Risk factors for poor adherence to antipsychotic medications influence treatment planning

Creating a personalized treatment plan requires a systematic assessment of an individual’s array of risk factors for poor adherence.Reference Velligan, Weiden and Sajatovic^6, Reference Ascher-Svanum, Zhu, Faries, Lacro and Dolder^10–Reference Shuler¹³ LAIs can be part of the solution, depending on the obstacle. Four broad categories of risk factors can be conceptualized, each with several aspects to consider (Table 1). More than one factor may be present, and they may change over time. Each factor that is present requires a different strategy; for example, cognitive impairment leading to poor adherence can be remedied by additional structure and reminders (or LAIs), whereas not being able to access a pharmacy or problems storing medications in a communal setting will require quite different approaches. Community stigma can be partly addressed by public advocacy. Poor adherence is often unintentional—there are simply too many obstacles that get in the way. This is different from intentional nonadherence, where a conscious choice is being made not to follow a treatment plan; in that instance, motivational interviewing may help.

Table 1. Selected Risk Factors for Poor Adherence to AntipsychoticMedication

What do guidelines recommend?

In a systematic review of schizophrenia clinical practice guidelines on acute and maintenance management with antipsychotics,Reference Correll, Martin and Patel¹⁴ LAIs were noted to be primarily recommended for patients who are nonadherent to other antipsychotic administration routes, and a smaller number of guidelines also suggested that LAIs should be prescribed based on patient preference. Most guidelines recommended LAIs as maintenance therapy, and some also recommended LAIs specifically for patients experiencing a first episode. The American Association of Community Psychiatrists Guidelines¹⁵ suggest that LAIs may offer a more convenient mode of administration or potentially address other clinical and social challenges, as well as provide more consistent plasma levels. A summary of recommendations for LAIs in the treatment of schizophrenia is provided in Table 2.

Table 2. Recommendations for LAI antipsychotics in the treatment of schizophrenia

AACP, American Association of Community Psychiatrists; AFPBN, Association Française de Psychiatrie Biologique et Neuropsychopharmacologie; APA, American Psychiatric Association; BAP, British Association of Psychopharmacology; CINP, International College of Neuropsychopharmacology; CPA, Canadian Psychiatric Association; LAI, long-acting injectable; no, not recommended; NA, not applicable; NICE, National Institute for Health and Care Excellence; NJDMHS, New Jersey Division of Mental Health Services; PPA, Polish Psychiatric Association; PORT, Patient Outcomes Research Team; RANZCP, Royal Australian/New Zealand College of Psychiatrists; SIGN, Scottish Intercollegiate Guidelines Network; TMAP, Texas Medication Algorithm Project; UNHCR, United Nations High Commissioner for Refugees; WFSBP, World Federation of Societies of Biological Psychiatry; yes, recommended.

The consensus guidelines regarding the determination that a patient has treatment-resistant schizophreniaReference Howes, McCutcheon and Agid¹⁶ recommend that to rule out “pseudo-resistance” due to inadequate treatment adherence, patients should receive at least one trial with a LAI, given for at least 6 weeks after it has achieved steady state (generally at least 4 months from commencing treatment).

There is less literature regarding guidelines specifically for the use of LAIs in bipolar disorder or schizoaffective disorder. The French Association for Biological Psychiatry and Neuropsychopharmacology suggested that LAIs can be considered a first-line treatment for schizoaffective disorder and a second-line treatment for bipolar disorder.Reference Llorca, Abbar, Courtet, Guillaume, Lancrenon and Samalin¹⁷ General and focused guidelines regarding the treatment of bipolar disorder have mentioned the use of LAIs as first line for maintenance therapy.Reference Jeong, Bahk and Woo^18, Reference Chou, Chu and Wu¹⁹

