Treatment-Resistant Depression

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Treatment-resistant depression affects about 30% of people diagnosed with major depressive disorder. Here is what you should know about treatment- resistant depression and the range of options for treatment.

Jennifer Coughlin, M.D., is co-founder and co-director of Johns Hopkins’ Brain Health Program and an associate professor of psychiatry and behavioral sciences. Ana Soule, C.R.N.P., is a psychiatric nurse practitioner at the Brain Health Program with dedicated expertise in the diagnosis and treatment of young adults with mood disorders.

What is Treatment-Resistant Depression?

While there is no official definition of the term, some researchers define treatment-resistant depression as lingering depression symptoms in patients who have taken multiple antidepressants or antidepressant classes as directed.

Treatment-Resistant Depression in Young Adults

Severe depression symptoms can take a particular toll on young people. Teen suicide is on the rise: Data from the Centers for Disease Control and Prevention (CDC) show that the segment of high school students who experienced thoughts, plans or attempts to kill themselves increased from 2011 to 2021.

“With young adults, it’s especially important to get the diagnosis and treatment in place,” Soule says.

Coughlin agrees. “Depressive disorder often first appears among people in their late teens to early 20s,” she says. “Finding effective depression treatment in youth and young adults is critical when young people are making decisions and developing habits and coping mechanisms that can affect their lives’ trajectories and preparations for their futures.”

Why am I still depressed after taking antidepressants?

Treating depression varies from person to person, and it can take several tries to find the approach that works best for you. That said, Soule empathizes: “It can be very frustrating to have a growing list of medications that haven’t worked for treating your depression.”

There can be several reasons why your medication isn’t helping. If you’re already under the care of a psychiatrist, it’s always important to let them know if you’re not responding to the medication and explore why it might not be working.

Next Steps for Treatment-Resistant Depression

Getting major depression under control may take several tries with different approaches, such as consulting with experts in mood disorders, adjusting medications, adding therapy or considering other procedures.

Second Opinion Consult

If you have been working with a primary care practitioner, a pediatrician or general mental health professional, it may be worth getting a second opinion with a specialist in depression. This may be a psychiatrist or a psychiatric nurse practitioner.

An in-depth consult provides perspective and a chance to learn how various depression treatments work and what may be available.

Coughlin notes that at some treatment facilities, such as hers at Johns Hopkins, the consult may include talking with family to gather additional information for a more comprehensive patient history.


Psychoeducation is a type of patient education doctors use to help an individual find the treatments that are most likely to ease depression symptoms.

One gap of understanding observed by mental health experts treating depression is that patients tend to stop using their medications before they build up in the system and start to reverse symptoms ― what is called reaching the therapeutic threshold. This can take several weeks.

Psychoeducation helps patients understand:

  • How long it takes to get to the therapeutic threshold
  • The process of finding the most effective therapeutic dosage
  • How to weigh a particular drug’s benefits with its side effects

“Medication may still be an option, but a patient may not be on the right dose for therapeutic effect,” Coughlin says. With that in mind, the practitioner may recommend:

  • Reviewing adherence: how regularly you are taking your medicine as directed
  • Increasing the dosage
  • Adding another medication
  • Switching to a different medicine
  • Giving you more time on your current medicine(s) to reach the therapeutic threshold
  • Genetic testing to help guide treatment

Exploring Other Risk Factors for Depression

Being open in your discussion with the psychiatrist or psychiatric nurse practitioner is essential for finding the best way to use your medications or consider another form of therapy.

When you visit the specialist: 

  • He or she will take a detailed history, review your meds and may recommend tests for physical ailments.
  • He or she will also check to see if another mental condition is causing your symptoms. 
  • The doctor will discuss your lifestyle and habits such as:
    • Sleep. Sleep problems, such as insomnia or sleeping too much, can be both a symptom and a risk factor for depression. Learn more about the relationship between depression and sleep.
    • Substance use. While people with depression may use alcohol and other drugs to try and feel better, some of these substances can counteract depression medication and make you feel worse. The risk of substance use disorder or addiction is real in people with unresolved depression or anxiety.
    • Exercise. Exercise releases feel-good hormones such as serotonin that can help keep depression at bay. However, your doctor understands that once in the grip of major depression, it may be extremely difficult for you to summon the motivation to exercise.

