Mental health disorders such as depression typically respond well to first-line, evidence-based treatment, but some types of depressive disorders don’t respond well to these initial treatments, which means mental health researchers spend significant time exploring new ways to understand how depression develops, including the role of genetics in treatment-resistant depression (TRD).
When we read our news feeds these days, we consistently see stories about mental health. The Office of the Surgeon General of the United States (OSG) has issued several proclamations over the past several years related to mental health.
Surgeon General Mental Health Advisories, 2021-Present
- 2021: The OSG published “Protecting Youth Mental Health.” This advisory warned about the ongoing mental health crisis among youth and teens. Millions of those teens are now adults with mental health disorders such as depression and treatment-resistant depression
- : The OSG published “Our Epidemic of Loneliness and Isolation: The U.S. Surgeon General’s Advisory on the Healing Effects of Social Connection and Community.” This advisory warned about the physical, mental, emotional, and social consequences of loneliness.
- 2023: The OSG published “Social Media and Youth Mental Health.” This advisory examines the impact of social media use on youth and adolescents. The report has implications for adults as well, as data shows a significant number of adults engage in heavy social media use, which can increase risk of poor mental health.
- 2024: The OSG published “National Strategy for Suicide Prevention.” This advisory presents our plan to reduce the rates of suicide in the U.S., which have steadily increased every year since 2002, with the exception of a two-year period between 2018 and 2020.
The existence of these advisories indicates a real problem. The Surgeon General has access to the latest data, input from the top scientists in every field, and the imprimatur of the executive branch of the federal government, all of which increase the importance of the topics the advisories address. These are nationwide issues that require the full commitment of both our citizens and elected officials – and according to the OSG, we’re currently in an all-hands-on-deck situation with regards to mental health, which makes any research that can expand our understanding of mental health disorders not only a good choice, but an essential one for our future wellbeing.
New Research on Genetics and Treatment-Resistant Depression (TRD)
In February 2024, a group of researchers published a paper called “Genetic Correlates of Treatment-Resistant Depression” in the Journal of the American Medical Association. The research team organized their efforts around this question:
“What are the predisposing characteristics among individuals who develop treatment-resistant depression (TRD)?”
Scientists and mental health professionals know the factors associated with developing TRD are complex. To date, we don’t have a complete understanding of the impact of genetics on the development of treatment-resistant depression (TRD). Previous research identifies distinct correlations between genetic factors and major depressive disorder (MDD), but this is the first study to directly assess the genetic component of TRD.
In order to learn more about the connection of genetics to treatment-resistant depression, researchers designed an analysis with the following goal:
“To investigate the genetic factors associated with TRD using polygenic scores (PGS) across various traits and explore their potential role in the etiology of TRD.”
To ensure we’re all on the same page, here’s a definition of the term polygenic score (PGS)
“A polygenic score (PGS) aggregates the effects of many genetic variants into a single number which predicts genetic predisposition for a phenotype.”
We’ll also take a moment to define the word phenotype, since it may not be familiar to everyone:
“Phenotype refers to an individual’s observable traits, such as height, eye color and blood type. A person’s phenotype is determined by both their genomic makeup (genotype) and environmental factors.”
That’s an important distinction to understand. Genotype is your default physical starting point, while phenotype is a combination of genotype and individual experiences that impact the expression of inherited genes.
Let’s take a closer look at this new publication – and learn whether the data can help our patients with TRD.
About the Study: Genetics and Treatment-Resistant Depression (TRD)
To determine the association of genetics and genetic phenotype with the etiology – i.e. the origin or cause – of treatment-resistant depression, the research team used data from the All of Us Research Program. It’s worth taking a moment to share the goals of this essential, forward-looking research effort, funded by the National Institutes of Health (NIH):
“The All of Us Research Program is a historic effort to gather information from one million or more people living in the United States…the mission of the All of Us Research Program is [to use genetic data] to accelerate health research and medical breakthroughs, enabling individualized prevention, treatment, and care for all of us.”
