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.