Supporting mental health may improve hydroxyurea adherence in sickle cell disease

Some illnesses announce themselves visibly, such as measles with its trademark rash. Sickle cell disease does not. Despite being the most common clinically significant inherited blood disorder, it is completely invisible from the outside, even though it can impact nearly every aspect of a person’s life. The hallmark banana-shaped red blood cells of sickle cell disease cause symptoms including pain crises and fatigue. The severity of these symptoms can disrupt school, work and relationships, yet patients may still struggle to have those burdens recognized.

When hydroxyurea, a drug used to treat sickle cell disease that St. Jude helped pioneer for use in children, was first approved to treat the disorder in 1998, it was (and remains) the only readily accessible pharmaceutical to address these symptoms. However, hydroxyurea usage is facing its own hidden crisis, which St. Jude researchers are trying to bring to light.

“We have observed for many years now that less than half of adults in the United States who have sickle cell disease take hydroxyurea, and why has been unclear,” said Andrew Heitzer, PhD, ABPP-CN, Department of Psychology & Biobehavioral Sciences. “What has been even less clear is why some stop taking it, even after experiencing its benefits.”

To understand which patients with sickle cell disease stop taking hydroxyurea, and why, many scientists worked together. The Sickle Cell Disease Implementation Consortium, a multi-site study with the St. Jude portion led by principal investigator Jane Hankins, MD, MS, St. Jude Global Hematology Program director, Department of Global Pediatric Medicine member, which is funded by the National Heart Lung and Blood Institute, surveyed a large group across multiple years. The results, published in JAMA Network Open with Hankins as senior author, uncovered that mental health and medication adherence influence each other in ways that reframe the underuse of hydroxyurea and inspire new interventions.

A negative feedback loop between mental health and medication adherence

First and corresponding author Heitzer and his team first looked at executive functioning, the collective name for attention, planning and organization skills. This was a good place to start because a deficit of those skills could plausibly lead to missed medications. The results showed there was a relationship between executive functioning and medication adherence that flowed both ways.

“We found that patients who took the medication were less likely to have problems with executive functioning at a future time point; but pre-existing poor executive functioning was predictive of less future use,” Heitzer said. “That means if patients are on the medication early, they are protecting their brain, and if they are already protecting their brain, they are able to stay on the medication as well.”

The findings suggest that the two experiences exacerbate each other: missed medications lead to worse executive functioning, leading to further missed doses, whereas compromised executive function leads to missed doses, which in turn worsen executive functioning. In both cases, a negative feedback loop emerges that decreases treatment adherence.

In addition, self-reported depression correlated with decreased medication adherence. Depression is also linked to decreased executive functioning, so the findings paint a broader picture of mental health, cognition and hydroxyurea use — one that also represents an opportunity.

“These findings show that providing psychosocial and behavioral interventions may be helpful in keeping patients on these types of medications,” Heitzer said. “While apps and adherence tools exist to help people remember when to take their medications, these results show that it’s also important to understand how patients feel about taking the medication and how that intersects with their mental health and daily habits. We need to learn why they chose to discontinue or never start its use.”

Who holds off on hydroxyurea?

When Heitzer and colleagues examined who chose not to use hydroxyurea, they found several other trends that indicated how patients’ thoughts about themselves were driving treatment decision-making. One of the most striking patterns involved female study participants, particularly those over 20 years old, who were more likely than their male counterparts to stop taking hydroxyurea. “We discovered that many of these women quit taking the drug in adulthood, likely due to family planning and feared health complications during pregnancy,” Heitzer explained. 

The current findings demonstrate that these medication decisions involve complex decision-making and can be difficult to predict. That complexity was apparent in another intriguing finding from the study, which showed that patients with the two most severe forms of disease (either of the HbSS/SB0-thalassemia genotypes) displayed declining hydroxyurea use over time. “That was surprising to us because we believed that those with the more severe genotypes would benefit from treatment the most,” Heitzer said. “Many of these patients receive hydroxyurea from childhood. However, based on interviews with patients outside of the study, one of the reasons they stop is that over time they perceive a loss of efficacy.” 

By contrast, patients with less severe forms of the disease were more likely to start treatment as adults. That may be because their disease status worsened, and they had yet to try hydroxyurea. Together, these trends reinforce the idea thought patterns and other psychological aspects drive use.

Intervening against the invisible

While sickle cell disease may be considered an invisible chronic condition, St. Jude researchers, such as Heitzer, are taking a closer look to better see and respond to patients’ needs with targeted interventions. Already, Heitzer leads an ongoing study for pediatric patients at St. Jude has to help train caregivers how to best support their children through the unique challenges they face.

Currently, we are teaching a group of caregivers how to prepare their child with sickle cell disease for school and provide functional skills,” Heitzer said. “While this type of intervention is designed to be helpful for kids, our study suggests this type of support could be helpful at all stages of their lives.” 

Adult needs, however, can become more complicated over time as mental health becomes an increasing factor negatively impacting their lives.

“We know adults and children’s needs are different, as pediatric patients with sickle cell disease have relatively low levels of depression, psychosocial difficulties and loneliness. But those issues become more pronounced as they transition into adulthood,” Heitzer continued. “Sickle cell can be an invisible condition, and a lot of patients struggle with employment and isolation in a lot of ways. Many feel don't have a community that really supports or sees them.”

Motivated by these results, Heitzer’s future work is exploring research that provides such assistance for adults, including psychosocial and behavioral interventions and a sense of community.

Helping patients feel seen

The central message of the JAMA Network Open study is that hydroxyurea use cannot be reduced to whether patients with sickle cell disease remember to take a pill. It is shaped by the many dimensions of a person’s life beyond the clinic — whether as a parent, employee, partner or caregiver — realities that may be less visible when medical care focuses solely on the condition and not the person living with it.

 “To promote the use of hydroxyurea, we need to build trust with patients,” Heitzer said. “We need to ask about their mental health, depression, anxiety and daily lives, so they feel seen. This positive patient-provider relationship can most effectively facilitate resources for these patients.”

By recognizing the invisible mental and emotional challenges that accompany living with sickle cell disease, researchers hope to help more patients stay on a therapy that can meaningfully improve their lives.