Is There a Connection Between Adverse Childhood Experiences and Treatment-Resistant Depression?

Summary: Yes, there is a connection between adverse childhood experiences and treatment-resistant depression. Adverse childhood experiences (ACEs) are associated with increased risk of developing chronic physical and mental disorders.

Key Points:

• Individuals who report one or more adverse childhood experiences are at increased risk of developing depression (MDD), anxiety (GAD), and posttraumatic stress disorder (PTSD).
• Evidence shows individuals who report on or more ACEs are at increased risks of developing treatment-resistant depression (TRD).
• A new study on a large cohort of twins indicates that likelihood of developing TRD increases with each additional ACE.

What are Adverse Childhood Experiences (ACEs)?

In order to understand the connection between adverse childhood experiences and treatment resistant depression – called ACEs – we need to understand what we mean when we use the term. Here’s a reliable definition of ACEs provided by Kaiser Permanente, the organization that funded the first study to identify ACEs, use the term, and describe the impact of ACEs on physical and mental health:

“Adverse childhood experiences (ACEs) are things that happen before adulthood that can cause trauma or they’re things that make a child feel like their home isn’t safe or stable.”

Experts identify the following experiences as adverse, with negative long-term consequences, when they occur during childhood, or before the age of 19:

• Emotional, physical, or sexual abuse, including rape
• Emotional or physical neglect
• Witnessing and/or experiencing domestic violence or violence in the community
• Growing up with a parent or primary caregiver with a mental health disorder
• Growing up in a home with an individual with alcohol or substance use disorder (AUD/SUD)
• Experiencing racism and/or bullying
• Having a family member incarcerated
• Experiencing economic hardship

Individuals who report one or more of the experiences above are at increased risk of:

• Physical and neurological developmental disorders
• Impaired emotion regulation
• Impaired cognitive function
• Difficulty with social functioning
• Decreased impulse control
• Increased risk of chronic disease and disability

As we can see, ACEs can cause problems throughout the lifespan of any individual who experiences them. The Centers for Disease Control (CDC) reports that decreasing ACEs in the U.S. has the potential to reduce nationwide rates of heart disease, depression, and obesity among adults.

What is Treatment-Resistant Depression (TRD)?

The publication “Treatment-Resistant Depression: Therapeutic Trends, Challenges, and Future Directions” define TRD as follows:

“Treatment-resistant depression (TRD) is a subtype of major-depressive disorder (MDD) that shows unsatisfactory response after at least two attempts at treatment with at least two types of antidepressant medications.”

Estimates of the current rates of TRD among adults in the U.S. based on data from the 2023 National Survey on Drug Use and Health (2023 NSDUH) show the following:

Treatment-Resistant Depression Among Adults 18+ in the U.S.

• Total: 2.5% (6.6 million)
• 18-25: 5.5% (1.8 million)
• 26-49: 3.1% (3.2 million)
• 50+: 1.35% (1.6 million)

Untreated TRD can lead to the following negative outcomes

• Problems at work, school, and in relationships
• Difficulty managing daily activities including maintaining healthy levels of eating, sleeping, and exercising
• Increased risk of additional mental health disorders
• Increased risk of chronic disease

To learn more about TRD, please read the following article on our blog:

Are Rates of Treatment Resistant Depression Increasing?

The information above gives us context for understanding the importance of ongoing research into TRD. Evidence indicates TRD is associated not only with emotional distress and pain, but also lifelong risk of disability.

Let’s take a look at the connection between ACEs and TRD in the study we mention above, in the introduction to this article.

About the New Study: Who, What, When, and How

In the publication “Adverse Childhood Experiences and Treatment-Resistant Depression,” a group of researchers from Sweden, China, and the U.K. analyzed data on depression, treatment-resistant depression, and adverse childhood experiences among a large group of individuals who participated in two different twin studies in Sweden. Here’s the question they sought to answer:

“Are adverse childhood experiences (ACEs) associated with treatment-resistant depression (TRD) after accounting for unmeasured familial confounding?”

We know what ACES and TRD are, but what is familial confounding?

In this case, it means the researchers want to distinguish individual experiences that may cause or contribute to TRD from shared family experiences that may cause or contribute to TRD, i.e. this ACE is associated with and/or increases risk of TRD, as opposed to this family factor.

Studying twins is one way to handle what researchers call confounding factors. Here’s how experts on familial confounding define the term in the context of twin studies:

“Sibling and co-twin control studies account for familial confounding by comparing exposure levels among siblings (or twins). If the exposure-outcome association is causal, the siblings should also differ regarding the outcome.”

