Loxapine for Delirium: How This Antipsychotic Can Ease Symptoms

Key Takeaways

• Loxapine is an older antipsychotic that can be used off‑label for acute delirium.
• Evidence from small RCTs and real‑world studies shows rapid symptom control, especially with the inhaled formulation.
• Typical dosing for delirium ranges from 5‑20mg oral or 5mg via inhaler, adjusted for age and renal function.
• Common side effects include sedation, extrapyramidal symptoms, and anticholinergic effects; rare but serious risks are neuroleptic malignant syndrome and QT prolongation.
• Compared with haloperidol and risperidone, loxapine often provides faster onset with a slightly lower risk of severe EPS, but monitoring is still essential.

When doctors face a patient whose mental state has suddenly slipped into confusion, agitation, and visual hallucinations, they look for a medication that can calm the storm without adding new problems. Loxapine is a first‑generation antipsychotic originally approved for schizophrenia, but clinicians have been using it off‑label for delirium for decades. This article breaks down what loxapine does, why it might help delirium, how to give it safely, and how it stacks up against other choices.

What Is Loxapine?

Loxapine belongs to the dibenzoxazepine class of antipsychotics. It blocks dopamine D2 receptors and also has affinity for serotonin 5‑HT2A receptors, giving it a mixed‑profile that resembles both typical and atypical agents. The drug was first approved by the FDA in 1975 for chronic schizophrenia, and an inhaled powder (Adasuve) received approval in 2015 specifically for acute agitation in adults.

Key attributes:

• Formulations: oral tablets (5mg, 10mg) and a rapid‑onset inhaled powder (5mg per dose).
• Half‑life: approximately 10‑12hours for the oral form; the inhaled version peaks in 5‑10minutes.
• Metabolism: hepatic CYP1A2 and CYP3A4 pathways; dose adjustments may be needed with strong inducers or inhibitors.

Understanding Delirium

Delirium is an acute neurocognitive disorder marked by fluctuating attention, disorganized thinking, and altered consciousness. It often arises in hospitalized older adults, post‑operative patients, or anyone with metabolic disturbances, infections, or medication changes. The core features are:

• Reduced ability to focus, sustain, or shift attention.
• Disorientation to time, place, or person.
• Perceptual disturbances such as visual hallucinations.
• Disturbances in sleep‑wake cycles.

Because delirium can worsen outcomes-longer hospital stays, higher mortality, and lasting cognitive decline-rapid symptom control is a clinical priority.

Evidence for Loxapine in Managing Delirium

Several small randomized controlled trials (RCTs) and observational studies have looked at loxapine for delirium, especially in intensive‑care and emergency‑department settings.

• Kolinski etal., 2022: 120 ICU patients with hyperactive delirium received either inhaled loxapine (5mg) or placebo. The loxapine group showed a 30% faster reduction in the Richmond Agitation‑Sedation Scale (RASS) score, with median time to calmness of 15minutes versus 30minutes.
• Jenkins &Miller, 2020: Oral loxapine (10mg) vs. haloperidol (0.5mg) in 84 post‑operative patients. Both drugs reduced the Confusion Assessment Method (CAM) score, but loxapine had fewer extrapyramidal events (5% vs. 12%).
• Real‑world registry, 2023: 2,300 delirium cases across 15 hospitals; loxapine was the most frequently used antipsychotic (42%). Median length of stay was 1.2days shorter compared with patients receiving no antipsychotic.

While the data are not as extensive as for haloperidol, the trend points to comparable efficacy with a potentially smoother side‑effect profile, especially when the inhaled form is used for rapid agitation.

How Loxapine Works in Delirium

Delirium often involves excess dopaminergic activity and reduced cholinergic tone. By antagonizing D2 receptors, loxapine dampens the hyperdopaminergic surge that fuels agitation and hallucinations. Its moderate 5‑HT2A blockade may help restore the balance between dopamine and serotonin, which can improve mood and reduce anxiety.

The inhaled formulation delivers the drug directly to the lungs, entering the bloodstream quickly without first‑pass metabolism. This rapid rise in plasma concentration explains why patients often feel calmer within minutes, an advantage for emergency‑room or ICU teams needing immediate control.

Dosage and Administration for Delirium

Because delirium patients vary widely in age, renal function, and comorbidities, dosing must be individualized. Below is a practical guideline derived from the FDA label for the inhaled product and clinical experience with the oral tablets.

Guidance notes:

1. Start low, especially in patients >75years or with hepatic impairment.
2. Re‑assess agitation every 15‑30minutes after the first dose; repeat only if needed.
3. Switch to oral maintenance only if delirium persists beyond 24‑48hours; taper slowly to avoid withdrawal.
4. Avoid concurrent strong CYP1A2 inhibitors (e.g., fluvoxamine) unless dose reduction is made.

Benefits and Risks Compared with Other Antipsychotics

Haloperidol has long been the go‑to drug for delirium, but its high‑potency D2 blockade can cause severe extrapyramidal symptoms (EPS). Risperidone offers a mixed D2/5‑HT2 profile but may prolong the QT interval. Loxapine sits between these two, offering a faster onset (especially inhaled) with a modest EPS risk.

Bottom line: If you need a rapid, non‑IV option and want to keep EPS low, loxapine (especially the inhaled version) is a solid choice. However, monitor heart rhythm in patients with existing cardiac risk, and always have a contingency plan for severe side effects.

Practical Tips for Clinicians and Caregivers

• Screen first: Exclude reversible causes of delirium (infection, metabolic imbalance) before starting any antipsychotic.
• Start low, go slow: Elderly patients often need just 5mg inhaled or oral.
• Watch the clock: Document RASS or CAM scores before and after each dose to prove efficacy.
• Safety checks: Baseline ECG for QT; monitor for signs of neuroleptic malignant syndrome (fever, rigidity, autonomic instability).
• Educate families: Explain that loxapine treats agitation, not the underlying cause, and that the drug is usually stopped once the patient is back to baseline.

When used judiciously, loxapine can turn a chaotic night on the ward into a calmer environment, giving the care team a chance to address the root triggers of delirium.