Management of Treatment-Resistant Depression: A Guide

Despite its name, many treatments can improve treatment-resistant depression. Approaches that may help include combining specific antidepressants, psychotherapy, and brain stimulation.

Doctors diagnose treatment-resistant depression when depression hasn’t improved enough after trying two different antidepressant types.

However, many other treatment approaches can help improve treatment-resistant depression.

Still, finding the best treatment and management strategies for treatment-resistant depression can take time and trial and error. Talk with a doctor for support if you feel your depression treatment isn’t working well enough.

This article discusses medical and self-care approaches for managing treatment-resistant depression.

Reviewing your medication may improve treatment-resistant depression. For example, doctors may start by trying another antidepressant type or adjusting your current medication’s dosage.

Another key treatment approach for treatment-resistant depression is combining two different antidepressants.

Combining medications for treatment-resistant depression usually involves taking typical antidepressants with another, less commonly used medication.

Typical antidepressants can include:

• tricyclic antidepressants, such as:
  • amitriptyline (Elavil, Vanatrip)
  • nortriptyline (Aventyl, Pamelor)
• selective serotonin reuptake inhibitors (SSRIs), such as:
  • fluoxetine (Prozac, Rapiflux, Sarafem)
  • sertraline (Zoloft)
• selective serotonin noradrenaline reuptake inhibitors (SNRIs), such as:
  • duloxetine (Cymbalta, Yentreve)
  • venlafaxine (Effexor)

In addition, doctors may prescribe:

• Atypical antidepressants: Atypical antidepressants do not fit into the main classes of antidepressants. Among others, options such as bupropion (Wellbutrin, Zyban) and mirtazapine (Remeron) may help treatment-resistant depression.
• Second- or third-generation antipsychotics: Also called atypical antipsychotics, these medications can help treat psychotic conditions and depression. They may work well with SSRIs and SNRIs for treatment-resistant depression.
• Triiodothyronine (T3): T3 is a thyroid hormone produced by the thyroid gland. Evidence indicates there may be a link between thyroid health and mood disorders. As a result, some research suggests T3 medications may help treat depression.
• Lithium: Lithium is a mood-stabilizing medication that may work well with tricyclic antidepressants.

Read more about mood-stabilizing medications, including lithium.

Psychotherapy or talk therapy involves working with a licensed psychotherapist to identify and address mental health conditions. It is a key treatment for many types of depression.

Including psychotherapy alongside other approaches may also help improve their effectiveness. For example, a 2022 review suggests that psychotherapy can improve responses to some brain stimulation therapies and reduce the risk of depression returning afterward.

Types of psychotherapy that may help depression include:

• cognitive behavioral therapy (CBT), which helps you restructure negative or false beliefs
• psychodynamic therapy, which helps identify and address negative thoughts and behaviors
• interpersonal therapy, which helps you work on your relationships with others
• therapies to address trauma, such as:
  • eye movement desensitization and reprocessing (EMDR) therapy
  • somatic or mind-body therapy

Read more about the types of psychotherapy.

If depression hasn’t improved after trying multiple other approaches, doctors may recommend brain stimulation therapies. Examples include:

• Transcranial magnetic stimulation (TMS): Doctors use TMS to help treat depression. As part of TMS, doctors use noninvasive magnets to stimulate brain cells and improve function.
• Electroconvulsive therapy (ECT): ECT is a noninvasive procedure whereby a doctor uses a medical device to pass electrical waves through the brain.
• Deep brain stimulation (DBS): With DBS, surgeons implant electrodes in the skull that pass electrical currents through the brain.
• Vagus nerve stimulation (VNS): VNS involves surgery to implant a small electric device. This device sends electrical pulses to a nerve to help regulate brain function.

Your medical team may consider only brain stimulation therapies if treatment-resistant depression is severe or other treatments are not working.

As brain stimulation may cause side effects, talk with your doctor to help you weigh the benefits and possible concerns.

In addition to medical approaches, the following may help with treatment-resistant depression.

Learn more about whether depression can go away and how to treat depression.

Psychotherapy can be an effective strategy for treatment-resistant depression. However, you may find that not all therapy types and psychotherapists are the best fit for you.

If you’ve tried psychotherapy and it hasn’t helped, consider trying again with another therapy type or healthcare professional.

Similarly, if you can, talking with a few doctors may help you find someone who makes you feel supported.

Finding the motivation or energy for self-care can be difficult for some people with depression. However, medical treatments like psychotherapy and medication sometimes offer the support you need to get started.

Contact a doctor if you are finding treating your depression challenging, or if you have other questions.

Doctors may also be able to suggest social support groups and low cost care.

Eating a balanced diet may improve mood with depression.

Experts generally consider Mediterranean diets and anti-inflammatory diets to be relatively balanced.

If you can, talk with a doctor or registered dietitian for personalized advice, as nutritional needs can vary per person.

Some people may find it difficult to access recommended foods or follow a balanced diet — especially while managing health conditions. Approaches that may help include:

• trying nonmeat protein sources, such as beans and peas
• buying frozen fruits and vegetables
• choosing canned meat, fruit, and vegetables labeled “low in sodium” or “no added salt,” or rinsing canned foods that contain salt
• choosing in-season produce

In addition to other treatments, physical activity is highly effective in improving depression symptoms.

Finding a physical activity or sport you find enjoyable may also help with motivation and mood.

Including your favorite activities in your daily life may help improve motivation and feelings of apathy.

Some hobbies may also help address depression symptoms while providing enjoyment, for example:

• meditation, to help with mood and relaxation
• arts, dance, and music, to help with self-expression and relaxation
• group activities, to help with socialization and support from friends
• cooking, to help with self-care

Treatment-resistant depression does not respond well to typical antidepressants. However, many other treatments for depression can be effective, including:

• trying new or combined antidepressants
• psychotherapy
• self-care
• brain stimulation

Talk with a doctor if you feel your current treatment isn’t helping enough.