Athena Care
Treatment Resistant Depression: Symptoms, Diagnosis & Treatment

Treatment Resistant Depression: Symptoms, Diagnosis & Treatment

What is Treatment Resistant Depression?

When two antidepressant medications from distinct classes, given for a sufficient amount of time and at a suitable dose, fail to have a clinically relevant impact, a patient is said to be suffering from treatment resistant depression (TRD),1 also known as refractory depression.

Treatments for depression, unfortunately, do not always work. Two-thirds of adults with depression find that the first medication they try is ineffective,2 and TRD affects nearly a third of all Americans who suffer from depression.3

Up to a third of patients with treatment resistant depression do not respond to many attempts at treatment. Unfortunately, this drug resistant depression is a fairly common occurrence in clinical practice, with up to 50% – 60% of patients failing to respond adequately to antidepressant medication.4

Jump to Section

Symptoms of Treatment Resistant Depression

Treatment resistant depression can present itself in many forms,5 including:

  • An inability to respond to psychotherapy or medication.
  • Insufficient response to traditional depression therapy.
  • After a brief period of improvement, depressive symptoms reappear.
  • Anxiety disorder or high anxiety.6
  • Depressive episodes become more intense and last longer.

People may suffer hopelessness due to treatments failing to perform well or at all. Symptoms of depression can last for months without alleviation or any significant improvement in mood.

TRD is simple to misdiagnose for many reasons, including the following:

  • Doctors frequently prescribe the incorrect dosage.
  • Patients often forget to bring their medications with them when they go somewhere.
  • People become upset and stop taking their medications.
  • Many things can lead someone to believe they’re suffering from medication resistant depression when the antidepressant treatment actually is or could work with minor adjustments.

There are a few ways to know if you’re dealing with treatment resistant depression:

  • You’ve found out which antidepressant to take and how much to take.
    • While everyone’s tolerance varies, most doctors advise trying up to four classes of antidepressants to discover your right fit.
  • Your other medications aren’t interacting in any way.
    • Some drugs, such as blood pressure medications, antibiotics, or steroids, can cause the enzymes that break down antidepressants to work too quickly, rendering the antidepressant ineffective.
  • You’ve received a clean medical report.
    • Hypothyroidism, chronic pain, hormone imbalances, and addiction are all medical conditions that can cause or worsen depression. If you don’t address the underlying causes of your depression, it will persist regardless of medication.

Does Insurance Cover Treatment Resistant Depression?

Yes, many insurance carriers provide coverage for severe depression treatment, including treatment resistant depression.

Athena Care has three mental health treatment centers in Tennessee, and we are in-network with most major insurance plans. Filling out our free and confidential online insurance verification form is the best method to determine if treatment for your TRD is covered.

Let our highly experienced, expert care coordinators handle the difficulties of contacting your insurance carrier for more information about your covered treatment options for TRD. After completing the form, a care coordinator will review your policy and clearly explain your options. Rest assured, all submitted and discussed information is kept private.

Risks & Causes of Treatment Resistant Depression

Treatment resistant depression follows many of the same patterns as depression, and it affects a wide range of people, including the following who are at greater risk:

  • People who have had previous bouts of depression
  • Women
  • Senior citizens
  • People with underlying medical issues such as chronic pain, substance misuse, and sleep disorders
  • Those who have bipolar disorder or post-traumatic stress disorder (PTSD)

The exact cause of TRD is unknown to doctors and researchers. However, the following are some theories:

  • Genetics: Researchers believe that genetic traits may influence how people’s bodies react to various antidepressants.
  • Misdiagnosis: When patients are inaccurately diagnosed with depression, they may respond poorly to typical depression therapies.
  • Metabolic abnormalities: Several studies have linked metabolic abnormalities and dietary deficits to treatment resistant depression. In one study, for example,7 folate (vitamin B9) deficiency was shown to be more common in persons with depression who were resistant to treatment.

Testing & Diagnosis

There are no universal diagnostic criteria for treatment resistant depression.8 However, according to some research, patients who show some improvement in their symptoms within a few weeks of starting an antidepressant are more likely to recover fully. Those who do not respond to treatment early on are less likely to improve completely, even after many weeks.9

If you’ve taken at least two different antidepressants for an adequate amount of time and haven’t seen remission or a 50% improvement in your mood, it may be time to inquire if you have TRD.

