Treatment-Resistant Depression: Why Standard Care Fails and What to Do About It

Treatment-Resistant Depression: Why Standard Care Fails and What to Do About It

Despite a dramatic rise in antidepressant use in the United States since 1988, the number of Americans suffering from depression has not decreased. This leaves clinicians with a stark reality: more medication, without improvement.

Antidepressant use rose nearly 400% from 1988–1994 to 2005–2008. By 2005–2008, about one in ten Americans was taking an antidepressant, making it the third most commonly used prescription drug class.

Since then the numbers have continued to rise. By 2023, 11.4% of U.S. adults reported taking prescription medication for depression. When individuals aged 12 and older are included, the rate likely exceeds 15%, given the post-2020 surge in youth prescribing and earlier data showing nearly 13% of those 12 and older using an antidepressant in the past month.

 

Depression Rates Continue to Rise

In fact, depression is not falling but rising sharply. In national CDC surveys, the share of adults screening positive for depressive symptoms rose from 18.5% in 2019 to 21.4% in 2022, a jump of about 16% in just three years. That means roughly one in five adults screened positive in a two-week window. 

At the same time, major depressive episodes remain common. In 2021, an estimated 21 million U.S. adults, 8.3 % of the population, experienced at least one major depressive episode in the past year. 

Polling tells the same story. Gallup, a global analytics firm, reports record highs in 2023, with roughly 30% of Americans saying a professional has diagnosed them with depression at some point. 

Worldwide the situation isn’t any better, with international statistics painting a sobering picture. The World Health Organization estimates that more than 330 million people are living with depression, and Global Burden of Disease analyses rank it as the leading cause of disability worldwide.

 

Why More Medication isn’t Fixing it

Across FDA-registered trials, the average antidepressant advantage over placebo was only 1.8 points on the Hamilton Depression Rating Scale, a very small effect size (~0.32) that is not clinically meaningful. 

In routine care, about half of patients do not respond to the first antidepressant trial, even when treatment follows best-practice protocols such as STARD Level 1. 

After decades of rising prescriptions, the limitations of standard pharmacological care are evident: for a large number of people, antidepressants do not provide meaningful relief.

Long-term data is no more encouraging. In a 12-year study that followed 431 adults with Major Depressive Disorder (MDD), 90% cycled through multiple severity states and were symptomatic almost 60% of the time. In plain terms, 90% did not achieve or maintain uninterrupted remission. This shows that lasting recovery from MDD is uncommon and the condition is both chronic and episodic, with symptoms easing and then returning over time.

This study mirrors what clinicians with years in mental health care see in practice: only a small number of patients with MDD achieve and sustain remission, while for the majority the experience is cyclical: a new prescription, a temporary lift, then another relapse. Clinicians also feel the fatigue and frustration: “I gave the patient the protocol, why didn’t it work?” 

The same pattern extends beyond medication. Many people try numerous treatments in addition to medication, including therapy, mindset practices, stress management, and other interventions, and still do not get well and stay well.

 

This pattern led to a new question

Across treatments, the pattern persists. People move from medication to medication and from therapy to therapy, yet lasting relief remains out of reach for most people. Depression is becoming increasingly chronic, persistent, recurrent, and often described as treatment-resistant. This reality raises the central question that inspired the Healing Depression Project: Is depression truly treatment-resistant, or are current treatments simply not effective?

 

A New Approach to a Complex Problem

The Healing Depression Project set out to test a new model of care. What happens when you address metabolic dysfunction and other physical root causes while also helping people build daily habits that support both brain and body health, all within a supportive residential setting?

This was the premise behind the 45-Day Healing Depression Project, a comprehensive program with a 30-day residential phase followed by 15 days of guided integration at home. It brings together Functional Medicine, Metabolic Psychiatry, a Therapeutic Ketogenic Diet, Lifestyle Habits Training, Psychodrama Group Therapy, Somatic Work, and Mindfulness Practices, all under one roof in a restorative retreat-style experience.

The program is guided by Achina Stein, DO, IFMCP, Beth Zupec-Kania, RDN, CD, Kat Toups, MD, IFMCP, Stacey Johnson, LPC, and founder Silvia Covelli. Together, they bring decades of clinical experience in psychiatry, nutrition, experiential therapy, and mind-body health, with a shared focus on helping participants achieve lasting recovery.

 

Listen to the story behind the Healing Depression Project and how their research is paving the way to make comprehensive functional care for TRD more accessible for everyone on the New Frontiers podcast.

 

Results that Redefined What’s Possible in Psychiatry

The Healing Depression Project team designed a structured study to objectively evaluate program efficacy and track participant progress over time. The goal is to demonstrate a model of care that integrates Functional Medicine and Metabolic Psychiatry as effective treatments for MDD, including treatment-resistant cases.

Their work is redefining what is possible in depression care, with early outcomes that are both hopeful and paradigm-shifting.

 

Study design (practice-based evidence)

The Healing Depression Project’s study is modeled on practice-based evidence and was conducted in a controlled residential setting as a prospective, single-arm evaluation of the 45-day program.

Ten participants (n = 10) with an average of 20+ years of treatment-resistant depression completed the program, which included a 30-day in-residence phase followed by 15 days of guided at-home integration.

Data were collected before the program, during the program, at the end of the 30-day in-residence phase, and at 3-month intervals for a planned 2-year follow-up.

