Treatment-Resistant Depression: What You Should Know

September 28, 2022

Nue Life

Nue Life

Top points

  • Treatment-resistant depression is defined as persistent major depression that does not improve after two courses of antidepressant medications.
  • Beyond medications, lifestyle changes and behavioral therapy may improve symptoms of treatment-resistant depression.
  • Alternative treatments like ketamine therapy have shown promising results in treating treatment-resistant depression.

Around one-third of people with depression suffer from severe depression that resists clinical practice treatment options. If you cope with a mood disorder like depression and feel like your depressive episodes have turned into a single, long-term never-ending episode, you may have treatment-resistant depression.

Sometimes, no matter how much therapy you seek or how good your medication combination is, treatment of depression can still be difficult. Here, we discuss what it means to have treatment-resistant depression, the signs to look for, and what you can do to move towards more effective treatment.

What Is Treatment-Resistant Depression?

Treatment-resistant depression is just as its name implies — depression that is resistant to treatment. Resistance usually shows as persistent symptoms that either remains the same or worsen.

These symptoms persist despite antidepressant medications, psychological counseling, or other antidepressant treatment. Sometimes your symptoms might even improve momentarily; however, with treatment-resistant depression, the relief is only momentary or short-term, and your symptoms return again.

There is no set time frame that your persistent symptoms must exceed before you can consider them to be resistant to treatment–if you feel that you are unable to tackle your depression and that your quality of life feels constantly upsetting despite various interventions, then it is valid to consider your mental illness as treatment-resistant.

However, healthcare providers typically define treatment-resistant depression as a type of major depression that does not yield improvement after two courses of antidepressant medications that have been in use for six or more weeks post-prescription.

What Is the Difference Between Chronic Depression and Treatment-Resistant Depression?

Many people who suffer from depression experience major depressive disorder, which means that their depressive episodes end after some period of time. However, if you have chronic depression, your symptoms are ongoing and long-term, meaning they never seem to fully go away.

Chronic depression is very long-term, and healthcare providers usually will not diagnose you with this depressive disorder unless you have at least two years of depression. However, treatment-resistant depression can appear before this length of time.

Treatment-resistant depression can turn into chronic depression, and chronic depression can encompass treatment-resistant depression. Most of the time, if you have chronic depression, your depression is also resistant to treatment since it persists for a long period of time.

However, chronic depression can still resolve, even if it lasts for a long time. As such, chronic depression might not always be treatment-resistant.

What Are the Signs of Treatment-Resistant Depression?

Signs of treatment-resistant depression include persistent symptoms, intense side effects, and worsening symptoms.

Persistent Symptoms

One sign that you might have treatment-resistant depression is that your symptoms persist despite intervention. Intervention could be antidepressant medications, as well as counseling or therapy.

In particular, if you have tried two different medications, each for longer than six weeks, and your symptoms show no sign of improvement, then you might have treatment-resistant depression.

Intense Side Effects

Another sign that you might have treatment-resistant depression is that you experience intense side effects that adversely affect your quality of life. Maybe you experience extreme sleep disruptions, such that you wake up early in the morning and can’t fall back asleep, or lie awake in bed for hours and are unable to fall asleep initially.

You might also notice that your appetite changes a lot, such that you skip meals and don’t feel hungry often. Another intense side effect you can feel with treatment-resistant depression is that you lose enjoyment in activities in which you normally find pleasure and joy.

Worsening Symptoms

Worsening symptoms may also indicate that you have treatment-resistant depression, especially if you have been trying to lessen your symptoms for a long period of time, yet they instead start to worsen.

What Can Help With Treatment-Resistant Depression?

From deep brain stimulation and electroconvulsive therapy to transcranial magnetic stimulation, the treatment options may sound complex and overwhelming. We’re here to demystify some of the most common treatment options for treatment-resistant depression and illuminate the ways that ketamine therapy with Nue Life can help.

Other Medications

Antidepressant medications, especially selective serotonin reuptake inhibitors (SSRIs) or norepinephrine reuptake inhibitors (SNRIs), are a common treatment option for depression. They work by balancing levels of neurotransmitters in the brain.

