Effective treatment of major depressive disorder and other mood disorders often necessitates an individualized approach, with antidepressant medications playing a critical role in symptom management and functional stability (1). However, drug shortages or manufacturer discontinuations can disrupt a patient’s treatment, placing them in vulnerable situations and leaving prescribers to find rapid solutions. These disruptions may compel prescribers to switch patients to alternative therapies, a process that carries clinical uncertainty, as the effectiveness and tolerability of a new treatment may vary across individuals (2).

Nefazodone, a second-generation antidepressant, is one of two antidepressants with the unique mechanism of action of blocking both the serotonin transporter and post-synaptic serotonin 2A receptors (3). It is also the only antidepressant carrying a United States Food and Drug Administration (FDA) boxed warning for severe liver toxicity, with an estimated risk of 1/250,000 to 1/300,000 patient-years of treatment, thus its clinical utility is primarily reserved for specialized cases (4). There are several reasons clinicians continue to use nefazodone despite its hepatotoxic risks, including its lower propensity to cause sexual side effects relative to other serotonergic antidepressants and its demonstrated benefit in treating sleep disturbances associated with post-traumatic stress disorder given its minimal impact on disrupting sleep architecture (5–7). Nefazodone is not endorsed as a first-line treatment option and is typically incorporated after failed trials of other treatments (8). Therefore, it is sometimes used for resistant forms of depression, despite a lack of studies demonstrating its benefit in this population.

Nefazodone faced an FDA-declared shortage from September 2020 to June 2022, which allows us to observe prescribing patterns and switching behaviors during a period of constrained availability (9). Medication shortages such as this one highlight broader concerns regarding continuity of care, especially for patients reliant on stable pharmacologic regimens.

In this observational analysis, we aim to describe the prescribing trends and switching behaviors among patients impacted by the nefazodone shortage. Specifically, we examine the extent of drug switching, time-to-switching, and utilization patterns of alternative medications during and after the shortage period. Our research contributes to a limited body of literature on the implications of medication shortages for psychiatric patients, which has often been eclipsed by provider shortages (10–12).

We conducted a descriptive retrospective analysis of nefazodone utilization after the FDA declared shortage on September 18, 2020. Our findings showed that the shortage coincided with a change in utilization patterns for nefazodone, with a decrease in nefazodone claims, and a subsequent uptake and utilization of other antidepressants. After cessation of the shortage, nefazodone claims did not return to pre-shortage levels. This study addresses a largely neglected issue within the literature by focusing on the understudied area of psychiatric medication shortages and their impact on treatment patterns, providing practical information for both clinicians and policymakers.

Nefazodone is one of several second-generation antidepressants available; however, its unique mechanism of action is a barrier to finding an easily convertible and interchangeable equivalent. Given its utilization for specialized cases, we anticipated claims to rebound after conclusion of the shortage; however, there was only a small return in utilization. Most patients in our sample switched to alternative medications with minimal return to nefazodone, which may reflect the extended duration of the shortage. The length of the shortage may have allowed time for patients to adjust to their new medication, made prescribers hesitant to prescribe in fear of another shortage, or resulted in a lack of awareness that the shortage had ended. However, such adaptations may not always mitigate the immediate risks of disrupted care or reflect potential adverse effects of switching, emphasizing the need for continued research in psychiatric medication shortages.

We found that trazodone was the most common drug initiated during and after the shortage. This is likely because trazodone is the closest structurally and mechanistically equivalent therapy; however, it is largely used as a hypnotic in clinical practice secondary to its potent histamine antagonism (14). We hypothesized that mirtazapine would also be a common treatment alternative given it possesses some pharmacological overlap in blocking serotonin receptors; however, its utilization was less than other common antidepressants (3.9% during shortage), including two selective-serotonin reuptake inhibitors (i.e., escitalopram [10.6%], sertraline [7.4%]). Apart from trazodone, antidepressants initiated during the shortage aligned with first-line therapies recommended by the Canadian Network for Mood and Anxiety Treatments and the American Psychiatric Association guidelines, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and bupropion (8, 15). While our study does not assess clinical outcomes, the fact that most patients did not return to nefazodone following the shortage may reflect, in select cases, a transition to safer or more guideline-aligned treatments. Given nefazodone’s boxed warning for hepatotoxicity, it is possible that the shortage prompted prescribers and patients to consider alternative options they may not have pursued otherwise.

Our study’s focus on descriptive and quantifiable outcomes, such as time-to-switch and frequency of switches, offers an important foundation for understanding the impact of psychiatric medication shortages, an area where limited research exists. While prior studies have examined shortages in oncology and antimicrobial therapies, with many studies demonstrating significant negative, clinical, economic, and humanistic consequences, these findings may not be directly applicable to chronic mental health conditions (16). Many chemotherapeutics and antimicrobials are used for time-limited treatment courses, whereas psychiatric medications are often prescribed for long-term, continuous use, especially for treatment-resistant indications. Our study contributes to closing this gap for psychiatric medications by using nefazodone as a case study. Nefazodone use is largely limited to a small patient population for specific clinical purposes and therefore can be easily tracked in claims data compared to drug classes like psychostimulants, which have multiple therapeutic and generic alternatives within the class. Although the niche use of nefazodone enhances our ability to study switching patterns, these findings reflect a specialized context that could differ from experiences with other psychiatric medications or with shortages that are limited in time duration. Nonetheless, our work establishes a needed starting point for evaluating the broader impact of psychiatric medication shortages. While impacts across medication classes may be different, it is important to further investigate if psychiatric medication shortages have a similar impact compared to other therapeutic areas.

This research also underlines the critical need for evidence-based guidelines to support prescribers during shortages as they navigate sudden changes in available options for patient care. Shortages complicate the already complex process of tailoring treatment to individual patient needs, creating uncertainty in how best to proceed. Our findings suggest that intentional, patient-centered treatment decisions may be disrupted by supply chain issues. While our data did not capture direct patient or prescriber perspectives, these disruptions are likely to create challenges in practice. To address these challenges, future research should prioritize understanding patient and prescriber perspectives through mixed-methods approaches and assessing the long-term effects of treatment changes on patient outcomes.

In this descriptive analysis, the FDA-declared nefazodone shortage was followed by a decrease in the number of nefazodone prescription drug claims, an increase in the claims for other drugs, mainly trazodone, and an average time to drug switching of just over three months. This study can serve as a foundation for further exploration of psychiatric medication shortages and their impacts on patient outcomes. Such research will be essential to developing strategies and guidelines to ensure continuity of care and minimize the impact of shortages on vulnerable patient populations.