Outcomes were measured with four widely used and clinically validated assessment tools: 

• the Hamilton Depression Rating Scale (HAM-D17), 
• the Beck Depression Inventory (BDI-II), 
• a 9-question Patient Health Questionnaire (PHQ-9), and 
• the Generalized Anxiety Disorder Scale (GAD-7).

 

Outcomes from the program, measured by the study, were overwhelmingly positive:

• 100% of Participants Improved: All participants showed significant improvement by Day 30, with group mean symptom reductions of 60–73% across BDI-II, HAM-D17, PHQ-9, and GAD-7.
• Up to 90% Reached Remission or Mild Severity: By Day 30, 80% were in remission or minimal range on BDI-II, and 90% were in remission or mild on HAM-D17, with no participants remaining in the severe range.
• Exceptionally Large Within-Subject Effects: Cohen’s d (within-subjects) values of 1.6–2.3 across validated scales, far exceeding the effect sizes typically reported for antidepressants. (For context, designs differ, a PLOS Medicine meta-analysis of FDA-registered trials estimated the average antidepressant effect after subtracting the placebo effect at about 0.30 standard deviations.)
• Long-Term Outcomes: At the 6-month follow-up (latest time point available at the time of publishing), the mean BDI-II remained in the mild range (17.0), nearly 50% lower than baseline (32.3). Overall, 70% of participants were still in remission, minimal, or mild range compared with an average rating of severe at baseline.

These findings show evidence that an immersive model integrating therapeutic ketogenic nutrition, daily movement, habit training, psychodrama, somatic practices, and functional medicine psychiatry delivered in a controlled residential environment can lead to meaningful symptom improvement.

As is the case with most studies, some limitations have to be acknowledged. This study was not a randomized controlled trial and there was no control group. These results should be interpreted as practice-based evidence. Nevertheless, these results are very promising and warrant the need for further large-scale research studies.

 

The Role of Ketogenic Nutrition in Healing Depression

A key part of the residential phase was the therapeutic ketogenic diet, paired with daily ketone tracking. Participants were guided into a state of therapeutic ketosis and engaged in daily movement and sunlight exposure. The clinical team considers that this metabolic health approach strongly contributes to the rapid reduction in depressive symptoms in the group.

Recent research supports their observation. An IRB-approved pilot from Ohio State University (published in Translational Psychiatry) found that a well-formulated ketogenic diet reduced depressive symptoms by ~69% on the PHQ-9 and ~71% on the Hamilton Rating Scale for Depression (HAM-D) in 10 to 12 weeks.

In this study, 16 college students with major depressive disorder followed a ketogenic protocol and tracked ketones daily. Nutritional ketosis was achieved on most days and, incredibly, improvements in symptoms were seen from week 2 onwards. 

The peer-reviewed study, although not randomized and without a control group, provides evidence that nutrition and metabolic interventions can meaningfully reduce depressive symptoms alongside standard treatment. 

It’s also a further testament to the approach taken by the Healing Depression Project: combining fuel stability (therapeutic ketosis) with nervous-system regulation (movement, breathwork, yoga, sleep regulation), deep processing (psychodrama therapy), and skill building (habit training), and delivering these elements together, can shift depression symptoms quickly and substantially.

The takeaway for clinicians and patients is practical and hopeful. Ketogenic nutrition is not a fringe idea in depression care; it is a measurable lever that can be integrated into standard care to help patients achieve and sustain relief from symptoms.

 

A 45-Day Immersive Reset for Treatment-Resistant Depression

So what does the Healing Depression Project’s program look like? For 30 days, participants live at a lakefront ranch in Austin, Texas, followed by 15 days of guided integration at home. 

The daily cadence during the 30-day in-residence phase makes the hard things doable: therapeutic ketogenic meals are prepared on site with regular ketone tracking, daily exercise and meditation, somatic practices, habit training, and sleep support routines. 

This is paired with intensive, trauma-focused psychodrama group therapy, and functional medicine psychiatry including specialized testing, lab work, and individualized care plans. All of these elements are woven into a tightly held schedule so the work actually happens. 

This is an immersive, coordinated model designed for people with chronic, treatment-resistant depression who’ve tried many things and are ready for a fully supported reset.

 

The Team Behind the Healing Depression Project

The Healing Depression Project’s program is led by a multidisciplinary team of experts, including renowned functional medicine physicians, psychiatrists, nutritionists, therapists, life and health coaches, behavioral and trauma specialists, and meditation and yoga teachers. Meet the clinicians who lead this work:

• Dr. Achina Stein, DO, DFAPA, ABIHM, FACN, IFMCP – Medical Director
• Dr. Kat Toups, MD, DFAPA, IFMCP – Research Director
• Beth Zupec-Kania, RDN, CD – Ketogenic Nutrition Protocol Developer
• Stacey Johnson, LPC, MAMFT – Therapy Director

 

Be Part of the Next Chapter in Depression Recovery

If you work with patients who have not responded to standard treatments, and who could benefit from an immersive functional and metabolic psychiatry approach, there is now a place you can refer them. 

The Healing Depression Project runs two programs every year, and early application is encouraged since each program is limited to only ten participants.

They are now accepting applications for the next program in March, 2026. Scholarships covering up to 70% of the program cost are available. The team is looking for 10 committed individuals who are ready to transform their lives.

If you’re a clinician with a patient who may be a fit, or a person living with long-standing depression ready to change your life, book a call today to learn more and check scholarship eligibility.

Want to learn more? Request a free copy of the Healing Depression Project’s Program Brochure here. The brochure explains the full 45-day program, key treatments, expected outcomes, and how this approach differs from standard care.