Schizophrenia is a severe mental disorder with heterogeneous outcomes that depend heavily on symptom stability as a prerequisite for psychosocial rehabilitation and reintegration. Long-acting injectable antipsychotics (LAIs) are a relevant treatment tools that can help advance meaningful outcomes through improved antipsychotic adherence and relapse prevention, deliver pharmacokinetic advantages less achievable with oral formulations, improve patient autonomy, increase functioning, and reduce the risk of premature mortality even more than oral antipsychotics. However, LAIs remain largely underutilized. Non-modifiable and modifiable risk factors for relapse are summarized, potential advantages and disadvantages of LAIs are reviewed, and myths and misconceptions regarding LAIs are outlined and contrasted with evidence. This information is crucial when engaging in shared decision-making and motivational interviewing to educate patients and caregivers about the treatment option of LAIs, including in early illness stages. Since the first episode and early phases of schizophrenia are a defining time, choosing treatments with the greatest potential for improved outcomes is key. In adults with multi-episode schizophrenia, LAIs have shown superiority over oral antipsychotics for relapse/hospitalization and a variety of multiple other efficacy, effectiveness, functionality, and survival metrics. Additionally, LAIs have shown superiority over oral antipsychotics in patients with first-episode/ or early-phase illness, at least in meaningful subgroups of studies and patients that point toward superiority in settings, individuals, and treatment paradigms that more closely match clinical care. Based on this evidence, hesitancies to discuss and offer LAIs in clinical care need to be overcome, framing LAIs not as a last resort but a viable first-line/earlyphase treatment option that can meaningfully transform the long-term course of schizophrenia.

In this review, the aim is to differentiate between the 3 second-generation antipsychotics available as long-acting injectables (risperidone/paliperidone, aripiprazole, and olanzapine) and their varied formulations. Differences and similarities among the available products are discussed, including the amenities of care: route of administration (intramuscular or subcutaneous), injection frequency, needle gauge and length, injection volume, injection site, reconstitution procedures, initiation with oral medication or multiple injections, refrigeration requirements, post-injection observation requirements, drug–drug interactions preventing use or requiring dosing adjustments, adjustments requirements for late or missed doses, availability of patient assistance programs, and access barriers for off-label use. Effectiveness in acute and maintenance treatment are reviewed using the metrics of number needed to treat and number needed to harm.

Non-adherence and even partial adherence to antipsychotic treatment can increase the risk of relapse in patients with schizophrenia. One strategy to improve adherence is through the use of long-acting injectable (LAI) antipsychotics. Multiple LAI antipsychotic options are available, which differ in terms of their formulation, administration, initiation, and maintenance dosing schedule. This article provides a practical guide to the conversion from oral to LAI antipsychotic treatment for the available LAI formulations as well as evidence-based principles for maintenance treatment.

The failure to make LAI the default route over the same oral when both are available is a lost opportunity to improve outcomes for people with schizophrenia. A striking example is the lost opportunity to improve life expectancy. A sophisticated pharmacoepidemiologic study from Sweden matched antipsychotic prescriptions with mortality rates and found that receiving an LAI version improved longevity by about 30% compared to its equivalent oral counterpart. Published a decade ago, it seems to have had little impact within US mental health services. This paper attempts to explain some of the reasons for complacency in adapting LAIs as a preferred approach for oral that have an LAI option available. Hypotheses include (1) not appreciating the importance of accurate information to guide present and future treatment recommendations, (2) considering LAIs primarily for adherence interventions rather than their more general benefit as a superior information platform, (3) how fear of disclosing nonadherence is a primary cause of misinformation, and (4) complacency with status quo acceptance of misinformation without fully appreciating how it harms future outcomes. The outcome benefits that come from changing from the oral to the LAI, if available, will continue. Advances in formulation technology have greatly improved the safety and flexibility of recent LAIs compared to earlier formulations, and formulation advances will allow for additional antipsychotics currently limited to oral formulation to expand to having an LAI version readily available.

Long-acting injectable (LAI) antipsychotics are not routinely offered and, thus, are underutilized despite their many advantages over oral formulations. In this special collection of articles, the reader will find overviews of the art and science of prescribing this important treatment option. Guidance is offered regarding incorporating LAIs in treatment planning, including inpatient, outpatient, and jail settings. Reviewed is the evidence surrounding the use of LAIs for patients in their first episode of schizophrenia, as well as switching from oral agents and other common issues that come up in day-to-day practice. Also provided is a comprehensive summary of each of the currently available formulations of LAIs, and some pragmatic reasons why one would be considered over another. In the end, the reader will come away with the notion that LAIs are not a “last resort” but an important and useful treatment modality that ought to be considered more often.

Long-acting injectable (LAI) antipsychotics are highly effective tools for managing serious mental illness, yet their clinical utility is often compromised by logistical and pharmacological complexities. This review serves as a practical guide to optimizing LAI therapy by addressing common clinical hurdles. Maintaining a consistent injection schedule is essential to successful treatment. To improve adherence, clinicians should implement proactive reminder systems—such as phone calls or text messages—and involve family or caregivers in the care plan. When injections are delayed, management strategies must be tailored to the specific medication and the length of the “dosing window”. For example, aripiprazole monohydrate (Abilify Maintena) allows a ±7 day window, whereas paliperidone palmitate (Invega Sustenna) provides a +14 day window. If these windows are exceeded, catch-up protocols may involve administering the next dose as soon as possible, utilizing supplemental oral antipsychotics for a bridge period (e.g., 14 days for aripiprazole or 21 days for risperidone), or restarting initiation loading regimens entirely. Clinically significant drug interactions, such as the reduction of aripiprazole or risperidone levels by carbamazepine, can lead to symptom breakthrough. Conversely, CYP450 inhibitors like fluvoxamine or fluoxetine may increase antipsychotic concentrations, necessitating dose reductions. Adverse effects, including drug-induced Parkinsonism and akathisia, should be managed by reducing the LAI dose or switching to agents with lower risk profiles, such as aripiprazole-based products. For akathisia, short-term adjunctive treatments like vitamin B6 or mirtazapine may be utilized until dose adjustments reach steady state. Patient-centered care requires a collaborative approach to substance use, which can exacerbate symptoms or interfere with LAI effectiveness. Clinicians must also engage in nonjudgmental discussions when patients request a return to oral therapy, carefully considering the pharmacokinetic properties of the LAI to time the transition safely. Ultimately, a proactive management plan that addresses these clinical variables is essential for reducing relapse risk and improving long-term quality of life.

Long-acting injectable antipsychotics (LAIs) can lead to improved outcomes for people with schizophrenia, schizoaffective disorder, and bipolar disorder, as they guarantee medication delivery during the injection interval. Contemporary guidance on the use of LAIs includes considering not only patients with poor or uncertain adherence but also patients who would prefer monthly administration (or longer) of their maintenance medication, including those in their first episode of illness. This narrative review discusses the incorporation of LAIs in treatment planning across different settings: acute inpatient units, community mental health outpatient clinics, and jails. Implementing this treatment modality requires the recognition of eligible patients, providing information to patients and their families about the benefits and drawbacks of LAIs, and educating all members of the treatment team.