A psychiatrist will review your medical history and then conduct the following:10

  • Inquire about any circumstances in your life that may be contributing to your depression
  • Examine your response to treatment, including medications, psychotherapy, and other treatments you’ve tried
  • Review all medications you’re taking, including over-the-counter meds and herbal supplements
  • Check if you’re taking your meds as directed and following treatment recommendations
  • Consider physical health factors, including thyroid abnormalities, chronic pain, or heart problems, which can sometimes cause or worsen depression
  • Consider a diagnosis of another mental illness: bipolar disorder, for example, can cause or worsen depression and may necessitate alternative therapy; dysthymia, a moderate but long term form of depression; or a personality issue that contributes to the depression not improving

Treating Treatment Resistant Depression

If medication management and psychotherapy aren’t working, you should consult a psychiatrist about other options to treat depression, such as:

  • Transcranial Magnetic Stimulation (TMS): TMS treatment uses magnetic fields to stimulate nerve cells in the brain, which helps to alleviate depression symptoms.
  • Spravato (Esketamine): Spravato treatment consists of a prescription nasal spray taken alongside an oral antidepressant, used to treat adults with major depressive disorder (MDD) and TRD.
  • Electroconvulsive Therapy (ECT): A carefully measured quantity of electricity is sent into your brain while you’re sleeping, causing a mild, brief seizure. ECT triggers changes in brain chemistry that can quickly reverse significant depression symptoms.
  • Acceptance and Commitment Therapy: This is a type of cognitive behavioral therapy that assists you in adopting good habits when negative ideas and emotions cloud your mind.
  • Vagus Nerve Stimulation (VNS): Electrical impulses activate the vagus nerve. This treatment involves implanting a device in your chest wired to a nerve in your neck. This treatment is only used if other brain stimulation therapies such as ECT and TMS have failed to improve depressive symptoms.

In addition, it’s important to stick to your treatment plan, refrain from drinking or using recreational drugs, manage stress, sleep well, and exercise. Don’t accept a treatment that only partially alleviates your depression or one that works but has severe side effects. Work with your doctor or another mental health professional to identify the best treatment for you, even if it takes time and effort.


  1. Jaffe, Dena, et al. “The Humanistic and Economic Burden of Treatment-Resistant Depression in Europe: A Cross-Sectional Study – BMC Psychiatry.” BioMed Central, BioMed Central Ltd, 7 Aug. 2019, bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-019-2222-4
  2. Bruce, Debra, Phd. “Treatment-Resistant Depression: Other Treatments for Severe Depression.” WebMD, WebMD LLC, 3 June 2008, www.webmd.com/depression/guide/treatment-resistant-depression-what-is-treatment-resistant-depression
  3. Wiles, N., et al. “Clinical Effectiveness and Cost-Effectiveness of Cognitive Behavioural Therapy as an Adjunct to Pharmacotherapy for Treatment-Resistant Depression in Primary Care: The CoBalT Randomised Controlled Trial.” National Library of Medicine, Queen’s Printer and Controller of HMSO, May 2014, www.ncbi.nlm.nih.gov/books/NBK261988
  4. Fava, Maurizio. “NCBI – WWW Error Blocked Diagnostic.” Diagnosis and Definition of Treatment-Resistant Depression, Society of Biological Psychiatry, 15 Apr. 2003, pubmed.ncbi.nlm.nih.gov/12706951
  5. Morin, Amy, LCSW. “What Happens When Your Depression Doesn’t Respond to Treatment?” Verywell Mind, Dotdash Media, Inc., 2 Nov. 2020, www.verywellmind.com/what-is-treatment-resistant-depression-4588737
  6. Owens, Alexandra. “Treatment-Resistant Depression: Why Depression Meds Don’t Always Work.” Psycom, Remedy Health Media, LLC, 15 Mar. 2022, www.psycom.net/treatment-resistant-depression
  7. Pan, Lisa A., et al. “Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior.” American Journal of Psychiatry, vol. 174, no. 1, 2017, pp. 42–50. Crossref, https://doi.org/10.1176/appi.ajp.2016.15111500
  8. The Healthline Medical Network. “How to Manage Treatment-Resistant Depression.” Healthline, Healthline Media, 5 May 2020, www.healthline.com/health/treatment-resistant-depression#diagnosis
  9. Kudlow, Paul A., et al. “Predicting Treatment Response in Major Depressive Disorder: The Impact of Early Symptomatic Improvement.” The Canadian Journal of Psychiatry, vol. 57, no. 12, 2012, pp. 782–88. Crossref, https://doi.org/10.1177/070674371205701211
  10. Mayo Clinic Staff. “Treatment-Resistant Depression.” Mayo Clinic, Mayo Foundation for Medical Education and Research (MFMER), 10 Apr. 2021, www.mayoclinic.org/diseases-conditions/depression/in-depth/treatment-resistant-depression/art-20044324.

If you suspect that you or someone you love suffers from mental health disorders, contact Athena Care today.

One of our friendly associates will help you get the help you need. Take this first step to feel better and take control. 

(615) 320-1155