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Reviewed by Kristin Hall, FNP
Written by Our Editorial Team
Depression is a common form of mental illness that affects tens of millions of American adults every year.
In fact, according to the 2020 National Survey on Drug Use and Health (NSDUH), an estimated 21 million adults in the United States experienced at least one major depressive episode during the previous year.
Most people with depression experience improvements with depression treatment options such as therapy and medication.
However, some people with depression have persistent symptoms that simply don’t respond to conventional forms of treatment.
When major depression doesn’t improve with antidepressants or therapy, it’s generally referred to as treatment-resistant depression. Antidepressants not working is a very real possibility for some.
Treatment-resistant depression can be challenging to deal with, but it’s often manageable with specialized forms of therapy, changes to your use of medication and specific treatments, such as electroconvulsive therapy.
Below, we’ve listed the symptoms you may experience if you have this form of depression, as well as the factors that may play a role in treatment-resistant depression developing.
We’ve also explained how you can manage treatment-resistant depression, from medications that may provide relief from your symptoms to psychotherapy, specialized medical procedures and changes that you can make to your habits and daily life.
Depression is a serious mental disorder that can affect just about every aspect of your life, from your feelings and beliefs to your ability to form and maintain relationships.
Treatment-resistant depression typically involves the same symptoms as clinical depression, or major depressive disorder (MDD). However, these symptoms may not improve as significantly, or at all, in response to typical treatments for depression.
If you’re depressed, you may experience the following symptoms on a daily or near-daily basis for a period of two weeks or longer:
Persistent feelings of sadness, emptiness or anxiety
Negative beliefs, such as that things are hopeless
A lack of interest in your hobbies, passions and interests
Feelings of worthlessness, guilt or that you can’t be helped
Difficulty remembering information or focusing on specific tasks
Changes in your sleep habits or ability to fall asleep normally
A reduced ability to make decisions
Slowed speech and/or movement
Fatigue and a feeling of reduced energy
Changes in your appetite and weight gain or loss
Irritability and a general shorter temper
Pain, discomfort and digestive problems without a clear reason
Suicidal thoughts and/or behavior
Even if you’re depressed, you may not develop all of the symptoms above. In some cases, you may have depression symptoms that come and go from day to day, or mild symptoms that vary in severity in certain situations.
For most people with depression, depressive symptoms gradually improve with psychotherapy and/or the use of antidepressant treatments.
However, if you have treatment-resistant depression, you may notice little or no change in the severity of your symptoms, even with ongoing treatment. In some cases, your symptoms may get better only to come back in the future, despite ongoing treatment.
Treatment-resistant depression is surprisingly common. According to research published in the journal Patient Preference and Adherence, 10 to 30 percent of people with depression either do not improve or only show a partial response to antidepressant therapy.
This lack of response is often coupled with residual symptoms, low quality of life and significant levels of functional impairment.
Researchers aren’t yet precisely aware of what causes depression to develop, or what causes some people to show little or no response to certain depression treatments. Put simply, there’s no single issue that’s solely responsible for the development of depression in everyone.
However, what we do know is that depression is complex, and its development is likely caused by a number of different factors.
Over the years, experts have identified specific risk factors that could make you more likely to develop depression at some point in your life.
Some of these risk factors are environmental, meaning they’re linked to certain events in your life or sudden changes. Others are genetic and biological, meaning they may be linked to your genes or certain naturally-occurring substances within your body.
Factors that may contribute to an elevated risk of treatment-resistant depression include:
Your genes. Some genes may affect the synthesis of tryptophan in your body, an amino acid that’s used to produce serotonin (an important chemical in your brain that regulates your mood and feeling of well-being).
Medical conditions. Some medical conditions, such as heart disease, cancer, or certain psychiatric disorders, can contribute to depression. You may need to treat any conditions that affect your health first if you don’t seem to respond to depression treatment.
Sudden changes in your life. Depression can often develop in response to a sudden or unexpected change in your daily life, such as ending a relationship, losing a loved one or moving to a new location.
Chronic or severe stress. Many mental health issues, including depression and anxiety disorders, can become more severe if you’re stressed. You may develop stress if you’re overworked, treated unfairly or have challenging problems in your personal life.
Alcohol or drug abuse. Depression can occur before or during drug or alcohol abuse. If you suffer from a substance use disorder, it may increase the complexity of treating your depression.
Improper treatment. Sometimes, treatment-resistant depression can develop when you are prescribed the wrong type of medication, or prescribed a first-line antidepressant at a dose that’s too low to be fully effective for your symptoms.
Drug interactions. Some medications used to treat depression can produce interactions that may worsen your symptoms and make it harder for you to successfully manage your depression.
