Research: Long‐Acting Injectables: A Strategy to Mitigate Nonadherence in Bipolar Disorder
Originally published in Bipolar Disorders, An International Journal of Psychiatry and Neurosciences
First published: 14 February 2025
https://doi.org/10.1111/bdi.70005
Despite our best efforts, partial or nonadherence to treatment is common in bipolar disorder. Varying definitions of nonadherence make a clear prevalence difficult to determine, but a recent nationwide bipolar disorder cohort study identified rates of nonadherence to treatment to be as high as 60%, with a mean prevalence of 40% [1]. The study included > 33,000 individuals with bipolar disorder, and approximately 60% were nonadherent at least once during the monitoring period. This begs the question, why? Nonadherence to pharmacologic treatment is not unique to bipolar disorder, but rates are notoriously high in mental health conditions. Reasons are multifactorial but include the number of comorbidities, young age, co-occurring substance use disorders, limited primary support system, psychotic symptoms, intensity of manic symptoms, and limited insight, amongst others [1, 2].
The consequence of nonadherence to treatment, especially in early disease bipolar disorder, can be dire. Manic exacerbations have been shown to result in brain damage, functional and cognitive impairment, and worse outcomes [3, 4]. Additionally, potentially due to increased impulsivity, bipolar disorder is strongly associated with increased loss of life due to suicide. The best way to prevent these exacerbations and deleterious outcomes is by maintaining adherence to efficacious treatment, thereby preserving brain function and quality of life.
In a recent article published in bipolar disorders, Vieta and colleagues expound on the landscape of long-acting injectable (LAI) antipsychotics for the treatment of bipolar disorder and provide expert consensus recommendations [4]. Key findings include moving past the preconceived notion that LAIs can be used only for bipolar disorder patients with severe disease, and utilizing LAIs as early as possible in the bipolar disease course, ideally during the first manic episode [4]. Historically, LAIs have been reserved for patients with chronic nonadherence to treatment and schizophrenia. However, robust evidence supports that LAIs can enhance fidelity to treatment, reduce psychotic and manic exacerbations, and reduce the risk of rehospitalization when compared to oral antipsychotics [4].
Bipolar 1 disorder can be difficult to treat, and individuals will often require multiple medications. However, polypharmacy has also been shown to reduce adherence [1]. LAIs can lower this burden by limiting the number of daily medications, providing consistent medication serum levels, and eliminating the guesswork about treatment adherence status. Using an LAI as the core treatment allows for rational polypharmacy and the utilization of other medications, such as lithium, in a synergistic manner. However, individuals are often not given the option of an LAI due to lack of healthcare provider awareness.
In recent years, there has been a paradigm shift in the availability of LAI antipsychotic medications, with several new formulations having been brought to market and others in advanced clinical development. These new formulations have varying “amenities of care,” allowing the patient and provider to individualize treatment. Options to consider include the following: method of administration (intramuscular versus subcutaneous), injection intervals (ranging from 2 weeks to 6 months), injection sites, number of initiation doses, duration of oral antipsychotic supplementation, needle size, injection volume, prefilled syringe, dose strength, and approved indication, amongst others [5, 6].
Whether a patient will be receptive towards receiving an LAI depends on how the option is communicated, and LAIs should not be considered as a punitive treatment [6]. If considering an antipsychotic medication for bipolar disorder, LAIs should be offered during the initial treatment discussion, normalizing their use in the early management of bipolar disorder. Moreover, discussing LAIs early in the bipolar disease course can reduce stigma and the perception that it should only be used as a “last resort.” As part of shared decision-making, the initial conversation should discuss potential benefits and drawbacks of LAIs and what the patient's treatment goals are. Moreover, providers should take the time to review the expanding list of available LAI formulations.
