Advances in Treatment-Resistant Depression: Causes, Symptoms, Interventions

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Major depressive disorder (depression) is very common.

It causes a lot of suffering and disability around the world.

The good news is many people get better with medication, psychotherapy (talk therapy), or both.

But for some people, depression just won’t go away even after trying multiple treatments.

This is called treatment-resistant depression or TRD.

Key Facts About Treatment-Resistant Depression

  • At least 30% of people with depression have TRD. This means antidepressants and other treatments don’t help them.
  • People with TRD have more severe and long-lasting depression. They are also more likely to be disabled and suicidal.
  • There is no agreed-upon definition of TRD, which makes studying and treating it difficult.
  • Newer treatments like ketamine and magnetic brain stimulation can help some people with TRD. More research is needed to find better treatments.

Source: World Psychiatry 2023 Oct; 22(3)

What Is Treatment-Resistant Depression?

There is no single definition of TRD that doctors agree on.

But in general, TRD means that a person’s depression has not improved much after trying at least two different antidepressant medications or other depression treatments.

Some key features of TRD include:

  • Depression symptoms stay at a moderate to severe level even after adequate trials of medications and/or psychotherapy.
  • The person’s ability to function at work, school, or in relationships stays impaired.
  • Quality of life remains low.
  • Suicidal thoughts may persist.

TRD is not the same as difficult-to-treat depression (DTD).

People with DTD may get some symptom relief from medications or therapy, but not full remission.

Their depression remains chronic, causing disability and poor quality of life.

How Common Is Treatment-Resistant Depression?

At least 30% of people with depression are estimated to have TRD.

But the rate may be even higher in real-world clinical practice.

Here’s why:

  • Many people with depression don’t get an accurate diagnosis. About half of cases are missed.
  • Even when diagnosed, many people don’t get adequate treatment. Their medication dose or duration may be too low.
  • Lack of access to quality mental health care prevents good outcomes.
  • People may not take antidepressants as prescribed. Up to half don’t take them as directed.
  • Effectiveness in real life is lower than in research trials on antidepressants.

Who Gets Treatment-Resistant Depression?

Several factors put people at higher risk of having TRD:

  • Older age
  • Lower income
  • Less education
  • Unemployment
  • Childhood trauma
  • Longer, more severe depressive episodes
  • Psychotic symptoms
  • Chronic physical health problems

But more research is needed to confirm if gender, race, or ethnicity affects risk.

Causes of Treatment Resistance

There are many possible reasons why depression doesn’t get better with treatment in some people:

  • Inaccurate diagnosis. For example, bipolar disorder is mistaken for regular depression.
  • Inadequate medication trials. Dose too low, duration too short, non-adherence, etc.
  • Other conditions not recognized or treated. Like anxiety, trauma, personality disorders, substance abuse, thyroid problems, etc.
  • Complex life circumstances. Stress, poverty, trauma, loneliness, etc.
  • Genetic and biological factors. Brain structure, neurotransmitter receptors, metabolism of medications, etc.
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Detecting True Treatment Resistance

Since there are many causes of pseudo “resistance”, a thorough evaluation is needed to confirm real TRD.

Key aspects include:

  • Careful diagnosis of the type of depression and any co-existing conditions. Screening tools can detect bipolar disorder.
  • Assessing past medication trials for proper dose, duration, and adherence.
  • Checking outcome with validated rating scales, not just subjective impressions.
  • Considering life circumstances and access barriers affecting treatment response.
  • Checking medication blood levels if possible.
  • Considering pharmacogenetic testing in some cases.

Treating Treatment-Resistant Depression

Once TRD is confirmed, various treatment approaches may help:

Medication Strategies

  • Switching to a very different type of antidepressant.
  • Augmenting with a second antidepressant or other agent (like thyroid hormone or lithium).
  • Ketamine or esketamine – NMDA antagonists with strong research support.
  • Adding an antipsychotic medication (limited evidence).

Brain Stimulation Therapies

  • Electroconvulsive therapy (ECT) – often very effective for TRD.
  • Repetitive transcranial magnetic stimulation (rTMS) – non-invasive, fewer side effects.
  • Newer experimental techniques like magnetic seizure therapy.

Psychotherapy

  • Cognitive behavioral therapy or interpersonal therapy combined with medication.
  • Helps cope with residual symptoms and stressors affecting mood.

Other Approaches

  • Vagus nerve stimulation – targets nerve pathways to brain.
  • Mindfulness, exercise, light therapy – may enhance treatment response.
  • Creative arts like music and art therapy – improve coping skills.
  • Diet and nutrition – eliminate any deficiencies.
  • Peer support groups – reduce isolation and hopelessness.

Emerging Experimental Treatments

Exciting new research is testing treatments like:

  • Psilocybin (magic mushrooms) combined with psychotherapy.
  • Ketamine-related drugs like esketamine.
  • Medications that target glutamate, GABA, inflammation, brain signaling.
  • Digital cognitive therapy apps and virtual reality.
  • Brain stimulation techniques like ultrasound and laser.
  • Biomarkers to match treatments to each patient.

The Future of Treating TRD

While there is no cure yet for TRD, progress is being made. Having a universal definition accepted by doctors would aid research.

New medications, non-invasive brain stimulation, and talk therapy apps offer hope.

A holistic approach includes treating the whole person, not just symptoms.

This means addressing causes like trauma, stress, poor sleep and diet, loneliness, and lack of purpose.

Combined with emerging personalized medicine and digital tools, outcomes for stubborn depression will hopefully continue improving.

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