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January 2010

Lithium, Thyroid Function, and Depressive Relapse
Patients with bipolar disorder treated with lithium may develop depressive episodes due to changes in thyroid function.

Fighting Fire with Fire: Injectable Heroin for Heroin Addicts?
Diacetylmorphine merits consideration as a treatment of last resort for heroin addicts who don’t respond to methadone therapy.

Asenapine to Treat Schizophrenia and Bipolar Disorder
The new antipsychotic asenapine (Saphris) appears comparable to other second-generation agents but requires sublingual administration.

Clozapine Plus Other Antipsychotics
A paper by Taylor and Smith suggests that adding another antipsychotic to clozapine (Clozaril and others) for treatment-resistant patients has minimal therapeutic benefit.

Isotretinoin (Accutane) May Exacerbate Symptoms in Patients with Bipolar Disorder
Isotretinoin (Accutane) may destabilize mood in patients with bipolar disorder.

Stimulants Associated with Sudden Death in Young Patients
Stimulants such as methylphenidate may increase the risk of sudden unexplained death in young patients.

In Brief
Depression Risk Lower with 'Whole Foods' Diet; Anxiety during Menopause Not Improved by Black Cohosh

Asenapine to Treat Schizophrenia and Bipolar Disorder

January 2010

This past August, the U.S. Food and Drug Administration approved a new antipsychotic, asenapine (Saphris*), for the acute treatment of schizophrenia and the treatment of manic or mixed episodes in bipolar I disorder in adults.

Asenapine resembles other second-generation antipsychotics in being an antagonist at serotonin 5-HT2 and dopamine D2 receptors.1 It is also an antagonist at some norepinephrine and histamine receptor subtypes and a partial agonist at the 5-HT1A receptor. It lacks affinity for muscarinic and ß-adrenergic receptors.

Asenapine is administered sublingually. Its terminal elimination half-life is roughly 24 hours.1 Concomitant administration of the cytochrome P450 (CYP) 1A2 inhibitor fluvoxamine (Luvox and others) increased the area under asenapine's concentration-time curve by 29%. Giving asenapine together with paroxetine (Paxil and others) increased the levels of paroxetine by almost twofold. Mild to moderate hepatic impairment did not substantially affect asenapine levels, but severe hepatic impairment increased asenapine concentrations sevenfold.1 Therefore, asenapine doses should be substantially reduced in patients with severe hepatic impairment. Renal impairment does not require asenapine dosage adjustment.

For patients with schizophrenia, asenapine, 5 mg bid, showed greater efficacy than placebo in two 6-week, random-assignment, double-blind trials.2,3 (A third, similar trial failed to show efficacy.) A 10-mg bid dose was also significantly superior to placebo in one of these trials.3 In a 26-week study of 481 patients with prominent negative schizophrenia symptoms, Cazorla et al found asenapine, 5 to 10 mg bid, comparable in efficacy to olanzapine, 5 to 20 mg/day.4

In two trials of 976 adults with bipolar I disorder, flexible doses of asenapine between 5 and 10 mg bid for 3 weeks were statistically superior to placebo in treating acute manic or mixed episodes.5,6 As an active comparator, olanzapine also separated from placebo. Of patients who participated in these two bipolar trials, 504 who were clinically stable were maintained under blind conditions on their initial active drug treatment. Maintenance of benefit was comparable between olanzapine and asenapine.7 In another 12-week trial, asenapine proved superior to placebo as an adjunct to lithium or valproate (Depakote and others) in patients in an acute manic or mixed episode.

The following tables show adverse events occurring with asenapine versus comparison treatments.

Table 1

Table 2

There was a small positive relationship between the QTc interval and plasma concentrations of asenapine. No patient in trials of asenapine had a QTc interval exceeding 500 msec.

Like other antipsychotics, asenapine carries a boxed warning against its use in elderly patients with dementia-related psychosis, because it may increase the risk of death, cerebrovascular accidents, and transient ischemic attacks. The most frequent adverse effects associated with asenapine in clinical trials of patients with schizophrenia were restlessness, decreased oral sensitivity, and drowsiness. Patients with bipolar disorder reported drowsiness, dizziness, movement disorders, and weight gain. Asenapine has been linked with cases of tardive dyskinesia, and it should be discontinued if a patient experiences symptoms of the neuroleptic malignant syndrome. Other serious conditions to watch for are hyperglycemia, diabetes mellitus, and orthostatic hypotension. Presumably, α1-noradrenergic and histamine-H1 receptor blockade mediates sedation and hypotension with asenapine.

Asenapine will be available in 5- and 10-mg tablets. Each tablet should remain in its blister pack until needed and then removed with dry hands. It is to be administered sublingually to optimize its bioavailability upon absorption, as it is extensively metabolized in the liver. Its bioavailability is 35% when taken sublingually but falls to less than 2% if swallowed. Patients should be advised to place the tablet under their tongue, allow it to dissolve completely, and not to eat or drink for 10 minutes. The tablets should not be crushed, chewed, or swallowed whole. The labeled dosing for treatment of acute schizophrenia is 5 mg bid. For bipolar I disorder, the starting dose is 10 mg bid, with the option of decreasing to 5 mg bid, if adverse effects dictate.

There may be patients who will respond uniquely well to asenapine. How it will compare in efficacy with the increasing list of available antipsychotics will require additional research, which will undoubtedly take a number of years. As we said in our earlier piece on iloperidone (BTP 2009;32:47-48), the goal is to individualize the sequence for each patient, taking into consideration tolerability and cost. Asenapine is the only antipsychotic that requires sublingual administration. The practical challenge will be to find patients with schizophrenia or bipolar disorder who will cooperate with the proper sublingual use of this new compound.

*The proposed trade name in the European Union is Sycrest.

1Weber J, McCormack PL: Asenapine. CNS Drugs 2009;23:781-792.

2Potkin SG, Cohen M, Panagides J: Efficacy and tolerability of asenapine in acute schizophrenia: A placebo- and risperidone-controlled trial. J Clin Psychiatry 2007;68:1492-1500.

3Kane JM, Zhao J, Cohen M, et al. Efficacy and safety of asenapine in patients with acute schizophrenia [abstract no. NR4-051]. 161st annual meeting of the American Psychiatric Association, Washington, D.C., May 3-8, 2008.

4Cazorla P, Panagides J, Alphs L, et al. Asenapine versus olanzapine in patients with predominant, persistent negative symptoms of schizophrenia [abstract no. NR4-082]. 161st annual meeting of the American Psychiatric Association, Washington, D.C., May 3-8, 2008.

5Panagides J, McIntyre RS, Alphs L, et al. Asenapine in acute mania: A randomized, double-blind, placebo- and olanzapine-controlled trial (ARES 7501004) [abstract no. 720]. Biol Psychiatry 2007;61(Suppl 8):222S-223S.

6Hirschfeld RMA, Panagides J, Alphs L, et al. Asenapine in acute mania: A randomized, double-blind, placebo- and olanzapine-controlled trial (ARES 7501005) [abstract no. NR333]. 160th annual meeting of the American Psychiatric Association, San Diego, CA, May 19-24, 2007.

7Citrome L: Asenapine for schizophrenia and bipolar disorder: A review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic. Int J Clin Pract 2009;63:1762-1784.