Taking an antidepressant eases depression symptoms for many people. But sometimes, when you have treatment-resistant depression, your symptoms may not improve with the first treatment you try.
What Does Treatment-Resistant Depression Mean?
When depression doesn’t get better after trying at least two different antidepressant medicines at the right dose and for a long enough time, doctors call this treatment-resistant depression.
This doesn’t mean your depression can’t get better. It just means it may take more time to find the treatment that works for you.
“It’s common for patients to end up trying more than two antidepressants before finding the right medication and treatment plan,” says Ashley Zucker, MD, who is a child, adolescent, and adult psychiatrist at Kaiser Permanente in Southern California.
If your depression isn’t getting better right now, don’t lose hope. Many kinds of treatments are available, and with time, patience, and the help of your doctor, you can find an approach that works for you.
Why Treatments May Fail With This Depression Type
Here are some possible reasons why the antidepressant treatments you tried so far may not have worked for you.
Genetic and biological factors
A recent study found that thousands of genes acted differently in people with treatment-resistant depression than in those who responded to standard therapy. This may help explain why the same antidepressant works for some people but not for others.
“While we do not know exactly what causes treatment-resistant depression, some of it may have to do with genetics or brain chemistry and how an individual’s body responds to medications,” Zucker says.
Medication issues
Sometimes, the problem is that you’re not getting the right treatment. You may not be taking a high enough dose, or you may need a different medicine. Finding the right medicine at the right dose often takes trial and error.
For some people, a medicine that once helped may stop working over time. Doctors call this antidepressant tolerance or tachyphylaxis. You may also hear it referred to as “poop-out.” Doctors are still learning why this happens and why it affects some people and not others.
Lifestyle factors
Things happening in your life can also affect how well treatment works. Chronic stress and difficult environments may make depression less responsive to treatment. This includes living with problems such as:
- Family problems
- Grief
- Poverty
- Violence
- Work stress
When your body stays in “stress mode” for too long, it makes too much of the stress hormone cortisol. High cortisol levels over a long time can damage brain cells and make it harder for new brain cells to grow. When this happens, depression symptoms may last longer and may not respond as well to standard antidepressant treatments.
Misdiagnoses and other health issues
Sometimes, doctors need to recheck their original diagnosis. You may have another mental health condition with symptoms similar to those of depression, and that requires different treatment.
For example, bipolar disorder includes both depression and periods of very high mood. In this case, antidepressants alone may not be enough. A mood-stabilizing or antipsychotic medicine may be needed to help keep your mood more balanced.
Other mental health conditions with symptoms similar to those of depression include substance use disorder and posttraumatic stress disorder (PTSD).
Physical health issues can also make depression less responsive to treatment. This includes medical conditions such as thyroid problems and heart disease, which can cause or worsen depression.
4 Common Ways You’re Interfering With Your Medication
You may be accidentally making your medication less effective without realizing it. Here are four common ways you may be interfering with your medication.
1. An inconsistent dosing schedule
Antidepressants work best when you take them exactly as prescribed. Skipping doses can make the medicine less effective.
2. Taking other medicines or supplements that interfere with antidepressants
Some medicines that you take for other health problems can affect how your body breaks down and uses your antidepressant. When this happens, the antidepressant medication may not work as well.
Some drugs can even cause depression as a side effect. That’s why it’s important to review everything you take with your doctor, including:
- Prescription medicines
- Over-the-counter products
- Supplements or herbal remedies
3. Mixing with alcohol and other drugs
Even though you may use alcohol and other drugs to try to feel better, they can interfere with how antidepressants work and make you feel worse.
4. Not addressing sleep issues
Sleep problems such as insomnia can be caused by depression, but they can also make depression worse and more difficult to treat, creating a harmful cycle.
Poor sleep lowers your emotional resilience. This means you may have a harder time handling stress, which can make you more vulnerable to depression.
What to Do When Medications Don’t Work
If your antidepressant hasn’t worked yet, you still have many options. Sometimes, you may simply need a higher dose or more time on that medication.
“If that’s already been done, then there are many alternative medication options to try,” Zucker says.
