 160 mg/day; or placebo in almost 600 patients.2 Both active drugs were superior to placebo, but both prolonged the QTc interval to comparable degrees. Iloperidone caused less akathisia than ziprasidone but a small increase in blood glucose and cholesterol and more weight gain than ziprasidone.
Kane and associates pooled data from three prospective multicenter long-term studies of iloperidone.3 Each began with a 6-week stabilization phase, followed by 46 weeks of double-blind maintenance treatment. Patients were assigned at random to iloperidone, 4 to 16 mg/day, or haloperidol, 5 to 20 mg/day. More than 1600 patients showed at least a 20% clinical improvement during the 6 weeks of stabilization and entered maintenance. Time to relapse, the primary efficacy analysis, was comparable between iloperidone and haloperidol. Without a placebo comparison, these studies cannot establish efficacy in relapse prevention—only the lack of difference between the two antipsychotics.
In these long-term trials, iloperidone increased body weight more than haloperidol and prolonged the QTc interval to a slightly greater degree. Iloperidone also produced slight increases in total cholesterol, triglyceride, and glucose levels. Haloperidol caused significantly more extrapyramidal reactions than iloperidone.
Like many other second-generation agents, iloperidone has a greater affinity for 5-HT2A receptors than for D2 receptors, but it is a mixed antagonist for both. It also has low to moderate affinity for other dopaminergic, serotonergic, and histaminergic receptors. Its clinical profile reflects iloperidone's relative lack of antagonism at muscarinic and histaminic receptors. The moderately high affinity of iloperidone and one of its active metabolites for the α1-norepinephrine receptor frequently causes postural hypotension.
The most common adverse reactions associated with iloperidone in 4- and 6-week trials were dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight gain. Twelve to eighteen percent of iloperidone-treated patients gained at least 7% of their initial body weight. Dizziness, orthostatic hypotension, and tachycardia, which might reflect α1-norepinephrine antagonism, are more likely at higher doses and may be attenuated by a gradual dose titration schedule, which is recommended. Like other antipsychotics, iloperidone's labeling will contain a boxed warning about an increased risk of death if it is used to treat dementia-related symptoms in elderly patients.
Iloperidone is less likely to cause extrapyramidal symptoms, akathisia, and hyperprolactinemia than first-generation antipsychotics, risperidone, or ziprasidone. Iloperidone is more likely to cause weight gain and orthostatic hypotension than ziprasidone, while the effects of ziprasidone and iloperidone on triglycerides, cholesterol, and the QTc interval are similar.
Iloperidone is metabolized primarily by two cytochrome P450 isoenzymes—CYP3A4 and CYP2D6. One of its metabolites has brain activity; the other may cause side effects. Its half life is roughly 18 hours but in 2D6 poor metabolizers, it can be greater than 24 hours. Iloperidone plasma levels can be increased by drugs that inhibit 2D6 activity, such as fluoxetine (Prozac and others) and paroxetine (Paxil and others), as well as by those that inhibit 3A4, such as ketoconazole and grapefruit juice. Smoking, which induces 1A2, does not affect iloperidone plasma concentrations.
Iloperidone's target dose range is 6 to 12 mg bid. Limited evidence suggests that higher doses might bring enhanced efficacy. Because postural hypotension can be an early problem, iloperidone should be titrated up to the target dose over 4 to 7 days, beginning with 1 mg bid. However, this gradual dosing schedule may delay the onset of therapeutic benefit. When patients are concomitantly taking drugs that inhibit CYP2D6 or CYP3A4, the target dose should be reduced by about half. Iloperidone may be taken with or without food. Bioavailability from tablets is 96%, with peak plasma concentrations achieved 2 to 4 hours after an oral dose. Iloperidone is available as 1-, 2-, 4-, 6-, 8-, 10-, and 12-mg tablets.
Recent reports have questioned the benefits of second-generation antipsychotics compared with those of the first generation (BTP 2009;32:21-22). The relative safety of second-generation drugs is less obvious than we originally believed, although they do have a much lower incidence of tardive dyskinesia and tardive dystonia. Some second-generation antipsychotics cause weight gain and other adverse metabolic effects. Exactly where iloperidone fits in that spectrum will require additional comparative study, but it clearly contributes to this problem. It has a modest potential to delay cardiac conduction but so far has not been associated with serious arrhythmias. Iloperidone should be avoided if possible in patients with significant cardiac abnormalities or electrolyte disturbances or who are taking other drugs that also can prolong the QTc interval—such as thioridazine (Mellaril and others), droperidol (Inapsine), pimozide (Orap), or methadone (BTP 2007;30:29-30).4
In concept, there may be patients who have failed to respond to or cannot tolerate other antipsychotics and will benefit from this new one. It has some pharmacologic differences from other agents and a somewhat different side effect profile. Iloperidone's efficacy appears roughly comparable to older medicines. But like all new drugs, it is expensive. Among other second-generation agents, risperidone and clozapine (Clozaril and others) are available in less expensive generic formulations, and of course, the whole first generation remains available. In low doses, first-generation agents may be reasonably well tolerated by many patients with schizophrenia and related disorders, albeit with a risk of permanent movement disorders.
Available treatments for schizophrenia leave much to be desired. In close consultation with patients and family members, clinicians must weigh the broad array of treatment options, the risks of short- and long-term adverse effects of medicine, and practical considerations such as cost in making treatment decisions case by case.
1Potkin SG, Litman RE, Torres R, Wolfgang CD: Efficacy of iloperidone in the treatment of schizophrenia: Initial phase 3 studies. J Clin Psychopharmacol 2008:28(Suppl 1):S4-S11.
2Cutler AJ, Kalali AH, Weiden PJ, Hamilton J, Wolfgang CD: Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol 2008;28(Suppl 1):S20-S28.
3Kane JM, Lauriello J, Laska E, Di Marino M, Wolfgang CD: Long-term efficacy and safety of iloperidone: Results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol 2008;28(Suppl 1):S29-S35.
4Weiden PJ, Bishop JR: Iloperidone for schizophrenia. Curr Psychiatry 2009;8:46-57.