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Understanding Treatment-Resistant Depression

By: | Tags: , , , , | January 8th, 2025

Written by Dr. Felix Grucci

Treatment-resistant depression (TRD) is a complex and challenging condition that affects countless individuals, often leaving patients and healthcare providers searching for effective solutions. Despite advancements in understanding and treating depression, TRD remains a significant obstacle to achieving full recovery for many. This blog delves into the nuances of TRD, exploring its definition, diagnosis, and the multifaceted approaches required to manage it. Through a detailed case study, we’ll shed light on the realities of treating TRD and discuss current strategies and future possibilities for addressing this pressing mental health concern.

Initial Assessment And Diagnosis

A 20-year-old female presents to your office with a chief complaint of “feeling miserable” for two weeks. During your assessment of this patient, you find out that during this two-week period, she has been experiencing a depressed mood most of the day each day, decreased total sleep hours, and decreased energy. The patient also notes that she is becoming more indecisive and, despite the low energy, is feeling very jittery/unable to sit still. The patient works as an executive and reports that her symptoms, especially indecisiveness, are affecting her ability to perform her duties at work and are causing difficulties in her social life. You begin to suspect this patient is experiencing Major Depressive Disorder.

You rule out prior manic/hypomanic episodes as well as other primary causes of her symptoms, such as substance use or a general medical condition, and finally, you evaluate for prior/current psychotic symptoms. After discussing the working diagnosis and treatment options with the patient, she agrees to start a selective serotonin reuptake inhibitor (SSRI) SSRI. You perform the appropriate suicide/homicide/violence risk assessments and recommend she schedule a follow-up appointment in 7-14 days.

Evaluating Early Treatment Progress

10 days later, the patient returned for her appointment, reporting no intolerable side effects or symptom improvement. You explain that the dose prescribed was a starting dose and that she will probably need her dose to be titrated, and a longer period before there are changes in her symptoms. Since there have been no intolerable side effects, you suggest a dose increase to what is considered in the therapeutic range for that medication, and you also complete an objective measure (such as the HAM-D). After assessing for suicide/homicide/violence risk, you and the patient agree to a follow-up appointment in three weeks.

When Improvement Remains Elusive

Three weeks later, the patient returns with no subjective improvement in symptoms. Another HAM-D is completed, which supports the patient’s observations. The patient is willing to continue this course of treatment, knowing that antidepressants may take time to work, but she wishes to try another dose increase. At this point, the patient asks about treatment resistance. You explain that it is possible this medication might not work for her and that a medication change may be necessary in the future, but it is probably too soon to consider her depression to be treatment-resistant. After assessing for suicide/homicide/violence risk, you and the patient discuss a dose increase and follow-up timeframe, ultimately agreeing on a five-week trial at the recommended maximum daily dose.

The patient reports feeling slightly better at follow-up, but the HAM-D score still has not changed. This patient has now undergone eight weeks of treatment with a dose of medication considered to be in the therapeutic range, and the patient wishes to try a new medication. You agree to switch the medication, and the process continues.

Defining And Measuring Treatment Resistance

In the above example, the question of treatment resistance arises, and the patient is informed that it is likely too soon to consider her depression treatment-resistant. Unfortunately, though, there is no set definition of treatment resistance. This writer has most frequently seen definitions involving the failure to respond to two trials of medication at an adequate dose for an adequate period of time. However, definitions using the failure of only one antidepressant or stratification of resistance have also been noted.

How is response measured? In the above example, the HAM-D was done consistently. It is recommended to use an objective measure to help guide management. This writer has frequently seen suggestions that anything less than a 25% symptom reduction (tracked by an objective measure) is considered a treatment failure.

What is meant by an adequate period of time? Each patient is unique and responds differently to medications. In the above example, the first medication was switched after a total treatment period of eight weeks at a dose within the therapeutic range with little to no improvement. Antidepressants may take longer than two months to reach full effect, but there is generally some symptom reduction by the 2-month mark.

Approaches To Treatment-Resistant Depression

When treating patients who report no improvement, preventing tunnel vision and continuously reassessing the diagnosis is important. Each follow-up visit is an opportunity to re-evaluate the working diagnosis and rule out other reasons (such as psychodynamic factors) for lack of response. It is also crucial to assess safety at each appointment, have a safety plan in place, and provide education about resources such as “9-8-8” or The National Suicide Lifeline Chat/Text options as a diagnosis of Treatment-Resistant Depression may carry a higher mortality rate from suicide and accidental poisonings.

There is no cookbook approach to Treatment-Resistant Depression. Treatment options, including switching medications, augmentation with other medications and/or procedures, and psychotherapy, all require careful discussion of risks and benefits with the patient. It is extremely important to be open and honest when speaking with the patient and to explain what the current research suggests and what information you use to guide your treatment recommendations. Most importantly, it is crucial to be empathetic and express that all hope is not lost each time a treatment does not work.

Hopefully, in the future, we will have a better, more agreed-upon definition of treatment-resistant depression and a better understanding of its causes. To end this post on a high note, the FDA granted a “Fast Track Designation” to a potential new treatment in early October 2024.