Identifying what an individual values most in a medication, ranging from the tolerability profile to dosing frequency, can enhance the collaborative nature of treatment, strengthen the therapeutic alliance, and optimize care. If an LAI antipsychotic is selected, the various amenities of care should be adequately discussed. However, practical limitations and obstacles to LAIs also exist, such as reimbursement barriers and the impact of telehealth from COVID-19. As several LAIs are new, insurers may be reluctant to authorize coverage, and if an individual is uninsured, identifying applicable patient-assistance programs will be needed. Additionally, with the rise of telehealth, healthcare providers are often seeing their patients virtually, making administering an LAI logistically challenging. Being aware of community resources, such as pharmacies and clinics able to administer injectables, will be necessary.
Nonadherence to treatment is high in bipolar disorder. LAIs are an underutilized pharmacologic option with evidence supporting their efficacy and role in maintaining fidelity to treatment. As their utilization increases and research grows, their inclusion in treatment guidelines is likely to follow [4].
Conflicts of Interest:
Justin Faden: Grant support — BioXcel Therapeutics. Consultant — Bristol Myers Squibb, Noven. Elina Maymind declares no conflicts of interest.
The events that are still unfolding have triggered thoughts of “this could have been me,” as I envision myself both as the person gruesomely attacked for being a certain religion and as the fleeing Palestinian civilian trapped in a horrific scenario beyond my control. Integrating one’s personal feelings can make patient care even more complex. Many of my Muslim and Jewish patients are suffering. So are many others with their own past traumas.
As physicians, we are trained to be evidence-based and piece together data points to develop a diagnosis and treatment plan for our patients. As psychiatrists specifically, we are taught to pay attention to every detail and nuance of patients’ narratives as we try to make sense of their life story and help to alleviate their suffering. Sadly, I hear of patients’ traumas and darkest moments daily.
For many people, not just those halfway across the world, life cannot move on. Many of us have deep ties to the region, to our faith, and to our history. For those who tragically lost loved ones, they may never move on to feeling fully whole.
One of my patients, who is developmentally immature and often struggles to have insight, came in a few days after the initial attacks with a somber affect. “How could babies be taken? ... They are just babies.” It was in this moment that I was struck with why I felt ill equipped to manage this.
In our work as psychiatrists, patients expect our help to explore different paths forward to come up with solutions that will lead to more fulfilling lives. Yet, in this case, I was speechless. It took a few moments to recognize that this patient was looking to me and our work together to find the ability to process what had happened. Even though the patient was not directly affected, the impact was still massive. Together, we ploughed ahead toward making some sense of these tragic deaths, a difficult task for both patient and doctor. Personally, I came away with concrete steps that I believe can be effective, in both my professional and personal lives.
The attacks of October 7 were sudden, unexpected, and gruesome, and as such, Maslow’s Hierarchy of Needs was immediately called into question. Without securing food and safety with certainty, one cannot move on to higher needs like love, esteem, and self-actualization.
Erik Erikson said, “The richest and fullest lives attempt to achieve an inner balance between three realms: work, love, and play.” Living among chaos and terror doesn’t afford one the ability to do any of these things.
For those of us out of harm’s way, we need to acknowledge that the events that occurred were derived from complex situations that have evolved over time. These are beyond the control of one person, and we must accept that there are no simple answers. Instead, we should focus on that which we can directly control.
We can be kind and respectful of other people’s needs. We can shift our attitudes and perspectives about where our priorities lie. We can talk through our feelings with those we love. And perhaps more than anything, we can be grateful for what we have in our everyday lives, while still showing empathy toward those in the direct path of danger. Appreciating the positive will in no way devalue or de-emphasize the severity of this tragedy.
Until we focus on our own emotional well-being, we cannot effectively impart change in the world around us. Only then can we take this opportunity to consider how we can give back—both within our own community and globally. For those of us not in immediate physical and emotional crisis, peace and hope can be worked on, both internally and externally.
While we always strive to help our patients have a clearer voice and path forward that’s in line with their integrity and life goals, right now this everyday task seems more important than ever.