The research team leveraged this ambitious project by collecting data on a total of 292,663 patients from 50 states across the U.S., which included information from genome sequences, individual records, and responses on general health survey questions. The first step involved assessing the following metrics to assess the impact of genetics on treatment-resistant depression:
- Presence of major depressive disorder (MDD) that responds to treatment (trMDD)
- Presence of treatment-resistant depression (TRD)
- Conversion of trMDD to TRD
The second step involved analyzing those metrics for correlation with the eight following domains – previously associated with TRD – to determine a final polygenic score (PGS) for TRD:
- Education and cognition
- Metabolic, somatic complaints, and inflammation traits
- Personality
- Psychiatric disorders
- Sleep patterns
- Substance use
We’ll share the results of the study in a moment. First, we’ll ensure we’re all on the same page by offering a definition of TRD, sharing the latest prevalence statistics, and reiterating the need for an increased understanding of the origin and causes – i.e. the etiology – of treatment resistant depression.
What is Treatment-Resistant Depression (TRD) and How Many People Have It?
Here’s a definition of treatment-resistant depression (TRD) offered by the study authors:
“A major depressive disorder (MDD) with poor response to two trials of different classes of antidepressants.”
Here’s the latest prevalence data on TRD in the U.S.:
- MDD: 8.9 million patients
- TRD: 2.8 million patients
That’s 31% of patients with MDD.
Evidence shows TRD is associated with increased prevalence and risk of:
- Anxiety disorders
- Stress disorders
- Substance use disorder
- ADHD
- Eating disorders
- Psychotic symptoms
- Bipolar disorder
- Insomnia
- Neuroticism
Treatment-resistant depression is also associated with the following negative physical consequences:
- Chronic pain
- Cardiovascular disease
- Immune system dysfunction
- Diabetes
- Inflammatory conditions
The study authors also note the following negative circumstances associated with the phenomenon of treatment-resistant depression (TRD):
- Treatment cost:
- 20%-30% more expensive than trMDD
- Use of services:
- 70% more visits to emergency room
- 70% increase in outpatient treatment
- 70% increase in prescription medication
- Inpatient hospitalization:
- 40% increase in likelihood of inpatient psychiatric hospitalization
- Personal consequences:
- Loss of productivity at work
- Increased rates of permanent disability
That’s a clear picture of the scope of the problem and the potential consequences of TRD, which confirm the need for studies like this one. Millions of people in the U.S. have a condition that’s demonstrably more expensive to treat than typical depression, and includes an alarming array of unquantifiable negative consequences that degrade life across almost all areas, from relationships, to work performance, to academic achievement, to long-term physical health.
With that in mind, let’s take a look at what the researchers found.
Genetics and Treatment-Resistant Depression: The Results
PGS associated with TRD:
- Education/Cognition
- Sleep
- Personality
- Temperament
PGS with no association with TRD:
- Mental health disorders
- Including MDD
- Substance use
- Metabolic issues
- Somatic Complaints
- Inflammation traits
Genetic propensity for the following components of depressive affect, but not presence of MDD, increased risk of TRD:
- Tenseness: 28% increased risk
- Unenthusiasm: 23% increased risk
- depressed mood: 21% increased risk
- Lethargy: 15% increased risk
Genetic propensity for the following traits increased risk of TRD:
- Insomnia: 6%-15% increased risk
- Neuroticism: 11% increased risk
- Feeling fed up, having mood swings, loneliness: 6%-8% increased risk
A genetic propensity for the following traits decreased risk of TRD:
- Higher educational attainment: 9%-16% decreased risk
- Higher intelligence: 5%-9% decreased risk
The researchers determined which PGS scores predicted transition from trMDD to TRD, i.e. depression that responds well to treatment changing to treatment-resistant depression. The following PGSs were associated with faster transition from trMDD to TRD:
- Education/Cognition
- Sleep
- Personality
- Temperament
Finally, the presence of the following PGSs predicted slower transition from trMDD to TRD:
- Higher educational attainment: 9%-16% decreased risk
- Higher intelligence: 5%-9% decreased risk
Here’s how the research team describes these results:
“This study not only highlights the genetic predispositions linked to TRD—it also demonstrates the complex interplay of traits affecting the development of TRD, emphasizing the need for tailored intervention strategies to manage TRD effectively.”
