Loxapine Use in Schizophrenia and Bipolar Disorder
Primary Indication and Evidence Base
Loxapine is FDA-approved for the treatment of schizophrenia, with established efficacy in both newly hospitalized and chronically hospitalized acutely ill schizophrenic patients. 1 The drug has been used in psychiatry for over 40 years with a well-established safety and efficacy profile comparable to other typical and atypical antipsychotics. 2
Clinical Positioning in Treatment Algorithm
For Chronic Schizophrenia Management
Loxapine can be used as a first-line antipsychotic medication for patients with schizophrenia, consistent with APA recommendations that patients be treated with an antipsychotic and monitored for effectiveness and side effects. 3
In comparative trials, loxapine demonstrated equivalent efficacy to haloperidol and was superior to placebo in reducing thought disorder, hallucinations, and persecutory ideation in adolescents with schizophrenia. 3
Continue loxapine treatment for at least 12 months after the beginning of remission if the patient responds favorably. 3
For Acute Agitation in Schizophrenia or Bipolar Disorder
Inhaled loxapine (5 mg or 10 mg) provides rapid treatment of acute agitation, with onset of effect within 10 minutes and peak plasma concentrations reached in a median of 2 minutes. 4, 5
The number needed to treat (NNT) versus placebo for ≥40% reduction in agitation at 2 hours is 3 for bipolar disorder and 4-5 for schizophrenia, comparable to intramuscular antipsychotics or lorazepam. 5
Inhaled loxapine offers a noninvasive alternative to intramuscular injection, potentially avoiding mechanical restraint and facilitating patient cooperation during acute episodes. 6
Dosing and Administration
Oral Formulation
- Use adequate dosages for 4-6 weeks before determining treatment failure, as individual responses to different antipsychotics are variable. 3
Inhaled Formulation
Administer 5 mg or 10 mg as a single dose via the Staccato® delivery device, with apparent dose-response relationship favoring the 10 mg dose. 4, 5
Monitor patients for signs and symptoms of bronchospasm for 1 hour post-administration as mandated by FDA Risk Evaluation and Mitigation Strategy (REMS). 5
Critical Safety Considerations and Contraindications
Pulmonary Screening Requirements
Loxapine is absolutely contraindicated in patients with airways disease associated with bronchospasm or acute respiratory signs or symptoms. 4
Pre-screen all patients for pulmonary disease including asthma and COPD before administering inhaled loxapine, as spirometry studies identified potential for bronchospasm particularly in persons with asthma. 5
Exclude patients with clinically significant acute or chronic pulmonary disease from treatment consideration. 4
Adverse Effect Profile
At high doses for chronic treatment, loxapine has an adverse effects profile comparable to typical antipsychotics, including extrapyramidal symptoms (EPS). 2
Most common adverse events with inhaled formulation include dysgeusia and sedation, with relatively rare EPS and akathisia. 4, 5
Monitor for acute dystonia, parkinsonism, and akathisia; treat acute dystonia with anticholinergic medication if it occurs. 3
Baseline Assessment Requirements
Document targeted psychotic symptoms and any preexisting abnormal movements before initiating treatment to avoid later mislabeling them as medication side effects. 3
Obtain baseline renal and liver function tests, complete blood counts, and electrocardiograms as indicated. 3
Assess tobacco use, substance use, physical health, psychosocial factors, and risk of suicide and aggressive behaviors as part of comprehensive evaluation. 3
Treatment Failure and Alternative Strategies
If insufficient effects are evident after a 6-week trial using adequate dosages, switch to a different antipsychotic agent. 3
For treatment-resistant schizophrenia after failure of at least two therapeutic trials (at least one atypical antipsychotic), transition to clozapine as the evidence-based next step. 3, 7
For patients with substantial suicide risk or persistent aggressive behavior despite loxapine treatment, clozapine should be strongly considered per APA guidelines. 3, 7
Special Populations
Adolescents
Loxapine has demonstrated efficacy in adolescents with schizophrenia in controlled trials, though the long-term use in early-onset schizophrenia has not been extensively studied. 3
Depot formulations are not recommended for children with very early-onset schizophrenia due to inherent risks with long-term neuroleptic exposure. 3
Bipolar Disorder
For bipolar mania with agitation, combine loxapine with a mood stabilizer (lithium or valproate) rather than using antipsychotic monotherapy, as combination therapy is superior. 8
Inhaled loxapine is specifically approved for acute agitation in bipolar disorder with demonstrated efficacy. 4, 5
Monitoring During Treatment
Use quantitative measures (PANSS, CGI, or similar scales) to assess response within 4 weeks and determine intervention effectiveness. 8
Monitor for metabolic effects, extrapyramidal symptoms, liver function, sedation, and falls risk throughout treatment. 8
Encourage patient choice between oral and depot preparations for long-term treatment to improve adherence, though depot use should be reserved for adolescents with documented chronic symptoms and poor compliance history. 3