Poor treatment adherence is a consistent challenge in the management of schizophrenia, with recent findings showing nonadherence rates of 26.5% to 68.8% among patients receiving oral antipsychotic medications.1 A wide range of factors have been implicated in treatment nonadherence in this population, such as poor symptom control affecting perceived value of receiving medication, intolerable adverse effects, substance abuse, and various social, economic, and health system factors.2

Nonadherence to antipsychotic medication significantly increases the risk of relapsing in schizophrenia. A 2014 systematic review demonstrated that 77% of patients who discontinued medication relapsed within 1 year, and 90% of patients relapsed after 2 years.3 Other findings show that patients who discontinued medication were nearly 5 times more likely to experience relapse within 5 years compared with patients with continued medication use.4

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With “each relapse, the onset of therapeutic effect of medication may be slower, treatment may be less effective, and patients may experience greater hardships and financial burden,” as well as progressive impairment in brain function, including social, occupational, and safety issues, according to research published in September 2019 in the Journal of Clinical Psychiatry.2 One study reported a 4-fold increase in suicide attempts among patients with schizophrenia who had a history of treatment discontinuation for ≥30 days compared with those with uninterrupted treatment.5

Long-acting injectable (LAI) antipsychotics represent a valuable strategy to improve treatment adherence and reduce the risk for relapse in patients with schizophrenia. In a 12-month trial of 86 patients with first-episode schizophrenia, the relapse rate was 33% among those taking oral antipsychotics vs 5% among those receiving LAIs.6 Another study of recently diagnosed patients with schizophrenia found that the risk for relapse was nearly 30% lower with LAIs compared with oral medication.2


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LAIs have also been linked to decreased rates of hospitalization compared with oral antipsychotics: 20% to 30% lower in a 2017 trial of more than 30,000 patients.7 However, LAIs remain underprescribed by physicians. This may be a result of “inaccurate perceptions about the medications and their patients’ attitudes toward them,” and clinicians may not adequately discuss LAIs as a treatment option, wrote the authors of the 2019 paper.2

They emphasize the importance of effective communication and recommend that clinicians begin discussing LAIs as an option from the start of treatment. In addition, they suggest that clinicians remain “nonjudgmental, respectful, collaborative, flexible, and empathic,” and that they “help patients recognize the disparity between where they are now and where they would like to be ideally, with medication being one tool to help them reach their goals.”

Dolores Malaspina, MD, professor of psychiatry, neuroscience, and genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai in New York City, and Justin Havemann, psychiatrist at the Center for Behavioral Health at the Cleveland Clinic Marymount Hospital in Garfield Heights, Ohio, gave their insight about treatment adherence and the use of LAIs in schizophrenia.

Psychiatry Advisor: What are some of the main barriers to treatment adherence in patients with schizophrenia?

Dr Malaspina: The available antipsychotic medications do not remedy the core cognitive and socioemotional features of schizophrenia. These illness features, which include impaired planning, problem solving, and motivation, are the ones that limit a person’s capacity to comply with daily dosage regimens.

Other issues are the side effects, costs of medications, difficulty in maintaining adequate refills of prescribed medications, poor attendance at clinic visits, and impaired follow-through to obtain ordered prescriptions.

Dr Havemann: A failure to adhere to the recommended treatment regimen is one of the biggest challenges for patients with schizophrenia. The barriers are significant and include the socioeconomic realities of many schizophrenic patients, who are predominantly low-income and are at greater risk for homelessness, insecure housing, and an inability to pay for necessary medications.

Moreover, patients with primary psychotic disorders are more likely to exhibit deficits that pervade multiple cognitive domains that are critical to the orderly administration of medications, including executive functioning.

Finally, many patients with schizophrenia exhibit a lack of insight that often results in poor compliance. There may even be an outright refusal to take appropriate medications, particularly when there is paranoid thinking regarding the medications or the prescriber.

Psychiatry Advisor: How should clinicians address these issues in practice?

Dr Malaspina: Strategies to increase medication compliance include a once-daily dosage of pills and behavioral training that can overcome executive deficits. LAI medications are underused, particularly before discharge from inpatient units or emergency room settings.

Dr Havemann: It is critical that physicians who treat patients with schizophrenia establish rapport and a collaborative relationship designed to ensure that the patient is an active participant in his or her care. This is an essential first step in establishing and maintaining both insight into the illness and trust that the medications are appropriate and safe. 