Use of long-acting injectable antipsychotics in acute inpatient settings

LAIs are generally thought of as a long-term strategy; thus, their initiation in acute inpatient settings is not always considered despite their potential therapeutic benefits. In a retrospective study that included 94,989 hospitalizations from 2010 to 2016 throughout the United States due to schizophrenia, schizoaffective disorder, or bipolar disorder, very modest rates of LAI utilization were observed.Reference Liu, Patterson, Sahil and Stoner²⁰ The rate of LAI monotherapy use was 1.1%, and the rate for the combination of LAI with non-LAI medication was 10.3%. The efficacy of the acute use of LAIs has been demonstrated in a meta-analysis that included 66 studies with 16,457 participants.Reference Wang, Schneider-Thoma and Siafis²¹ The American Psychiatric Association Practice Guideline for the Treatment of Patients With SchizophreniaReference Keepers, Fochtmann and Anzia²² has suggested that LAIs be considered when patients are transitioning between settings, such as when patients are being discharged from an inpatient unit (eg, at inpatient discharge, on release from a correctional facility), and also earlier in the course of schizophrenia.Reference Kane, Schooler, Marcy, Achtyes, Correll and Robinson^23–Reference Subotnik, Casaus and Ventura²⁵ In treatment planning, it should be noted that the use of a LAI is not a panacea, as observed in a Medicaid database study of 1,312 inpatients with schizophrenia where the type of antipsychotic received was not significantly associated with probability of a follow-up visit and that substance-related disorders significantly decreased it.Reference Farr, Smith, Pesa and Cao²⁶ A potential confound is severity of illness and complexity of the medication regimen; in a retrospective cohort study of 1,197 adults with schizophrenia and who initiated LAI treatment during a psychiatric inpatient stay, patients prescribed a combination of LAI and oral medication upon discharge had a higher risk of rehospitalization compared with those prescribed a LAI alone.Reference Patel, Liman and Oyesanya²⁷ In a small single-center prospective study of 51 patients, more than 40% of patients receiving a LAI in the hospital did not follow up in the outpatient setting despite discharge planning.Reference Ross, Adams and Crouse²⁸ The authors concluded that before initiating a LAI, “multiple factors should be considered, including outpatient adherence, access, feasibility of outpatient continuation, and transition of care plan.”

Use of long-acting injectable antipsychotics in Community Mental Health outpatient settings

In contrast to acute hospital settings, LAIs are more often considered part of a long-term treatment strategy. Utilization rates of LAIs have been estimated to be approximately 17% among Community Mental Health Center patients, as ascertained in a study of 41,401 patients in South Carolina.Reference Lohman, Scott, Verma, Jones and Fields²⁹ Both prospective and retrospective studies have demonstrated that LAIs outperform oral antipsychotics in decreasing rates of relapse, hospitalization, and all-cause discontinuation,Reference Kirson, Weiden and Yermakov^30, Reference Kishimoto, Hagi, Kurokawa, Kane and Correll³¹ as well as exhibiting a decrease in all-cause mortality.Reference Aymerich, Salazar de Pablo and Pacho³² Several obstacles to increased use of LAIs in community settings have been identified and include a lack of advocacy, difficulty with provider buy-in, limited availability of peer specialists, and a lack of infrastructure.Reference Velligan, Sajatovic and Sierra³³ Nonetheless, there is an opportunity in outpatient settings to introduce the idea of LAIs to potential patients using the techniques of shared decision-making,Reference Elwyn, Frosch and Thomson³⁴ motivational interviewing,Reference Lewis-Fernández, Coombs, Balán and Interian³⁵ and ongoing engagement with caregivers.Reference Citrome, Belcher, Stacy, Suett, Mychaskiw and Salinas³⁶ Site staff training in shared decision-making and roleplaying was noted to have a success rate of almost 80% for first-episode and early-phase schizophrenia to receive at least one LAI injection in a cluster-randomized clinical trial.Reference Kane, Schooler, Marcy, Achtyes, Correll and Robinson²³ Patients can be accepting of LAIs, provided they are presented in a positive light with sufficient information, as demonstrated in a study of communication patterns in the offer of LAIs that included 10 community mental health clinics.Reference Weiden, Roma, Velligan, Alphs, DiChiara and Davidson³⁷ In the initial encounter, only 9% of the communication of psychiatrists presenting LAIs focused on positive aspects and yielded acceptance of LAIs for 11 of the 33 communications. When re-approached with better information, among almost all those who declined, subsequently stated they would be willing to try a LAI. Identified as patient barriers to LAIs include lack of awareness, sense of coerciveness, fear of injections or needles, and limited insurance coverage.Reference Getzen, Beasley and D’Mello^38–Reference Potkin, Bera, Zubek and Lau⁴⁰ Identified as clinician barriers include insufficient knowledge or experience, perceived lack of time, insufficient ancillary support, overestimation of adherence, lack of confidence, and stigma.Reference Lindenmayer, Glick, Talreja and Underriner³⁹

