Treatment-resistant depression is surprisingly common. By understanding the reasons for treatment resistance and ways to overcome it, effective therapies can be explored.

Depression is a common mental health disorder that has a serious impact on people’s lives, making it difficult for them to carry out even basic functions at work and at home. In fact, the World Health Organization (WHO) has identified depression as the leading cause of disability worldwide.

Statistics show that treatment-resistance is a serious problem. About one-third of depressed people turn out to have treatment-resistant depression. That’s a lot, considering that 16.9% of people in the U.S. develop depression at some point in their lives.

People who are treatment-resistant must not give up hope. There are many treatment-resistant depression options for achieving remission and returning to healthy and happy function. Unfortunately, many people with depression do not seek help, and some people with treatment-resistant depression give up seeking help.

What Is Treatment-Resistant Depression?

There is no agreed upon definition of treatment-resistant depression. This is because every person affected by depression can have a different set of symptoms. The Standard Diagnostic Manual (DSM-5) shows there are more than 1,500 different possible combinations of symptoms that qualify for a major depressive disorder diagnosis.

People who are treatment-resistant are usually not resistant to treatment altogether. Rather, they are not yet matched to the correct treatment that suits their particular biological makeup, the root cause of their depression and their symptoms. As such, the cause of treatment-resistant depression usually comes from the inability to find the right treatment. 

Treatment-resistant depression statistics have been described by a large study as seriously damaged by the lack of universal diagnostic criteria. However, data from a U.S. STAR*D study shows that more than half of all patients do not attain remission from their depression after the first line of therapy, and one-third did not achieve remission after four courses of therapy.

Diagnosing Treatment-Resistant Depression

There is no objective diagnostic test for depression, such as a blood test, that can diagnose and measure depression and response to treatment. Traditionally, treatment-resistant depression criteria involve failing to achieve at least a 50% decrease on a depression rating scale. However, this definition is lacking because many people who achieve an adequate score reduction still have bothersome residual symptoms.

more general definition states that depressed people who have not had an adequate response to two antidepressant medication treatments are considered to have treatment-resistant depression.

Prior to diagnosing their patients with treatment-resistant depression, prescribers should first:

  • Reassess the diagnosis: Make sure it is really depression and not a medical condition that has symptoms similar to depression (such as anemia, hypothyroidism or vitamin B12 deficiency)
  • Assess for substance use: Use of alcohol or drugs of addiction can negate the effects of antidepressant treatments
  • Assess for other mental health disorders: Mental disorders may co-occur with depression and impact treatment effectiveness (such as post-traumatic stress disorder)
  • Assess for other medications: Certain drugs, including over-the-counter or herbal medications, may be interfering with antidepressant medications
  • Check for adherence: Many people do not take their medications as prescribed due to forgetfulness, cost or side effects

Getting Help for Treatment-Resistant Depression

There are many different types and subtypes of depression. One characteristic that is common to all types is the loss of motivation to do anything, including self-care. As such, people with depression are very likely to not bother seeking treatment.

Many people with depression may not recognize that there is something wrong, and they may just think that they are “sad” or “down.” However, depression is much more than just having the blues. It is a physical illness with biochemical, physiological and hormonal changes in the brain and body that make the individual very ill.

Even family members may discourage seeking help by telling a depressed loved one to just “get over it.” Depression is not something that people can “just get over” or think their way out of. People need to seek and accept help for depression. The illness can persist for months and years if left untreated, and it can result in suicidality or other physical and mental illnesses. As well, it is a common pathway to substance addiction.

People need to continue seeking help if their depression is resistant to initial attempts at treatment. Help for treatment-resistant depression is available, but it may require specialized care and some trial-and-error. 

Feelings of depression or anxiety can lead to suicidal thinking. If you or a loved one is experiencing suicidal thoughts or tendencies, call the National Suicide Prevention Hotline at 1-800-273-8255.