However, where the cognitive and socioeconomic barriers are substantial, the use of LAI antipsychotic medications are preferable. This obviates the need to remember (or agree) to take daily oral medications and increases scheduled contact with provider services, since injections are primarily available in the clinical setting.

Psychiatry Advisor: What are the benefits and risks of long-acting injectable antipsychotics, and what are considerations for clinicians in prescribing these agents?

Dr Malaspina: There are benefits of LAI antipsychotics for most patients, as these can overcome the executive planning and compliance issues that impair adherence to oral medications in most patients. Predictable treatment can better foster and maintain wellness without as many psychotic relapses, as these significantly increase the likelihood of needing hospitalization and involuntary treatment.

Dr Havemann: Generally, the risks of LAI antipsychotic medications do not differ substantially from their immediate-acting oral counterparts. These primarily include the extrapyramidal movement symptoms typically associated with first-generation antipsychotic medications and the metabolic side effects associated with second-generation medications. There are rare injection site reactions and the incidental pain associated with the injection itself, and particular products may require additional postinjection monitoring to avoid cardiopulmonary complications. 

The benefits, however, are substantial and primarily affect adherence to the recommended regimen. This is thought to result in improved morbidity, greater functioning in the community, and fewer admissions to the hospital for patients who find treatment compliance otherwise challenging. Accordingly, LAI antipsychotic medications are an appropriate choice for patients who have demonstrated poor adherence to an appropriate oral regimen.

In any event, it is important to establish both tolerance and efficacy with the immediate-release oral medications before transitioning to the long-acting form. Often, it is also necessary to bridge the oral product for a period of time after the initial injection dose has been administered. These time frames differ from product to product and with regard to whether the physician elects to load the patient.

Psychiatry Advisor: What should be the focus of future research and educational efforts in this area?

Dr Malaspina: LAIs are a very valuable treatment option that is still underused.

Patients are suspicious as a part of their condition, and many US patients, particularly minority persons, are frightened to submit to injections.

Better patient education about how the medication is the same as the pill form, in that the LAI medication also washes out of their system, albeit slower, and how it will decrease the amount of daily effort they need to devote to their illness compared with taking pills may improve their willingness for treatment with a LAI.

Unfortunately, the injectables still do not treat the core socioemotional and cognitive deficits of the disease, and they still have side effects. 

Educating office-based practitioners to administer the injections might help to increase their usage.

Dr Havemann: Research and development of ever-longer acting injectable antipsychotics is ongoing and should continue. For instance, there are now several products on the market that have extended the injection intervals from 1 to 3 months. This is a step in the right direction, but it has the potential to reduce the number of contacts with the clinic, which should be balanced against the benefits of close follow-up. 

Moreover, many patients with schizophrenia or other psychiatric illnesses that are also treated with LAIs also benefit from medications that are unavailable in LAI forms, such as valproic acid, lithium, and antidepressant medications. Research exploring the development of long-acting forms of these agents would be welcome.

References

1. Salzmann-Erikson M, Sjödin M. A narrative meta-synthesis of how people with schizophrenia experience facilitators and barriers in using antipsychotic medication: Implications for healthcare professionals. Int J Nurs Stud. 2018;85:7-18.

2. Kane JM, Correll CU. Optimizing treatment choices to improve adherence and outcomes in schizophreniaJ Clin Psychiatry. 2019;80(5):IN18031AH1C.

3. Zipursky RB, Menezes NM, Streiner DL. Risk of symptom recurrence with medication discontinuation in first-episode psychosis: a systematic review. Schizophr Res. 2014;152(2-3):408-414.

4. Robinson D, Woerner MG, Alvir JM, Bilder R. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorderArch Gen Psychiatry. 1999;56(3):241-247.

5. Herings RM, Erkens JA. Increased suicide attempt rate among patients interrupting use of atypical antipsychotics. Pharmacoepidemiol Drug Saf. 2003;12(5):423-424.

6. Subotnik KL, Casaus LR, Ventura J, et al. Long-acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a recent first episode of schizophrenia. A randomized clinical trial. JAMA Psychiatry. 2015;72(8):822–829.

7. Tiihonen J, Mittendorfer-Rutz E, Majak M, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophrenia. JAMA Psychiatry. 2017;74(7):686-693.