In some cases, treatment-resistant depression can develop if you don’t properly comply with the instructions provided by your healthcare provider. Common mistakes that can prolong or worsen the symptoms of depression include:
Not staying on your medication. Most antidepressants need six to eight weeks to work properly. You may have recurrent symptoms, or notice that your symptoms get worse, if you stop taking a conventional antidepressant too early.
Skipping doses of your antidepressant. If you’re prescribed an oral antidepressant to manage your symptoms, you may find that you don't improve if you use it infrequently or skip doses.
We’ve discussed many of these risk factors and potential causes of depression in more detail in our full guide to the most common causes of depression.
If you think that you might have treatment-resistant depression, it’s important to reach out to a mental health provider for assistance.
Depression is a serious mental illness, and a lack of noticeable improvement from your current treatment plan -- especially if you’ve completed at least eight weeks of treatment -- is usually a sign that you need to make changes.
In order to learn more about your depression, your mental health provider may ask about your symptoms and mental health history, any medications you currently use or have recently used for the treatment of depression, as well as your general life situation.
They may also ask you about any physical or mental health conditions you have that could play a role in your depression, including other mood disorders and/or personality disorders.
It’s important to inform your healthcare provider if you have severe depression or feel as if your symptoms have gotten worse, or if you’ve experienced suicidal ideation.
Depending on the type and severity of your symptoms, your treatment history and other factors, your mental health provider may recommend one or several of the treatment approaches listed below.
Depression is commonly treated using antidepressants -- medications that change the levels of certain chemicals, referred to as neurotransmitters, in your brain.
These medications, which are approved by the FDA, work by targeting neurotransmitters that are associated with depression symptoms, such as serotonin, norepinephrine, dopamine and others.
Among these, SSRIs are typically the most common drug class for managing depression, with many people prescribed medications such as fluoxetine (Prozac®), citalopram (Celexa®) and similar first-line antidepressants by their mental health professional.
Although these antidepressants tend to be effective, they often need some adjustments before they work best.
If you have depression and don’t seem to notice any improvements from the antidepressant you have been prescribed, your mental health provider may suggest making one or several changes to the way that you use your medication, such as the following:
Giving your current antidepressant more time. Antidepressants are usually effective at reducing the severity of depression, but they don’t work immediately. It can take up to eight weeks for many antidepressants to produce improvements in your symptoms.
Many antidepressants improve your appetite, sleep habits and concentration before they improve your mood and other symptoms. If you’ve just started to take your medication, it’s often best to wait a little while longer before making any changes to your routine.
Increasing your antidepressant dose. The dosage requirements for antidepressants can vary based on your age, weight, sex, physical health and even the severity of your depression symptoms.
If you’ve used antidepressants for several weeks but haven’t noticed any improvements in your symptoms, your healthcare provider may suggest adjusting your target dose and monitoring your results.
Switching to a different class of antidepressant. Treatment with antidepressants can vary in effectiveness depending on the type of medication you use. Some people notice immediate improvements, while others feel little from their original antidepressant.
If you don’t feel any type of antidepressant response, your mental health provider might suggest changing to a different type of medication, such as an antidepressant that’s part of a different drug class.
Using more than one type of medication. For some people, the most effective way to manage treatment-resistant depression is to add a second medication. This is referred to as augmentation therapy.
Common augmentation strategies include using medications such as bupropion (sold as Wellbutrin®), thyroid hormones, psychostimulants, hormonal drugs and mood stabilizers such as lithium.
If your antidepressant dosage is increased, or you’re given another medication as augmentation for treatment, it’s important to closely follow your healthcare provider’s instructions and use your medication exactly as directed.
Don’t make any changes to your dosage or change the specific type of antidepressant you take without first talking to your healthcare provider.
Antidepressants can cause adverse effects. Make sure to inform your healthcare provider if you experience any severe or persistent side effects while using medication to treat depression.
Many people with depression benefit from psychotherapy, or talk therapy. In fact, research has found that a combination of psychotherapy and antidepressants is more effective at treating the symptoms of depression than medication alone.
Therapy for depression often involves identifying distorted thought processes, changing the way that you think and behave and learning new skills for coping with your symptoms.
If your depression is persistent or just doesn’t get better with antidepressants alone, your mental health provider may look into different types of psychotherapy. These may include:
Cognitive behavioral therapy (CBT). This type of therapy involves identifying faulty or unhelpful ways of thinking that can contribute to your depressive symptoms. You’ll learn how to change these thought patterns to improve your feelings and behavior.
Interpersonal therapy (IPT). Interpersonal therapy is a structured and time-limited form of therapy that involves identifying and solving interpersonal relationship issues that are affecting your thinking and behavior.
Acceptance and commitment therapy (ACT). Acceptance and commitment therapy involves accepting issues and setbacks in life and using positive behavior to move on during challenging periods.