We’ll discuss these results, and their analysis, in the following section.
The Connection Between Genetics and Treatment-Resistant Depression (TRD)
It’s interesting to note that PGSs for mental health disorders were not associated with increased risk of TRD or transition from trMDD to TRD. One possible explanation is that the increased presence symptoms associated with anxiety, trauma, and psychotic disorders among people with TRD demonstrate the complexity and severity of the symptoms of TRD itself, rather than the presence of another clinical mental heath disorder.
However, one subclinical mental health trait was clearly associated with both TRD and conversion from trMDD to TRD: neuroticism.
To be clear, neuroticism is a real clinical term: it has a meaning beyond casual use when we say we’re being neurotic about something in our lives, for instance. According to the study authors, neuroticism is a personality trait with the following characteristics:
- 40% heritable
- Associated with experiencing negative emotions
- Associated with poor mental health outcomes
In situations of high stress or emotion, study authors indicate that compared to people without neuroticism, people with trait neuroticism experience increased levels of:
- Anxiety
- Depression
- Anger
- Fear
The results show a clear connection between neuroticism and TRD, and a clear connection between transition from trMDD to TRD. Previous research shows a connection between neuroticism and severe MDD, while this study is the first to connect genetic predisposition for neuroticism and TRD, and the first to establish a genetic connection between neuroticism and transition from trMDD to TRD.
In addition, genetic predisposition to neuroticism – and its association with TRD – can explain the failure of first-line psychotherapies for TRD. In most cases, therapy requires cognitive flexibility. Neuroticism is associated with three traits that can undermine cognitive flexibility:
- Extreme sensitivity to negative stimuli
- Rumination
- Impaired emotion regulation
Reduced cognitive flexibility can have a negative impact on treatment progress, since most psychotherapeutic modalities rely on some form of cognitive restructuring and reassessment to manage symptoms and behaviors associated with depression.
How This Information Helps Our Patients
The connection between personality traits and TRD – rather than co-occurring mental health disorders – may be our primary takeaway from this article. The association of PGSs associated with neuroticism and TRD may explains why two of the therapies we offer are effective for TRD – transcranial magnetic stimulation and IV ketamine – when first-line medication and psychotherapy are often ineffective for TRD and TRD symptoms.
As we mention above, traditional psychotherapy relies on the ability of the patient to make accurate, relevant cognitive appraisals, and then follow those with appropriate and healthy attempts to restructure thoughts and improve appraisals. However, neuroticism has a negative impact on the overall capacity to develop and operationalize – i.e. apply – those skills in real-life situations.
That impairs treatment progress.
And that’s where transcranial magnetic stimulation and ketamine and/or Spravato® can help. Evidence shows both modalities can improve TRD, and neither rely on the type of cognitive restructuring or reappraisal common in first line psychotherapies like cognitive behavioral therapy (CBT) or dialectical behavior therapy (DBT).
Instead, they leverage changes in brain function to resolve and improve symptoms. TMS uses direct stimulation of specific brain areas to offer symptom relief, while IV ketamine uses medication to facilitate cognitive change, rather than talking, therapy homework, or various other distress-tolerance techniques. To be clear all those approaches work for MDD – and work well – but TRD is different and requires a new approach.
This new evidence confirms the validity or our commitment to these innovative treatment modalities, which give our patients new hope for recovery, and restore optimism for the future.
To learn more about TMS and Ketamine/Spravato® at Crownview Psychiatric Institute, please visit these pages:
Gianna Melendez
Jodie Dahl, CpHT