What is the use and management of asenapine (Saphris) in psychiatric treatment?

Asenapine Overview

Asenapine (Saphris) is an atypical antipsychotic FDA-approved exclusively for adjunctive treatment of bipolar I disorder in adults when combined with lithium or valproate, and is NOT approved for schizophrenia monotherapy in the United States. 1

FDA-Approved Indications

• Bipolar I disorder: Asenapine is indicated only as adjunctive treatment to lithium or valproate in adults with acute manic or mixed episodes 1
• NOT approved for schizophrenia: Despite research evidence showing efficacy, asenapine lacks FDA approval for schizophrenia treatment in current labeling 1
• Contraindicated in dementia-related psychosis: Carries a black box warning for increased mortality risk in elderly patients with dementia-related psychosis 1

Dosing and Administration

Standard Dosing Protocol

• Starting dose: 5 mg sublingually twice daily 1
• Recommended range: 5-10 mg sublingually twice daily 1
• Maximum dose: 10 mg sublingually twice daily 1

Critical Administration Requirements

• Sublingual placement only: Tablet must be placed under the tongue and allowed to dissolve completely—swallowing reduces bioavailability dramatically 1, 2
• 10-minute fasting period: Patients must avoid all food and drink for 10 minutes after administration 1, 2
• Twice-daily dosing: Required dosing frequency may reduce adherence compared to once-daily alternatives 2
• Tablet dissolves rapidly: Dissolution occurs within seconds in saliva 1

Pharmacological Profile

Receptor Binding Characteristics

• High 5HT2A:D2 affinity ratio: Similar to other atypical antipsychotics, with predominant serotonergic antagonism 3
• Multi-receptor antagonism: High affinity for 5HT2A, 5HT2B, 5HT2C, 5HT6, 5HT7 serotonergic receptors; alpha1A, alpha2A, alpha2B, alpha2C adrenergic receptors; and D3, D4 dopaminergic receptors 3
• Clozapine-like profile without anticholinergic effects: Broad receptor binding similar to clozapine but notably lacks appreciable muscarinic receptor affinity 3

Efficacy Evidence

Schizophrenia (Research Evidence Only)

• In a 6-week placebo-controlled trial, asenapine 5 mg twice daily significantly reduced Positive and Negative Syndrome Scale (PANSS) total scores compared to placebo (-16.2 vs -10.7, P<0.05), with efficacy comparable to haloperidol 4 mg twice daily 4
• Asenapine demonstrated efficacy for both positive and negative symptoms of schizophrenia in clinical trials 4, 3
• Evidence suggests metabolic neutrality with low propensity for weight gain compared to olanzapine 3

Bipolar I Disorder

• Two 3-week placebo-controlled trials demonstrated significant improvement in Young Mania Rating Scale (YMRS) scores, with therapeutic effects emerging after 2 days of treatment 5
• Response and remission rates exceeded placebo in acute mania trials 5
• A 12-week adjunctive therapy trial showed superiority over placebo when added to lithium or valproate for manic symptoms 5
• Long-term efficacy maintained over 52 weeks in extension studies 5

Safety and Tolerability Profile

Common Adverse Effects (≥5% and twice placebo rate)

• Somnolence: Most common adverse effect (23% vs 5% placebo), typically transient with highest incidence during first week 1, 5
• Oral hypoesthesia: Numbness or reduced sensation in the mouth 1
• Extrapyramidal symptoms (EPS): Occurred in 15-18% with asenapine vs 10% with placebo, though lower than haloperidol (34%) 4, 5
• Dizziness: Reported in clinical trials 5

Metabolic Effects

• Minimal weight gain: Less than 5% of patients experienced clinically significant weight change in trials 4
• Metabolically neutral: Minimal effects on plasma glucose, lipid levels, and prolactin compared to other atypicals 6, 3, 5
• Low prolactin elevation risk: Hyperprolactinemia-related adverse events occurred in only 0.4% vs 0% placebo 1

