02. Optimizing LAIs: Dosing Strategies, Formulation Choices, and Emerging Options

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Dose Optimization for Haloperidol and Fluphenazine Decanoate

Helen Tellegen, P.M.H.N.P.: The dosing interval for haloperidol decanoate and fluphenazine decanoate is three to four weeks. For a patient on fluphenazine decanoate 25 mg every four weeks who is still struggling with psychotic symptoms, how would you decide between increasing the dose versus decreasing the dosing interval?

Brian Miller, M.D., Ph.D., M.P.H.: This is another situation where collaborative decision making plays a central role. To my knowledge, there is no strong evidence that increasing the dose is superior to shortening the dosing interval, or vice versa.

I present both options to the patient:

• Option 1: Increase the dose while keeping the injection interval at four weeks.
• Option 2: Keep the same dose but shorten the interval from four to three weeks.

Whichever option the patient prefers, we try it first. If it doesn’t produce the desired result, we proceed to the other. When patients have a meaningful say in their treatment decisions, that engagement itself tends to improve outcomes.

Helen Tellegen, P.M.H.N.P.: Given that the initial dose of haloperidol decanoate should not exceed 100 mg — even when a patient’s oral dose would convert to a higher LAI dose — what strategies can ensure a safe and effective transition without increasing the risk of decompensation?

Brian Miller, M.D., Ph.D., M.P.H.: The approach depends on the clinical setting. For a patient who is hospitalized on a longer-term inpatient unit, one option is simply to start at 100 mg and monitor closely. For a patient where 100 mg of haloperidol decanoate every four weeks is expected to be subtherapeutic, another option is to increase the dose and/or duration of oral supplementation during the initial injection period to bridge the gap.

Helen Tellegen, P.M.H.N.P.: Would you ever recommend giving 100 mg on day one and then administering the remaining dose about a week later, rather than relying on an oral overlap?

Brian Miller, M.D., Ph.D., M.P.H.: That approach is reasonable and depends on the clinical situation — whether the patient is inpatient or outpatient, and how feasible it is to return to the clinic within a shorter timeframe.

This is analogous to what is done when initiating paliperidone palmitate, where an injection is given on day one and a second injection follows approximately one week later. A similar protocol can be applied with haloperidol decanoate. There is no single right answer — extended oral supplementation is one option, and the split-dose approach is another valid alternative.

Aripiprazole LAI Formulations

Helen Tellegen, P.M.H.N.P.: There are two LAI formulations of aripiprazole currently available. For a patient taking aripiprazole 30 mg oral daily who wants to transition to an LAI, how would you approach choosing between aripiprazole monohydrate and aripiprazole lauroxil?

Brian Miller, M.D., Ph.D., M.P.H.: Aripiprazole lauroxil offers more options in terms of dosing strength and greater flexibility with the dosing interval, which gives it an edge in the absence of other deciding factors.

Clinical considerations include:

• Patient preference and prior treatment experience
• Desired dosing interval, such as every four versus every eight weeks
• Practical considerations, including clinic workflow and access

Some patients value more frequent contact with the care team, while others prefer longer intervals between injections. In real-world settings, availability of samples or institutional familiarity may also influence the initial choice.

Risperidone LAI: Dosing Limitations of Uzedy

Helen Tellegen, P.M.H.N.P.: Uzedy, one of the LAI formulations of risperidone, offers several advantages — subcutaneous administration, an eight-week dosing option, and no requirement for an oral overlap or loading dose. However, its highest approved dose of 250 mg every eight weeks corresponds to approximately 5 mg of oral risperidone daily, which presents a challenge for patients stable on 6 to 8 mg orally. Is there a safe and effective workaround, or would it be more appropriate to consider an alternative LAI in these cases?

Brian Miller, M.D., Ph.D., M.P.H.: If there is established evidence for both tolerability and efficacy with risperidone, I would favor staying with a risperidone-based LAI rather than switching to an alternative injectable.

In routine practice, the highest oral risperidone dose I typically use is 6 mg daily. I have very few patients maintained above that level. Importantly, there is limited evidence that 8 mg daily offers meaningful advantages over 6 mg for most patients.

When a patient is stable on 6 mg daily, I discuss several options collaboratively:

• Trial the highest Uzedy dose, acknowledging it approximates their current regimen
• Consider short-term oral supplementation during the initial eight-week interval
• Monitor closely, recognizing that the LAI dose may functionally match higher oral doses for some patients

There is no formally established workaround. In many cases, 250 mg of Uzedy may be clinically sufficient even if it appears lower on paper.

Managing LAI Wearing-Off Effects

Helen Tellegen, P.M.H.N.P.: I’ve encountered both anecdotal reports and personal clinical experience suggesting that the paliperidone palmitate LAIs may wear off before the next scheduled dose — with some patients beginning to decompensate around week three after Invega Sustenna, and similar patterns reported with Invega Trinza and Invega Hafyera. Have you observed this in your practice, and if so, how do you manage it?

Brian Miller, M.D., Ph.D., M.P.H.: Yes, I have seen this early wearing-off effect. It’s worth noting that it is not exclusive to the paliperidone line of products — I’ve seen it with other LAI agents as well.

Management is actually more straightforward than some other clinical challenges, because the patient or caregiver can identify the pattern: symptoms consistently return in the last week before the next injection. At that point, the options are:

• Increase the dose while maintaining the current interval
• Shorten the dosing interval — for example, moving from every four weeks to every three weeks for a monthly formulation
• Adjust the injection schedule for longer-acting formulations (three-month or six-month), scheduling the next dose slightly in advance of when symptoms typically re-emerge

Helen Tellegen, P.M.H.N.P.: Do you ever encounter pushback from insurance when administering the injection earlier than the standard interval?

Brian Miller, M.D., Ph.D., M.P.H.: It sometimes flags, but in those cases we typically pursue prior authorization and provide clinical documentation explaining why earlier administration is necessary. It’s a minority of cases that result in significant pushback, and the prior authorization process is usually successful.

The Pipeline: Emerging LAI Formulations

Helen Tellegen, P.M.H.N.P.: Before we close, what is on the horizon for long-acting injectable antipsychotics? Are there significant innovations we can expect in the near future?

Brian Miller, M.D., Ph.D., M.P.H.: Several newer antipsychotics are currently in development as LAI formulations, including lumateperone, brexpiprazole, and cariprazine.

Having more treatment options is always beneficial. When selecting an antipsychotic, clinicians often have a sense early on whether a patient may be a good candidate for an LAI — and knowing which agents have an injectable formulation available shapes that initial selection. If new LAI formulations reach the market in the coming years, they will further expand our options when making that choice for individual patients.

Helen Tellegen, P.M.H.N.P.: Thank you so much, Brian Miller, M.D., Ph.D., M.P.H. This has been a genuinely informative discussion, and I appreciate you walking us through these important clinical considerations surrounding long-acting injectables.

Brian Miller, M.D., Ph.D., M.P.H.: Thank you, Helen, for a thought-provoking discussion on a number of important clinical issues. At the end of the day, our goal is to do whatever we can to minimize symptoms, prevent illness exacerbations, and help our patients lead as productive and fulfilling lives as possible.

References

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