References

Voineskos, D., Daskalakis, Z. J., & Blumberger, D. M. (2020). Management of Treatment-Resistant Depression: Challenges and Strategies. Neuropsychiatric disease and treatment, 16, 221–234. https://doi.org/10.2147/NDT.S198774

Brown, J. (2024). 4 Things We Now Know About Treatment-Resistant Depression. Johnson & Johnson. https://www.jnj.com/health-and-wellness/4-facts-about-treatment-resistant-depression 

Thase, M., & Connolly, K. R. (2023). Unipolar depression in adults: General principles of treating resistant depression. Retrieved from https://www.uptodate.com/contents/unipolar-depression-in-adults-general-principles-of-treating-resistant-depression?source=history_widget

Chaphalkar, A. (2024). Treatment-Resistant Depression Linked to Increased Mortality. Retrieved from https://www.mdedge.com/psychiatry/article/270961/depression/treatment-resistant-depression-linked-increased-mortality

Treatment-resistant depression. (2024). Retrieved from https://en.wikipedia.org/wiki/Treatment-resistant_depression

Nattasha Acevedo, MD

Dr. Acevedo received her medical degree from the Ponce School of Medicine in Puerto Rico and did her neurology residency at Montefiore Medical Center in New York. She went on to do a clinical neurophysiology fellowship at Emory School of Medicine in Atla nta, Georgia and then joined private practice in Fort Myers, Florida. She currently resides in San Juan, Puerto Rico. She likes running, paddle boarding and spending time with family.
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Bernadette Borte, MD

Dr. Borte received her medical degree from St. Matthew’s University School of Medicine in Grand Cayman. She completed her neurology residency at the University of Iowa Hospitals and Clinics in Iowa City, Iowa. Her areas of interest include inpatient neurology and acute stroke. When not working, she enjoys spending time outdoors with her family. Dr. Borte joined the TeleSpecialist family in March of 2019.
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Mazen Almidani, MD

Dr. Almidani is board certified in pediatrics by the American Board of Pediatrics and board certified in epilepsy, as well as neurology with special  qualification in child neurology by the American Board of Psychiatry and Neurology.  Dr. Almidani is happily married with 4 children. His oldest son has autism and his daughter has complicated seizures; both were a drive for him to become a neurologist. Dr. Almidani enjoys soccer, running and spending time with his family. He is very involved with his sons’ therapy and helping with daily challenges. He is double board certified in Pediatric and Adult Neurology and Epilepsy. He sees children and adults. He also participates in charities for children in Syria who may be underprivileged and/or affected by the war. Dr. Almidani joined TeleSpecialists in August 2020.
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Amanda Cheshire, MD

Dr. Cheshire received her medical degree from the University of Louisville School of Medicine in Louisville, Kentucky. She completed her neurology residency at the University of Cincinnati Medical Center in Cincinnati, Ohio. She did a fellowship in neurophysiology at the University of Michigan Medical School in Ann Arbor, Michigan. Dr. Cheshire is double board certified in neurology and clinical neurophysiology. She enjoys traveling, reading and music. She currently resides in Viera, Florida.  Dr. Cheshire joined TeleSpecialists in June 2019.
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Jessica Floyd, MD

Dr. Floyd completed her neurology residency at Mayo Clinic in Jacksonville, Florida followed by fellowship training in clinical neurophysiology with focus in EEG and epilepsy at the Medical University of South Carolina in Charleston, South Carolina. She has particular interest in hospital neurology and patient education as well as the blossoming specialty of lifestyle medicine. She strives to take advantage of every encounter with patients and medical staff to empower them to do their own research into how daily thoughts, choices, and habits can add up to create greater and longer-lasting brain and neurologic health for ourselves and our loved ones. She lives in Florence, South Carolina with her awesome husband of 13 plus years and three beautiful children. She is an avid yogi, astrologer, and lover of food and all things neurology! Dr. Floyd joined the TeleSpecialist family in July 2017.
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Nancy Futrell, MD

Dr. Futrell received her medical degree from the University of Utah in Salt Lake City, Utah. She also did her neurology residency at the University of Utah as well as a research fellowship in cerebral vascular disease at Jackson Memorial Hospital in Miami, Florida. She currently resides in Salt Lake City, Utah. She has authored 2 books and 50 peer reviewed papers. 
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Rebecca Jimenez-Sanders, MD

Dr. Jimenez Sanders received her undergraduate degree from Emory University, and her medical degree from the San Juan Bautista School of Medicine in Puerto Rico. She completed her neurology residency at the University of South Florida in Tampa, Florida, where she also did a specialized headache medicine and facial pain fellowship. She currently resides in Tampa, Florida with her husband and her two daughters. She is also fluent in Spanish and Italian languages, and enjoys photography, baking, boating, and biking.
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Cory Lamar, MD

Dr. Lamar received his medical degree from Meharry Medical College in Nashville, Tennessee. He completed his internship and residency at Wake Forest Baptist Health in Winston Salem, North Carolina. Following residency, he completed a clinical fellowship in neurophysiology, with a concentration in epilepsy. He currently resides in Florida and enjoys outdoor activities.
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Clifford Meyers, MD

Dr. Meyers received his medical degree from Brown University in Providence, Rhode Island and his MBA from the Simon School of Business at the University of Rochester in Rochester, New York. He completed his neurology residency at the University of Rochester, where he also did a neurophysiology fellowship. Dr. Meyers resides in Webster, New York with his wife and daughter. When not doing teleneurology, he enjoys playing sports with his wife and daughter.
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Tao Tong, MD

Dr. Tong received her medical degree from the University of Miami School of Medicine in Miami, Florida. She completed her neurology residency at Jackson Memorial Hospital in Miami, Florida, where she also did a neuromuscular/EMG fellowship.  She currently resides in College Station, Texas. Dr. Tong is married with two boys. She enjoys spending time with her family, traveling and reading.
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Shubhangi Chumble, MD

Dr. Chumble attended BJ Medical School. She is a board certified neurologist with a subspeciality interest in sleep medicine. Dr. Chumble did her residency at Howard University in Washington DC and has practiced neurology since 2001 in private and corporate settings. She lives in Melbourne, Florida and loves the sunshine state. Her hobbies include yoga, meditation, cooking , traveling and meeting new people. She also loves to do stained glass, pottery and painting. She joined TeleSpecialists in June 2019.
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