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How Effective Are the Newest Antipsychotics? [Free Article]

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Four new antipsychotics are beginning to gain some traction in the adult market. To be absolutely clear, among these only paliperidone (Invega) has been approved for use in children and adolescents (those age 12 and older). None of the other medications have been tested in this age group. But for those of us who see transitional age youth to whom we prescribe antipsychotics, here is a quick low down on paliperidone, iloperidone (Fanapt), lurasidone (Latuda), and asenapine (Saphris).

Paliperidone (Invega) is the oldest of the set, and is the active metabolite of risperidone (Risperdal). It has been touted as having fewer side effects than risperidone, but it seems to have outlived its honeymoon period: the literature abounds with case reports of the usual trouble-makers (weight gain, sedation, hyperprolactinemia) and serious side effects (dystonia, tardive dyskinesia, neuroleptic malignant syndrome). Thus, it appears to have much the same effect—both for better and for worse—as risperidone. The good news is that any patient who has been on risperidone in the past has already been exposed to paliperidone, so it’s reasonably safe (as safe as risperidone), though much more expensive than its mother compound

Table 1: Invega At-a-Glance

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Iloperidone (Fanapt) is FDA-approved for the treatment of schizophrenia in adults. There are four studies available on this drug: three short-term studies demonstrating comparable effect to haloperidol (Haldol) in treating acute psychosis in adults with schizophrenia, and one continuation study lasting 46 weeks (after a six week acute study) measuring side effects and time to relapse. The news is disappointing for relapse: while it was found “non-inferior” to haloperidol, median time to relapse was 50 days on iloperidone and 78 days on haloperidol; not statistically different. Further, iloperidone causes significant weight gain—in this study, 10.6 lbs as compared to haloperidol’s average 6.6 lbs. A disconcerting fact is that six people in the iloperidone group died—though only one of these deaths was attributed to the medication (Kane JM et al, J Clin Psychopharmacol 2008;28(2):S29–S35). Cognitive measures were not studied, but some hypothesize that it will improve cognition via serotonergic action, particularly at 5-HT7 receptors (Kane JM ibid).
Table 2: Fanapt At-a-Glance

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Lurasidone (Latuda) is FDA-approved to treat schizophrenia in adults. It works at 80 mg daily, and perhaps at 40 mg daily, with no increased benefit at doses higher than 80 mg daily. Time to onset of effect is three to seven days. The encouraging news is that it does not seem to make people fat or increase lipids or glucose, nor does it increase prolactin or cause QTC prolongation (L Citrome, Int J Clin Pract 2011;65(2):189–210). Studies of rats suggest it could cause cognitive enhancement, but the one study looking at cognitive measures in humans after treatment with lurasidone failed to clearly differentiate from ziprasidone (Geodon), and from the practice effect (Harvey PD, Schiz Res 2011;127:188–194). The study may not have been sufficiently powered, however. The down side of lurasidone is that it caused akathisia in 22% of study patients, with a number needed to harm of six.
Table 3: Latuda At-a-Glance

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Asenapine (Saphris) is FDA-approved for both schizophrenia and bipolar disorder in adults, at 5 mg twice a day and 10 mg twice daily respectively. It has the disadvantage of requiring sublingual administration, since its bioavailability is less than 2% if swallowed. Patients say the pill leaves a bad taste under the tongue, but there is now a black currant flavor that is a little better. Suggest to your patients that they chew a strong-flavored mint or gum before taking it, or suck on an ice cube. Patients must avoid any food or drink for 10 minutes after taking a dose. Furthermore, any meal eaten up to four hours after ingestion reduces the bioavailability by approximately 20%.

Asenapine causes some drug interaction mischief. It is metabolized by CYP 1A2, and so is subject to CYP1A2 inhibitors like fluvoxamine (Luvox). In addition, it inhibits CYP2D6, and can thus increase the serum levels of drugs metabolized by that system, such as paroxetine (Paxil).

Like lurasidone, asenapine seems to cause fewer metabolic problems than other atypicals. On the downside, it frequently causes sedation and akathisia (but less EPS than haloperidol), and infrequent elevations in prolactin. It also causes oral numbing in 4% of patients. Weight gain is primarily a problem in relatively skinny patients (BMI less than 23). Mild QTC prolongation occurs, but a more frequent cardiac side effect is reflex bradycardia (slow heart rate) with sinus pause. Although benign and self-limiting, this could easily frighten a patient. Efficacy studies were sufficient for FDA approval, but overall are unimpressive, with no increased efficacy over comparator drugs, and some studies failed to find a difference from placebo (Citrome L, Int J Clin Pract 2009;63(12):1762–1784).

Table 4: Saphris At-a-Glance

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TCPR Verdict: 

None of these newer agents have been adequately tested in children, and should be avoided in the pediatric age group. When you must use antipsychotics, we suggest sticking to the tried and true, such as aripiprazole (Abilify), which has a low side effect profile, and risperidone (Risperdal), which works especially well for aggression.