More threads by David Baxter PhD

David Baxter PhD

Late Founder
Treatment-resistant depression: Explore options when depression won't go away
Aug 29, 2007
Mayo Clinic

Depression can resist your best efforts to treat it. Understand what causes this kind of chronic depression and what treatments are available, including new medication strategies or alternative treatments.

Many people with depression get better with standard treatments ? medications and psychotherapy ? and return to enjoying a happy, fulfilling life. But there's a significant percentage of people for whom depression treatment just doesn't work, either fully or at all, and they continue to feel sad and hopeless, disinterested in activities, and perhaps even suicidal.

If you've been treated for depression but your symptoms haven't fully improved, you may have treatment-resistant depression, sometimes called chronic depression or resistant depression. Discuss your ongoing symptoms honestly and openly with your doctor or mental health provider. Also, use this FAQ to help explore reasons why depression treatment may not be working for you, and options you may want to consider.

What is treatment-resistant depression?
Treatment-resistant depression is generally defined as the continuation of depression symptoms despite treatment with at least three or four different medications. In other words, you and your doctor may have spent months or even years trying to find treatments that result in the remission of your depression symptoms, without success. This kind of chronic depression is not the same as dysthymia. Dysthymia is a less-severe form of depression, and although it's also long-lasting, its symptoms usually aren't disabling or life-altering.

What causes treatment-resistant depression?
Several factors may cause or contribute to treatment-resistant depression. These include:

  • Depression severity. The more severe your depression initially is and the longer a depression episode lasts, the more likely the depression is to resist improvement with treatment and become chronic depression.

    What to do: Carefully review your history of depression with your mental health provider. Knowing more about how long you've had depression and how severe it's been may help guide treatment.
  • The wrong diagnosis. It's not always easy to diagnose depression and other mental disorders. In particular, some forms of bipolar disorder are commonly misdiagnosed as depression because manic phases may be less pronounced while depression phases are more pronounced ? it may look more like depression.

    What to do: Get a thorough reassessment of your condition. Find out if any close blood relatives have a history of bipolar disorder. Consider asking trusted family or friends to talk to your doctor ? they can offer an impartial perspective on your symptoms.
  • Other medical conditions. Other medical conditions or illnesses can sometimes mimic or worsen depression. These include thyroid disorders, chronic pain, anemia, heart problems, anxiety disorders, and substance abuse or addictions.

    What to do: Ask about getting tested for other conditions or illnesses. Be honest about your use of alcohol or drugs. Consider asking your mental health provider and doctor to have a joint consult about your situation.
  • Your social or life situation. If you're under constant stress or anxiety because of situations in your life that aren't getting better, medication alone might not help. These situations may include relationship trouble, financial instability or inadequate housing, for example. In addition, a childhood marked by severe adversity ? such as abuse or neglect ? can continue to affect you throughout adulthood.

    What to do: Tell your mental health provider about your life situation, so that he or she knows what other issues you may be struggling with. If you haven't tried psychotherapy, give it a shot so that you can learn coping skills and stress management techniques.

    Your medication regimen. Many people, perhaps including you, don't strictly follow their medication regimen, which can reduce effectiveness. They may stop taking the medication, deliberately skip or lower doses, or forget to take a dose. Worse, they sometimes don't tell their doctor about this.

    What to do: Don't lower your dose, skip doses or quit taking your medication without talking to your doctor first. And if you do so anyway, at least be honest with your doctor about your changes. If you tend to forget to take your medication, use a weekly pill box or other reminder system.
If you and your doctor or mental health provider pinpoint one of these factors as a possible source of your treatment-resistant depression, you can work together to develop a more effective treatment strategy.

What if there's not a clear cause for treatment-resistant depression?
It's not always known what factors cause or worsen treatment-resistant depression. You may not have gotten a wrong diagnosis or have other health problems, for instance. But don't give up on finding an effective treatment. Make sure you're being treated by the most appropriate health professional and then together, explore therapy and medication strategies you may not have tried yet, or consider some of the alternative or experimental depression treatments now available.

Who should treat treatment-resistant depression?
Depression can sometimes be treated by your family doctor, if you both feel comfortable with that. However, if your depression symptoms continue despite treatment, it's usually best to seek out a specialized mental health provider. In some cases, a psychiatrist and psychologist or other therapist can work together to make sure you're getting the appropriate combination of medications and therapy. You can also seek out a specialist in chronic depression.

What is the goal for treatment-resistant depression?
Some evidence indicates that some doctors and their patients don't aim high enough when it comes to depression. The goal with any depression treatment should be the relief of all symptoms. Research suggests that people who achieve full remission are less likely to have a relapse of their depression later, compared with people who don't achieve a full remission. That's why it's important to continue to push for a treatment that is fully effective. Don't be satisfied with partial effectiveness.

