What are the guidelines for initiating long‑acting injectable antipsychotics in an adult with schizophrenia‑spectrum or bipolar disorder who requires maintenance therapy, has demonstrated or is at high risk for poor oral adherence, has tolerated an adequate oral trial of at least four weeks, and has no contraindications such as severe hepatic impairment, uncontrolled cardiovascular disease, neuroleptic malignant syndrome, or risk of post‑injection delirium syndrome?

Guidelines for Initiating Long-Acting Injectable Antipsychotics

Any patient requiring long-term antipsychotic maintenance treatment should be systematically offered LAI antipsychotics through shared decision-making, not just those with documented non-adherence or multiple relapses. 1

Patient Selection and Candidacy

Second-generation LAIs are recommended as first-line maintenance treatment after the first episode of schizophrenia, representing a paradigm shift from reserving LAIs only for treatment failures. 1, 2 This recommendation is particularly important because:

• 83-85% of eligible first-episode patients consent to LAI treatment when properly educated, with only 15% refusing in controlled studies. 1
• Patients with irregular medication-taking patterns are particularly appropriate candidates given the well-established relationship between non-adherence and relapse risk. 3, 4
• LAIs reduce hospitalization rates by 7-13% compared to oral monotherapy in large cohort studies. 1, 4

Pre-Initiation Requirements

Establish oral efficacy and tolerability before switching to an LAI formulation. 5 The evidence supports:

• An adequate oral trial of at least 4 weeks is appropriate to confirm response and tolerability before LAI initiation. 5
• For first-generation LAIs like fluphenazine, patients with no history of phenothiazine exposure should be treated initially with shorter-acting forms to determine response and establish appropriate dosage. 6
• The most important LAI selection factor is patient response and tolerability to previous antipsychotics. 5

Timing of Initiation

Treatment should start as soon as possible after improvement of acute symptoms, once dosage flexibility is no longer required. 3, 1, 4 Specifically:

• Oral or short-acting intramuscular medication is preferable for acute treatment when flexibility of dosage is desirable. 3
• Once acute symptoms have subsided and the patient is stabilized, conversion to LAI is appropriate. 3, 6

Drug Selection Algorithm

Choose the LAI formulation based on this hierarchy:

1. Previous medication experience and demonstrated response - Select the LAI version of an oral antipsychotic the patient has already tolerated successfully. 3, 5
2. Second-generation LAIs are preferred over first-generation agents due to better tolerability and fewer neurological side effects. 1, 2
3. Patient preference and pharmacokinetic properties should guide selection when multiple appropriate options exist. 3

There is no definitive evidence that any one LAI is superior to another in terms of efficacy, though they differ in side-effect profiles. 3

Oral Supplementation Strategy

The duration of oral supplementation should be determined by the time to attainment of therapeutic LAI levels, which varies by formulation. 5 Key considerations:

• An adequate therapeutic LAI trial is defined as the time to steady state plus 1-2 injection cycles. 5
• Continue oral antipsychotic coverage until the LAI reaches therapeutic plasma concentrations based on its specific pharmacokinetic profile. 5

Special Populations and Contraindications

First-generation LAIs are not recommended in early-course schizophrenia and are usually inappropriate in bipolar disorder. 7 Critical safety considerations:

• Olanzapine pamoate carries risk of post-injection delirium/sedation syndrome (PDSS), requiring a 3-hour observation period after each injection per risk-management protocols. 8
• Patients with severe hepatic impairment, uncontrolled cardiovascular disease, or history of neuroleptic malignant syndrome require careful risk-benefit assessment. 8

Monitoring and Dose Adjustment

At least one adequate LAI trial (time to steady state plus 1-2 injection cycles) is needed to identify lack of efficacy. 5 Implementation requires:

• Careful clinical monitoring at the time of each injection with appropriate dosage adjustments. 6
• For fluphenazine decanoate specifically, dosage should not exceed 100 mg, with cautious increases of 12.5 mg increments if doses greater than 50 mg are deemed necessary. 6

Common Pitfalls to Avoid

• Do not reserve LAIs only for patients who have already failed oral treatment - this outdated practice delays optimal intervention. 1, 7
• Do not assume patient refusal is permanent - clinicians should work through the therapeutic alliance to help patients understand potential advantages even if initially refused. 3
• Do not declare treatment resistance without considering pseudo-resistance from non-adherence - few clinicians obtain drug blood levels before considering treatment resistance. 3