Depression may occur with complicating factors:

  • Physical health problems: Metabolic disorders such as hypothyroidism, some forms of heart disease and other medical conditions can cause or aggravate depression.
  • Other medications: Certain drugs may have depression as a side effect or interfere with the effectiveness of your depression medication. It’s important to review all your medications with your doctor, including:
    • Prescribed medications
    • Over-the-counter products
    • Recreational drugs (including alcohol)
    • Supplements and herbal preparations
  • Life issues: Living with poverty, violence, unresolved grief or loss, family problems, work stress and other negative situations can complicate healing from depression.
  • Other mental health conditions: Personality disorders, post-traumatic stress disorder and substance use disorder are all treatable mental health conditions that can have symptoms similar to those of depression. Working with a doctor can help fine-tune your treatment.

Depression Therapy

Soule points out that psychotherapy (counseling or talking therapy) with a professional is a facet of depression treatment that can help. Therapy styles to address severe depression may include:

  • Cognitive behavioral therapy, a form of psychotherapy that helps people solve problems and identify thought patterns that contribute to negative feelings
  • Dialectical behavioral therapy, which addresses depression and suicidal thoughts and can help the person deal with behaviors such as self-harm and unhealthy substance use
  • Other forms of counseling or talking therapy

What You Need to Know Second Opinions with Johns Hopkins

The Young Adult Consultation Clinic offers second opinions for people ages 18-35 who are suffering from depression, anxiety, or bipolar illness and under the care of a psychiatrist or psychiatric nurse practitioner.

Procedures for Treatment-Resistant Depression

If medication and therapy don’t control depression symptoms, there are still many reasons for hope. More recent or improved advancements in severe or treatment resistant depression therapies include:

Electroconvulsive therapy (ECT)

Modern ECT for depression is a generally safe and effective treatment. A carefully controlled electrical current is passed through the brain to trigger a seizure — a rapid discharge of nerve impulses throughout the brain. Learn more about brain stimulation treatment at Johns Hopkins.


Ketamine is an anesthetic drug that may start to provide relief within hours in some people with treatment resistant depression. Ketamine is administered by injection. Another form given as a nasal spray is called esketamine.

Transcranial magnetic stimulation (TMS)

This treatment uses an insulated coil placed over the scalp, which generates brief, painless magnetic pulses (like those of an MRI), focusing on an area of the brain thought to play a role in mood regulation. Learn more about brain stimulation treatment at Johns Hopkins.

Deep brain stimulation (DBS)

Deep brain stimulation has several uses in treating neurological conditions such as Parkinson’s disease, and may have a role in addressing severe depression. DBS involves surgical implantation of wires inside the brain, which are connected to a very small stimulating device placed under the person’s collarbone, like a heart pacemaker. When successful, DBS may interrupt irregular brain signals that cause depression symptoms.

Psilocybin for depression

A new frontier for depression treatment is psilocybin, a drug derived from a type of mushroom. It is a hallucinogen, similar in some ways to LSD. When given in a controlled environment and accompanied by supportive psychotherapy, psilocybin can reduce depression symptoms in some people. Though psilocybin is not yet FDA-approved for treatment of mental disorders, it is being evaluated in studies to see its effect on depression, post-traumatic stress disorder, substance use disorders and other conditions.

Outlook for Treatment-Resistant Depression

Depression varies from person to person and a treatment that eases depression for one patient may not work for someone else. If your depression is not getting better with your current treatment, don’t give up: There are more options for relief than ever before, and together, you and your doctor can find the approach that works best for you.

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