The literature regarding LAIs for the management of bipolar disorder notes that LAIs are effective and well-tolerated maintenance treatments for both bipolar disorder and schizoaffective disorder, but show better efficacy in preventing mania than depression, and thus LAIs may be first-line for bipolar disorder and schizoaffective disorder patients with a manic predominant polarity.Reference Pacchiarotti, Tiihonen and Kotzalidis^41–Reference Belge and Sabbe⁴³ An expert consensus review advocates for the earlier use of LAIs in patients with bipolar disorder, ideally at the first manic episode, to aid in improving long-term outcomes.Reference Vieta, Tohen, McIntosh, Kessing, Sajatovic and McIntyre⁴⁴ For both schizophrenia and bipolar disorder, when patients discontinue therapy, the time to relapse is longer for LAIs compared with their oral equivalents.Reference Weiden, Kim, Bermak, Turkoz, Gopal and Berwaerts^45, Reference Kishi, Citrome, Sakuma and Iwata⁴⁶

Use of long-acting injectable antipsychotics in jails

It has been observed that severely mentally ill persons who come to the attention of law enforcement now receive their “inpatient” treatment in jails and prisons, partly due to a reduction of psychiatric inpatient beds, a phenomenon that is sometimes referred to as transinstitutionalization.Reference Lamb and Weinberger^47, Reference Prins⁴⁸ Relatively little has been published regarding the use of LAIs in jail settings. People who are jailed may be abruptly moved or bailed out prior to arrangements for ongoing mental health care and leave without medication. In a survey of Missouri county jails, only 57% of jails were able to provide LAIs.Reference Burval, Iuppa and Kriz⁴⁹ This may be an opportunity lost, as LAIs may provide a chance to provide additional time to seek ongoing care successfully. Here, treatment planning involving LAIs will require the availability of infrastructure, as well as institutional support.

Who is the ideal candidate for long-acting injectable antipsychotics?

As part of long-term treatment planning, any individual requiring maintenance antipsychotic treatment should be informed of the availability of LAIs as part of shared decision-making. There may be specific clinical characteristics that may further support the use of this modality.

Patient preference can be a key determinant of suitability for a LAI. In a study involving 1,402 individuals with schizophrenia, 77% reported preferring LAIs over daily oral medications, citing benefits such as improved quality of life, reduced anxiety about missed doses, and fewer disruptions to daily routines.Reference Blackwood, Sanga and Nuamah⁵⁰ In a survey conducted in France that included 206 patients with at least 3 months of LAI antipsychotic experience, injectable antipsychotics were the preferred formulation, and 70% of patients felt better supported in their illness by virtue of regular contact with the doctor or nurse who administered their injection.Reference Caroli, Raymondet, Izard, Plas, Gall and Delgado⁵¹

Many patients find the simplicity of monthly or quarterly injections preferable to daily oral medications, particularly if they are balancing work, travel, or personal responsibilities. Others cite relief from daily reminders of illness and reduced worry about missed doses.Reference Blackwood, Sanga and Nuamah⁵⁰ Offering LAIs as a standard part of treatment planning—rather than reserving them only for individuals with demonstrated nonadherence—aligns with recovery-focused, patient-centered care models and ensures equitable access to evidence-based interventions.