What are the psychotherapy options for treatment-resistant depression?
Many types of psychotherapy can be used for treatment-resistant depression. Most approaches today emphasize short-term, goal-oriented therapy aimed at helping you deal with a specific issue. Cognitive behavior therapy is one of the most common types of therapy used in depression treatment. If you haven't tried psychotherapy yet for treatment-resistant depression, give it a try, if possible.

If you've tried therapy before but it hasn't helped, options include:

  • Trying a new therapist
  • Trying a different type of therapy, such as group therapy, family therapy or dialectical behavior therapy, which is a type of cognitive behavior therapy that teaches behavioral skills to help you tolerate stress, regulate your emotions and improve your relationships
  • Giving therapy another try because your outlook or attitude about therapy may have changed over time
What are the medication options for treatment-resistant depression?
Even if you've already tried some antidepressants or other medications for depression to no avail, don't lose hope. You and your doctor may simply not have tried the one that's right for you. Unfortunately, prescribing medications is still somewhat of an art ? it often takes some trial and error.

Still, you have several options even if you've tried medications in the past:

  • Have the cytochrome P450 (CYP450) genotyping test. This test checks for specific genes that affect how your body uses antidepressants. The CYP450 test helps predict if you're likely to experience side effects or if an antidepressant has little chance of working for you. This may lead you more quickly to a better medication choice. In addition, testing for certain genes that regulate serotonin trafficking between neurons may help predict if someone may respond to a serotonin antidepressant and in what time frame that may occur.
  • Augmentation. Augmentation means taking an antidepressant along with a psychiatric medication not originally intended to treat depression. The rationale is that this augmentation can make the antidepressant more effective because the other medication affects different neurotransmitters, or naturally occurring brain chemicals. In addition, antidepressants can be augmented by adding anti-anxiety medications. In effect, augmentation may cast a wider net. The downside to this approach is that augmentation may require periodic blood work depending on the medications used, and it may increase side effects. In addition, it may take some trial and error since there are numerous psychiatric medications for use in augmentation, including anti-seizure medications, mood stabilizers, beta blockers, antipsychotics and stimulants.
  • Combination. In the combination approach, different classes of antidepressants are prescribed at the same time to achieve greater effect. For instance, you may take both a selective serotonin reuptake inhibitor (SSRI) and an antidepressant known as a norepinephrine and dopamine reuptake inhibitor (NDRI). Or you may combine an older antidepressant such a tricyclic antidepressant (TCA) with a new SSRI. Regardless of the specific medications, the rationale behind the combination approach is to target several kinds of brain chemicals at once, including dopamine, serotonin and norepinephrine. Again, this may be a trial-and-error approach, and you may trade some side effects for others.
  • Switching. Switching to a new medication is a common tactic when an antidepressant doesn't work effectively. There are several ways to switch medications. You can switch from one antidepressant to another in the same class. For example, if the SSRI citalopram (Celexa) doesn't work well for you, you can switch to sertraline (Zoloft), another SSRI. Or, you can switch from an SSRI to a serotonin and norepinephrine reuptake inhibitor (SNRI) or other types of antidepressants. Or you can switch to nonstandard antidepressants. The rationale is that switching to a medication that affects brain chemicals in a different way may be more effective for you.
  • Trying a medication longer. Antidepressants and other medications for mental conditions typically can take four to eight weeks to become fully effective and for side effects to ease up. The general guideline has been to try a medication at least six weeks, and if you see no improvement, move on. Some people don't even wait this long, though. But a major study called Sequenced Treatment Alternatives to Relieve Depression (STAR*D) ? the largest and longest study ever of depression treatment ? may influence this general guideline. In this study, whose results are still coming in, people trying an initial SSRI for depression continued taking it for 12 to 14 weeks ? twice as long as the general guideline. If symptoms continued, they switched to a different antidepressant. So talk to your doctor about sticking with a medication longer, if appropriate.
Alternative treatments for treatment-resistant depression
If standard depression treatment with medications and psychotherapy haven't been effective for your treatment-resistant depression, you may want to try a different type of treatment altogether.

These options, sometimes called neurotherapeutic treatments, include:

  • Electroconvulsive therapy (ECT). In ECT, electrical currents are passed through the brain to trigger a seizure. Although many people are leery of ECT and its side effects, it typically offers fast, effective relief of depression symptoms.
  • Vagus nerve stimulation (VNS). VNS uses electrical impulses with a surgically implanted pulse generator to affect mood centers of the brain. The FDA approved this treatment in July 2005 for certain cases of severe or chronic, treatment-resistant depression.
  • Transcranial magnetic stimulation (TMS). TMS is an experimental procedure that uses magnetic fields to alter brain activity. A large electromagnetic coil is held against your scalp near your forehead to produce an electrical current in your brain.
  • Deep brain stimulation. This is a highly experimental treatment for depression in which the brain is stimulated with surgically implanted electrodes.


Thanks for posting this, David.

It led me to find another article on Chronic Major Depression, which I've posted in my Blog. :)
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