Cardiovascular Considerations

• QT prolongation risk: Asenapine should be avoided in patients with QT prolongation history, cardiac arrhythmias, bradycardia, hypokalemia, or hypomagnesemia 1
• Avoid concomitant QT-prolonging drugs: Including Class IA and III antiarrhythmics and certain antibiotics (gatifloxacin, moxifloxacin) 1
• Orthostatic hypotension: Monitor blood pressure, especially in patients with cardiovascular disease or dehydration risk 1

Serious Warnings and Precautions

Black Box Warning

• Increased mortality in elderly with dementia-related psychosis: Asenapine is NOT approved for this population 1
• Cerebrovascular adverse events: Increased stroke and transient ischemic attack risk in elderly patients with dementia 1

Neuroleptic Malignant Syndrome (NMS)

• Requires immediate discontinuation and close monitoring if suspected 1

Tardive Dyskinesia

• Risk increases with duration of treatment and cumulative dose; consider discontinuation if clinically appropriate 1

Hematologic Monitoring

• Leukopenia/neutropenia/agranulocytosis risk: Perform complete blood counts in patients with pre-existing low WBC or history of drug-induced leukopenia 1
• Consider discontinuation if clinically significant WBC decline occurs without other causative factors 1

Seizure Risk

• Use cautiously in patients with seizure history or conditions lowering seizure threshold 1
• Seizures reported in 0.3% of patients in clinical trials 1

Cognitive and Motor Impairment

• Patients should be cautioned about operating hazardous machinery or driving until they know how asenapine affects them 1

Body Temperature Dysregulation

• May impair ability to reduce core body temperature; use cautiously with strenuous exercise, extreme heat exposure, dehydration, or anticholinergic medications 1

Dysphagia and Aspiration Risk

• Use cautiously in patients at risk for aspiration pneumonia 1

Contraindications

• Severe hepatic impairment (Child-Pugh C): Absolute contraindication 1
• Known hypersensitivity: To asenapine or any formulation components 1

Drug Interactions

• Antihypertensive drugs: Asenapine may potentiate hypotensive effects 1
• Paroxetine (CYP2D6 substrate/inhibitor): Reduce paroxetine dose by half when used with asenapine 1
• QT-prolonging medications: Avoid concurrent use 1

Clinical Positioning

Where Asenapine Fits in Treatment Algorithms

Asenapine does NOT fit into standard schizophrenia treatment algorithms as it lacks FDA approval for this indication. 7, 1

For bipolar I disorder:

• Use only as adjunctive therapy: Asenapine should be added to lithium or valproate, not used as monotherapy 1
• Consider for metabolically vulnerable patients: May be particularly valuable for patients at high risk for metabolic abnormalities given its neutral metabolic profile 3, 5
• Alternative to aripiprazole: May serve as an option in bipolar disorder for patients requiring metabolic neutrality 3

Practical Limitations

• Administration barriers reduce adherence: Sublingual-only route, twice-daily dosing, 10-minute fasting requirement, and need for patient cooperation create multiple compliance obstacles 2
• No cost advantage: Offers no economic benefit compared to generic alternatives like risperidone 2
• No clear efficacy superiority: Does not demonstrate advantages over other available atypical antipsychotics in head-to-head comparisons 2

Key Clinical Caveats

• Verify proper administration technique: Many patients may inadvertently swallow tablets, dramatically reducing bioavailability and therapeutic effect 2
• Monitor for time-limited somnolence: Highest during first week, typically resolves with continued treatment 6, 5
• EPS risk higher than olanzapine: Though lower than typical antipsychotics, extrapyramidal symptoms occur more frequently than with some other atypicals 3
• Not a first-line option: Given administration challenges, lack of superiority evidence, and restricted FDA indication, asenapine should be reserved for specific clinical scenarios where its metabolic neutrality provides clear advantage 2, 5