While LAIs offer important advantages for many patients, they are not always the right choice. For example, individuals who are adherent and stabilized on clozapine—the gold standard for treatment-resistant schizophrenia—are not candidates for a switch to a LAI. However, adding a LAI to a regimen that includes clozapine may have advantages as reported in multiple observational studies.Reference Caliskan, Karaaslan and Inanli^52–Reference Tien, Wang, Huang and Huang⁵⁶

Treatment planning for olanzapine pamoate

Treatment planning for the use of olanzapine pamoate is more complex than for other LAIs.Reference Citrome⁵⁷ When olanzapine pamoate was being developed, a small number of adverse events termed post-injection delirium/sedation syndrome (PDSS) were found in 0.07% of injections.⁵⁸ Because there are no clear, identifiable risk factors for PDSS, a Risk Evaluation and Mitigation Strategies (REMS) was instituted, and olanzapine pamoate can only be provided at registered healthcare facilities, where patients must be monitored by appropriately qualified staff for at least 3 hours after injection.⁵⁹ Similar guidance is in place in other countries.Reference Citrome⁵⁷ In addition, patients must be accompanied to their next destination upon leaving the facility. Although PDSS is not common, from a provider perspective, a clinic with 60 patients receiving an injection every 2 weeks might expect approximately one event per year.Reference Detke, McDonnell and Brunner⁶⁰ Thus, treatment planning for olanzapine pamoate will routinely require more intensive staff care and management compared with other LAIs. An alternate formulation of olanzapine LAI, administered subcutaneously and likely free of risk for PDSS, is in the late stage of clinical development.Reference Correll, Ahn and Bar-Nur⁶¹

Do formulary restrictions get in the way?

In a study of 493,006 people with schizophrenia living in the community conducted during 2002–2006, it was estimated that approximately 90% were covered by Medicare or Medicaid (with 26% having both), and approximately 7% were uninsured.Reference Khaykin, Eaton, Ford, Anthony and Daumit⁶² Prior authorizationReference Jackson, Fulchino and Rogers^63, Reference Salzbrenner, Lydiatt and Helding⁶⁴ and step therapy not only can delay the initiation of LAIs but also alter clinical decisions, with step therapy having the biggest impact on prescribing.Reference Salzbrenner, Lydiatt and Helding⁶⁴ However, a report of formulary restrictions in several thousand Medicare and dual Medicare/Medicaid plans in the United States, as recorded in 2019 and 2023, found that requirements for a prior authorization for LAIs (with the exception of olanzapine pamoate) were low (<12%) and declined between 2019 and 2023, and that requirements for step therapy were low as well (<4%).Reference Bunting, Cotes, Gray, Chalmers and Nguyen⁶⁵ Medicare recipients generally (>90%) have low out-of-pocket costs.Reference Doshi, Li, Geng, Seo, Patel and Benson⁶⁶ Thus, at least for the Medicare and Medicare–Medicaid population, fulfillment of a prescription for a LAI is not a major barrier for use.

Augmentation with psychosocial interventions

Treatment planning for LAIs can benefit from the consideration of psychoeducational strategies. In a meta-analysis that included 12 studies and 874 patients, the cumulative relapse rate was 28% for those receiving family intervention compared with 49% for usual care.Reference Pitschel-Walz, Leucht, Bäuml, Kissling and Engel⁶⁷ Another meta-analysis that included 1,534 participants across 18 studies concluded that interventions that included families were more effective in reducing symptoms than interventions directed at patients alone.Reference Lincoln, Wilhelm and Nestoriuc⁶⁸ Although these studies did not necessarily include LAIs in either treatment group, as a general rule, elements of psychoeducation, often in conjunction with family members or other individuals who engage in the patient’s life, are an integral part of good clinical practice.Reference Keepers, Fochtmann and Anzia²² Family members can serve as strong advocates for the use of LAIs, as evidenced by the finding that caregivers generally report having fewer barriers caring for patients receiving LAIs than caring for patients not receiving such treatments.Reference Citrome, Belcher, Stacy, Suett, Mychaskiw and Salinas³⁶