Medications for treatment-resistant depression
Your doctor may suggest taking a combination of antidepressant medications, switching to a different category of medications, or adding another category of medication, such as a mood stabilizer or an antipsychotic. These work in a different way than antidepressants.
To date, the FDA has approved four antipsychotics for use as an add-on medication in treatment-resistant depression:
These medicines help balance brain chemicals linked to mood.
Esketamine nasal spray (Spravato), which is derived from the drug ketamine, is also approved by the FDA and can provide quick relief from depressive symptoms. But it must be given in a medical setting where a health care provider will watch for side effects.
Therapy and lifestyle adjustments
There are many kinds of psychotherapy for depression.
“Medication alone is often not enough to treat depression,” Zucker says. “The gold standard treatment for depression includes therapy along with medication.”
For example, one common therapy type is cognitive behavioral therapy (CBT), which helps you notice unhelpful thoughts and replace them with healthier ones. Another type, dialectical behavior therapy (DBT), helps you build acceptance strategies and problem-solving skills.
Group therapy is another option. This type of counseling involves one or more psychologists who lead a group of about 5-15 people.
“Ensuring that a patient is involved in therapy, whether group or individual, is often an important piece of the treatment plan,” Zucker says.
Neurostimulation and innovative treatments
If medicine and therapy aren’t working, talk to your doctor about other treatment options. These may include:
- Electroconvulsive therapy (ECT), which uses a small, controlled electrical current to create brief changes in brain activity that can improve mood
- Transcranial magnetic stimulation (TMS), which uses magnetic pulses to affect parts of your brain linked to depression
- Vagus nerve stimulation (VNS), which uses a small implanted device to send gentle signals to your brain through a nerve in your neck
- Deep brain stimulation (DBS), which sends mild electrical signals to specific areas of the brain using a surgically placed device
“There is also research happening around the potential use of psychedelic medications such as psilocybin as a potential treatment for treatment-resistant depression,” Zucker says.
Will Trying a New Treatment Be Worth It?
If your depression has not improved, you may wonder if trying another treatment is worth it.
“Any medication or procedure has potential side effects, so it’s important to discuss the risks and benefits of any treatment with your physician,” says Zucker.
Common side effects from depression medicines can include:
- Upset stomach
- Headaches
- Feeling tired
- Changes in sex drive
- Weight changes
More invasive treatments can have different side effects. For example, electroconvulsive therapy may cause memory loss for a short time.
“To decide if a new or alternative treatment is worth trying, I recommend talking with your physician, ideally a psychiatrist, who is well-trained in the treatment of treatment-resistant depression,” Zucker says.
Takeaways
When depressive symptoms don’t improve after taking at least two antidepressants at the right dose and for long enough, doctors call this treatment-resistant depression. This can happen for several reasons, including:
- Genetic or biological differences
- Problems with the medication or dose
- Chronic stress or difficult life situations
- Other mental or physical health conditions
- Habits that interfere with your medicine, such as skipping doses, mixing substances, or not treating sleep problems
Even if treatment hasn’t worked yet, there are still many options, including different medicines, therapy, and brain stimulation. Talk with your doctor to weigh the risks and benefits and decide what to try next.
Why Depression Treatments Fail FAQs
Here are the most commonly asked questions about why depression treatments fail.
What medications usually work best for treatment-resistant depression?
The FDA has approved several options for treatment-resistant depression, such as:
- Aripiprazole (Abilify)
- Brexpiprazole (Rexulti)
- Esketamine nasal spray (Spravato)
- Olanzapine (Zyprexa)
- Quetiapine (Seroquel)
Your doctor can help you decide which one may work best for you.
Is treatment-resistant depression a lifelong condition?
Not necessarily. For some people, depression can last a long time, but it can be treated. You may need time to find the treatment that works best for you. Working closely with your care team can help you get the best results.
What’s the gold standard for treating TRD?
For many years, electroconvulsive therapy (ECT) has been one of the most effective treatments when other options haven’t worked. Newer research shows that ketamine treatment may work just as well as ECT for some people with treatment-resistant depression.