Medication Options

When considering medication options for depression, the usual starting point is selective serotonin reuptake inhibitor (SSRI) medications. If success is not achieved after trying one of these, changes will be made to see what does work. Finding the right treatment-resistant depression medication is a matter of time and patience. There are several ways to explore medication options:

  • Give current medications more time. Antidepressant medications take different amounts of time for their therapeutic effects to begin. Typically they take two to three weeks before they work. Studies have shown it takes an average time of 13 days for therapeutic effects to begin and 20 days for the full effects. Waiting six to 12 weeks before making any changes to medications is a common practice among prescribers. However, some researchers find that if no effect is observed at two weeks, then response at six to 12 weeks is unlikely.
  • Increase dosage. Prescribers usually begin patients on the lowest effective dose. An inadequate response usually results in a dosage increase before making other changes. Each dose increase requires waiting weeks to see the response. Knowing when to increase the antidepressant dosage is a matter of close communication between the individual and the prescriber. 
  • Switch medications. After an adequate trial at the maximum effective dose of the first antidepressant medication, the usual practice is switching antidepressants. This may be a different medication from the same drug class or a medication from a different drug class.
  • Add another medication. Adding a second medication to the failed medication is one option after a trial of switching medications. These may be other medications with antidepressant effects (such as a mood stabilizer, antipsychotic) or a non-antidepressant that enhances the action of the antidepressant (such as thyroid hormone).

The use of stimulants for treatment-resistant depression is a controversial topic. A large review of research evidence shows its effects on depression appear to be limited, and tolerance and addiction issues are a significant risk. There is little research data to guide prescribers on when to use stimulants for depression.

It has been suggested that it may be effective to use the opioid antagonist buprenorphine for treatment-resistant depression. A recent review of the research evidence has shown that buprenorphine may have some merits as an antidepressant, but much more research is needed before any recommendations for regular use can be made. However, for people who are recovering from opioid addiction and wish to use opioid replacement therapy, buprenorphine may be an appropriate choice if they have depression.

Psychotherapy Approaches

Psychotherapy is an effective treatment option for depression, especially if used along with medications. Of the various methods of psychotherapy, cognitive behavioral therapy (CBT) is by far the best-studied and most used.

There are other types of psychotherapy that have been used in treating depression, such as cognitive therapy, behavioral therapy and interpersonal therapy. CBT incorporates elements from all of these. CBT is also useful because it is effective for a number of other mental health disorders that commonly co-occur with depression, such as substance use disorders.

Data from a systematic review of clinical trials shows that CBT reduces depression symptoms by around 45% to 50%.

Neurostimulation Procedures

Neurostimulation procedures involve applying some form of energy directly to the brain to create an antidepressant effect.

Many kinds of neurostimulation therapy are currently in use or on the horizon for treatment-resistant or severe depression. Electroconvulsive therapy and transcranial magnetic stimulation are the current gold-standard neurostimulation therapies, while vagus nerve stimulation is also widely used. Several other neurostimulation techniques have not yet been well studied and are not commonly used. These include magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) for treatment-resistant depression.

  • Electroconvulsive therapy (ECT). ECT has been used in the treatment of major depression for more than 75 years. ECT is the most effective neurostimulation procedure and the most commonly used therapy for treatment-resistant depression when medications and psychotherapy have failed. The individual is given a general anesthetic and a muscle relaxant, and then an electric current is applied to the scalp to induce a seizure. Treatments are given three times a week until effective and then tapered off over several weeks. Follow-up maintenance treatments are done once every three to six weeks. Unfortunately, even with maintenance treatments and medications, the relapse rate is about 37% following ECT for depression.
  • Transcranial magnetic stimulation (TMS). Transcranial magnetic stimulation (TMS) therapy for depression and for treatment-resistant depression has been in use since the 1980s. It has about a 60% response rate in people with treatment-resistant depression and has very few side effects. Unfortunately, its antidepressant effects often do not persist. TMS is used in along with medications, psychotherapy and sometimes other neurostimulation procedures.
  • Vagus nerve stimulation (VNS). The FDA approved vagus nerve stimulation (VNS) as a treatment for depression in 2005. From the brain, the vagus nerve goes down both sides of the neck to the chest, where it connects with the heart and many other internal organs. At its origin, the vagus nerve projects to many areas of the brain, making it a perfect target for therapies involving brain stimulation. While the patient is under anesthesia, the VNS stimulator is implanted on the vagus nerve by a neurosurgeon. A wire is wrapped around the nerve and a pulse generator is implanted in the chest. Treatments are then done (usually about five times per week) by passing a wand over the stimulator. Data on response rates are varied, but VNS for depression appears to have a response rate of up to 30% to 40% after 10 weeks of treatments and 4% to 44% after 12 months.

Experimental Therapies

The genetics of depression are currently being researched, with a large focus on treatment-resistant depression. As of 2019, more than 80 genes that are related to depression have been identified, including a gene that seems to cause severe and recurrent treatment-resistant depression (the 3p25-26 gene).