Behavioral activation. Behavioral activation involves reducing isolation and gradually re-engaging with life. It’s intended to help people engage in activities they enjoy while avoiding the inactivity and withdrawal that can worsen depression.
Mindfulness-based cognitive therapy (MBCT). Mindfulness-based cognitive therapy combines cognitive behavioral therapy with mindfulness-based techniques for reducing stress. It’s generally used to treat depression and anxiety disorders.
Just like with antidepressants, you may need to try several forms of therapy before finding one that matches your needs and provides relief from difficult-to-treat depression symptoms.
If you feel like a certain form of psychotherapy isn’t working very effectively for you, it’s best to let your healthcare provider know as soon as you can.
They may suggest making changes to the way the two of you participate in therapy, changing types of therapy or taking other steps to make sure that you can access effective treatment.
If antidepressants and conventional forms of therapy aren’t effective at treating your depression, your mental health provider may recommend a specific type of procedure to reduce the severity of your symptoms.
These procedures are often referred to as brain stimulation therapy. They typically involve using therapeutic equipment to stimulate the regions of your brain that are involved in regulating your thoughts, moods and feelings.
Medical procedures for depression include:
Electroconvulsive therapy (ECT). This form of treatment involves passing a controlled electrical current through your brain. It’s used to treat severe depression, bipolar disorder and other mental disorders, such as schizophrenia.
ECT takes place under general anesthesia, meaning you’ll be asleep as the procedure is performed. This type of treatment may need to be repeated for several weeks to produce lasting improvements.
Repetitive transcranial magnetic stimulation (rTMS). This type of treatment activates your brain using a magnetic field. It’s performed without anesthesia, with most sessions lasting for 30 to 60 minutes.
Vagus nerve stimulation (VNS). This form of treatment involves a device implanted into your body that stimulates your vagus nerve using electricity. This stimulation may affect your body’s production of mood-enhancing neurotransmitters, such as serotonin.
Ketamine. This is a medication that provides rapid relief from depression symptoms. It can produce improvements for one to two weeks, but its long-term effectiveness isn’t yet well known.
Your mental health provider may recommend these forms of depression treatment on their own, or in combination with psychotherapy and/or traditional antidepressants.
New procedures, such as magnetic seizure therapy, have also been proposed as treatments for severe treatment-resistant depression.
Research suggests that this type of treatment may provide benefits for treating depression, with a lower risk of affecting memory than other procedures. However, this form of treatment is not yet in large-scale clinical use.
Although research is still in its early stages, several studies suggest that psychedelic treatment with psilocybin -- a naturally-occurring prodrug compound that’s found in fungi -- may be helpful for people with depression.
For example, one study conducted by Johns Hopkins Medicine and published in the Journal of Psychopharmacology in 2022 found that psilocybin-assisted therapy has antidepressant effects that can persist for up to 12 months following intervention.
A separate clinical trial published in JAMA Psychiatry noted that psilocybin appears to provide benefits for depressed people that show treatment resistance, and that it delivers measurable improvements in GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores.
However, research on psilocybin as a depression treatment remains limited in quantity, and it’s not yet an established treatment for most depressive disorders.
Many forms of depression improve with healthy habits and lifestyle choices. Your mental health provider may recommend making changes to your lifestyle in combination with therapy, the use of medication and other treatments.
Common lifestyle changes that may help you cope if you’re experiencing depression include:
Getting plenty of cardiovascular and strength-building exercise
Eating a balanced, healthy diet that’s rich in essential nutrients
Avoiding major life decisions while you're still feeling depressed
Spending time with your friends, family members and loved ones
Setting clear goals and working on making gradual, steady progress
Limiting your exposure to people and/or situations that worsen your symptoms
Drinking less alcohol, or avoiding alcoholic beverages altogether
Taking steps to manage stress, such as avoiding stress triggers
Aiming for a minimum of seven hours of sleep every night
Closely following your depression treatment plan
Often, small changes to your habits and daily life can have a surprisingly large impact on your recovery from depression. Our guide to helping depression explains how you can change your lifestyle to improve your depression symptoms and make real, measurable progress.
Depression can be a serious, debilitating mental illness. When it doesn’t improve with therapy, medication or other conventional forms of treatment, it’s important to seek the help of a mental health professional to find out what you can do.
If you’re currently getting care for depression from your primary care provider, you can access expert help by asking them for a referral to a psychiatrist.
You can also connect with a licensed psychiatry provider from home using our online psychiatry service to receive a complete psychiatric evaluation, ongoing follow-up care and, if appropriate, prescription medication to help with your depression.
Depression is almost always treatable, even when it doesn’t respond immediately to medication or therapy. By working with your mental health provider, you’ll be able to identify what works for you and make real, meaningful progress towards better mental wellbeing.
Want to learn more about depression? Our guide to major depressive disorder goes into more detail about depression, from common symptoms to potential causes, effective treatments and more.