In this twin study on ACEs and TRD, researchers examined data on 21,192 twins who participated in two long-term research efforts in Sweden: the Study of Twin Adults: Genes and Environment (STAGE) and the Young Adult Twins in Sweden Study (YATSS). All participants were born between 1959 and 1992 and completed questionnaires on their early experiences either in 2005/2006 or 2013/2014. Researchers cross-referenced survey responses about ACEs with diagnosis of major depressive disorder (MDD) and treatment and diagnosis of treatment-resistant depression (TRD), then applied statistical modeling to account for potential familial confounding and to verify their results.

Let’s take a look at what they found.

Dose-Dependent Connection Between Adverse Childhood Experiences and Treatment-Resistant Depression

In the total sample of over 20,000 people, researchers created a cohort of that included 17,814 twins with TRD and healthy controls. They then identified the prevalence of ACEs in the full cohort:

Presence and Number of ACEs Among Adult Twins from the STAGE and YATTS Datasets

• No ACEs: 12,256 individuals (69%)
  • Among individuals with TRD: 0.7%
• One ACE: 3347 individuals (18.7%)
  • Among individuals with TRD: 1.6%
• Two ACEs: 4189 individuals (6.8%)
  • Among individuals with TRD: 3.0%
• Three or more ACEs: 996 (5.6%)
  • Among individuals with TRD: 5.0%
• Prevalence of TRD overall:
  • 230 individuals: 1.3%

Next, they determined the impact of number of ACEs on likelihood of developing TRD, expressing the impact as an odds ratio (OR), which estimates the likelihood of a specific outcome after a specific exposure. In this study, the outcome was TRD and the exposure was ACEs.

Here’s what they found:

TRD Likelihood by Number of ACEs

• One ACE increases likelihood of developing TRD by 69% (OR: 1.69)
• Two ACEs increase likelihood of TRD by 325% (OR: 4.25)
• Three or more ACEs increase likelihood of TRD by 583% (OR: 6.83)

Their analysis indicates each additional ACE increases the likelihood of developing TRD by 69 percent. That’s what we mean by the heading of this section: the connection between adverse childhood experiences and treatment resistant depression depends on the number, i.e. the dose, of ACEs reported by the individual.

The more ACEs an individual reports, the greater their likelihood of developing TRD.

Next, the research team assessed the impact of type of ACE on likelihood of developing TRD.

TRD Likelihood by Type of ACE

• Rape: OR of 5.86, or 486% increased odds of developing TRD
• Physical neglect: OR of 5.82, or 482% increased odds of developing TRD
• Sexual abuse: OR of 4.62, or 362% increased odds of developing TRD
• Emotional neglect or abuse: OR of 4.43, or 343% increased odds of developing TRD
• Physical abuse: OR of 3.19, 219% increased odds of developing TRD
• Family violence: OR of 2.51, or 151% increased odds of developing TRD

Finally, they assessed the impact of category of ACE on likelihood of developing TRD.

TRD Likelihood by Category of ACE

• Emotional ACE (abuse or neglect): OR of 2.97, or 197% increased odds of developing TRD
• Sexual ACE (abuse or rape): OR of 2.01, or 101% increased odds of developing TRD
• Physical ACE (abuse or neglect): OR of 1.78, or 78% increased likelihood of developing TRD

We’ll discuss these results below.

Knowing Patients, Helping Patients: The More Providers Know, the More They Can Help

Here’s how the research team describes the results of their analysis:

“The finding that ACEs are associated with increased TRD risk independent of familial factors suggests ACE history may help identify individuals with major depressive disorder at high risk for treatment resistance.”

One thing this may mean for treatment professionals is that when they assess patients and diagnose major depressive disorder, they can consider offering an additional layer of support by including questions about ACEs to determine the likelihood of developing TRD. In an invited commentary on the study, an expert on ACEs observes:

“Despite growing awareness of the global burden of childhood adversity exposure and its long-term effects, the pace at which we are translating these research findings into clinical or public health practice seems remarkably slow.”

Given that the first study on ACEs appeared in 1998, the point is well-taken. Here’s how the same expert views the best next steps for mental health treatment providers:

“In the decade ahead, we must pivot as a field from characterizing risk to generating rigorous evidence that informs when, how, and for whom we intervene… [and develop] effective postexposure interventions that mitigate risk, and maybe even prevent ACEs in the first place.”

Translating data into action is more important now than ever, in light of high rates of mental health disorders among adults in the U.S. as reported in the 2024 National Survey on Drug Use and Health (2024 NSDUH). Using this data to better support people with known and identifiable risk factors for TRD may encourage patients and providers alike to explore new and innovative treatments more readily, and enable people with TRD to achieve their treatment goals more quickly and efficiently than under our current TRD protocols.