If one medication does not work, different antidepressants might help improve symptoms of treatment-resistant depression.

You might ask your doctor to prescribe a different class of medication altogether. It is rare to keep the first antidepressant you try as your treatment method–many people try three or four different medications before they feel that their treatment is effective.

Sometimes, your healthcare provider may prescribe a “cocktail,” or a combination of two or more medications at once. This combination method is called augmentation.

Other times, you might receive a prescription for a medicine whose primary use is not for depression, such as antipsychotic medications.

Sometimes medications that treat other mental health or even physical struggles make antidepressants more effective. For example, your doctor might prescribe anti-anxiety medications alongside another medication.

Behavioral Therapy

Cognitive behavioral therapy is another treatment option for symptoms of depression. Behavioral therapy stems from a belief that your thoughts influence your behavior, and that if you change your thoughts, you can change your behavior for the better.

With this type of psychological counseling, a therapist will help you pinpoint and reframe negative thoughts and beliefs into positive thoughts so that you can positively affect your behavioral response.  

Lifestyle Changes

In addition to other medications and behavioral therapy, you can implement lifestyle changes to help your treatment-resistant depression. These lifestyle changes include getting a good night’s sleep, eating a well-balanced diet, exercising more regularly, and reducing your stress.

Exercise and stress reduction, in particular, can help improve your mood to lessen your persistent symptoms. When it comes to stress reduction, there are many different options, such as yoga, meditation, journaling, and mindfulness.

You might additionally try to decrease your substance use, especially if this used to be substance abuse in the past.

Ketamine Therapy

If you struggle with treatment-resistant depression, the holistic ketamine therapy programs we offer at Nue Life could be a great alternative treatment.

Studies continue to show ketamine’s efficacy in treating mental health disorders, including a 2019 randomized, controlled trial in the American Journal of Psychiatry that stated, “Repeated ketamine infusions have cumulative and sustained antidepressant effects.”

One of ketamine’s primary mechanisms of action is that it works as an NMDA antagonist, binding to particular NMDA receptors in the brain. This triggers the production of the neurotransmitter glutamate, the most abundant excitatory neurotransmitter in the brain. This helps to “rewire” the brain out of negative thought patterns. This is a different neurotransmitter than SNRIs and SSRIs, which may explain why those who haven’t found success with traditional antidepressants may experience relief with ketamine treatment.

Nue Life offers at-home ketamine experiences so that you can have your treatment in the comfort of your own home.          

We focus on providing whole-person care, offering personalized ketamine treatment and after-treatment care in the form of integration group sessions and health coaching. This evidence-based treatment can help to catalyze growth and change in your life. It may be the healing that you’ve been searching for.

The Bottom Line

Treatment-resistant depression is a form of severe depression that does not respond to treatment. Healthcare providers usually consider depression to be resistant if it does not respond to two different medications and you have been on each medication for six weeks or longer.

If you experience persistent depression symptoms, intense side effects, or worsening symptoms, you might suffer from treatment-resistant depression. This type of depression can severely affect the quality of your life and leave you feeling hopeless.

However, just because your depression is resistant to treatment does not mean that your depression is untreatable. Other treatment options include other medications, lifestyle changes, behavioral therapy, and ketamine.

Talk to your primary care provider to find out the best strategy to help your treatment-resistant depression.

Treatment at Nue Life

Nue Life believes in holistic treatment, which means that what happens before and after your ketamine experience is equally as important as the experience itself. We want to ensure you have meaningful takeaways from your experiences and help you establish positive new neural pathways.

That’s why we provide one-on-one health coaching and integration group sessions with each of our programs. We’re here to help map out the mind and body connections in your brain and help you discover the insights that lead to true healing.


Treatment-resistant depression | Mayo Clinic

Treatment-Resistant Depression: What We Know and How To Manage It | Cleveland Clinic

Chronic and treatment resistant depression: diagnosis and stepwise therapy | NIH There’s No Shame in

Taking an Antidepressant | Cleveland Clinic

Pharmacological approaches to the challenge of treatment-resistant depression | PMC

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