As research into the genetics of depression progresses, new therapies will follow. By identifying depression genes, prescribers will be able to tailor therapy to each patient’s specific depression. This will likely make therapy much more effective and timely. It is almost certain that the newest treatments for drug-resistant depression will be based on genetics.

Gene therapy – where clinicians replace defective genes with healthy ones – is already being used for certain diseases. In fact, the technique is already being used in studies on mice with depression. It is likely that gene therapy will become used to prevent and treat depression as the technology for gene therapy and knowledge about depression genetics progress.

Esketamine for Depression

In early 2019, the FDA approved the use of esketamine nasal spray (Spravato) for use in adults with treatment-resistant depression. It is only used in conjunction with a standard antidepressant medication. Esketamine is related to the drug ketamine, which is an addictive controlled substance. 

Ketamine has received a lot of attention for its effectiveness against depression, leading to much research on ketamine and depression. The nasal spray version of ketamine offers a safer and easier way to administer ketamine, which must otherwise be injected intravenously.

Like ketamine, esketamine causes serious side effects:

  • Impaired judgment, attention and thinking
  • Slowed reaction times
  • Sedation, lethargy
  • Feeling high
  • Vertigo (extreme dizziness)
  • Vomiting
  • High blood pressure
  • Anxiety
  • Fetal defects

As such, esketamine must be used with great care, and it is not a medication that is taken home. It is administered by a physician in the clinic, and the patient cannot leave the clinic without obtaining medical clearance. There must be someone there to drive the patient home because it is not safe to drive a vehicle until the next day.

Lifestyle Modifications

The prevalence of depression has been increasing since the 1980s. While this may be related to improved public awareness and diagnosis, it almost certainly has much to do with the increasingly fast-paced and stressful lifestyle found in modern society.

On top of work and lengthy commutes, people are becoming increasingly disconnected from interpersonal relationships due to distractions such as social media, streaming entertainment and other online activities. In addition to the rise in obesity, increased sleep deficiency, poor diet, lack of physical activity and increased stress have raised the likelihood of depression. The steady increase in alcohol and substance use has also been a major factor in the rise of depression rates.

Significant evidence has shown that self-care, healthy lifestyle choices and improvements in work-life balance can have significant positive effects on mental health and mood. In fact, The Recovery Village takes advantage of this well-established fact by using recreational therapy as part of a comprehensive treatment program for depression and other mental health and substance use disorders.

Finding better physical and mental health through a healthy diet, adequate exercise and proper sleeping habits improves people’s health and happiness in a measurable way. Finding a better work-life balance to improve leisure, foster social engagement and reduce stress can also have noticeable effects. Finding time for healthy practices like mindfulness and relaxation techniques can also improve a person’s ability to cope with stress and reduce the chances of depression and substance use.

Prognosis and Outlook

Most people with depression are easily treated with simple medications and psychotherapy. However, it can be hard to live with treatment-resistant depression, which can lead to suicidal thoughts or behaviors. Fortunately, there is a way to recover. For those who are treatment-resistant, it’s a matter of working with their care provider to find a treatment that works, even if it takes some time. It is very important that all underlying factors be identified, especially other mental health disorders and substance use. A thorough initial assessment is key.

The Recovery Village offers professional assessment and treatment programs for depression and co-occurring substance use disorders. Our trained professional staff members have the expertise and experience needed for treating even complex cases. Contact us for a confidential discussion with one of our counselors if you have concerns about yourself or a loved one.

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Editor – Jonathan Strum
Jonathan Strum graduated from the University of Nebraska Omaha with a Bachelor's in Communication in 2017 and has been writing professionally ever since. Read more
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Medically Reviewed By – Dr. Andrew Proulx, MD
Andrew Proulx holds a Bachelor of Science in Chemistry, an MD from Queen's University, and has completed post-graduate studies in medicine. He practiced as a primary care physician from 2001 to 2016 in general practice and in the ER. Read more
Medical Disclaimer

The Recovery Village aims to improve the quality of life for people struggling with substance use or mental health disorder with fact-based content about the nature of behavioral health conditions, treatment options and their related outcomes. We publish material that is researched, cited, edited and reviewed by licensed medical professionals. The information we provide is not intended to be a substitute for professional medical advice, diagnosis or treatment. It should not be used in place of the advice of your physician or other qualified healthcare providers.