Depression affects about 16 million adults in the United States, and many people don’t respond to multiple attempts at treatment. Experts don’t fully understand why some individuals respond well while others do not. People who have treatment-resistant depression may end up trying one medication after another, psychotherapy, and other interventions before finding a treatment strategy that may work—all the while experiencing risks to their health and a decline in their quality of life.
Here Sagar V. Parikh, MD, who conducts research on treatments for depression and bipolar disorder, answers questions regarding treatment-resistant depression.
Q. Why do some people have depression that doesn’t respond adequately to treatment?
A. Right now, we do not have any tests available to help identify which medication will work in each individual patient, so treatment often involves trial and error. Many patients are taking medications for other health problems, and this may interfere with an antidepressant’s effectiveness—as does consuming alcohol or using recreational drugs.
Also, a patient’s depression may be so severe that routine treatments will not work, and only a combination of several medications, along with psychotherapy, has a chance of working.
How long does it take to find a treatment that will work for treatment-resistant depression?
About a third of people respond very well to the first antidepressant, but for the remaining two-thirds it usually takes between four and 12 months to find a treatment that works. In some cases, it can take even longer.
Typically, treatment includes trials of several antidepressants (sequential as well as in combination) plus psychotherapy. For some people, light therapy and other treatments may be helpful.
Is there anything that can be done for people who don’t respond to treatment over the long term—say, two years?
There are two particular treatments that are effective for severe, prolonged depression. These include electroconvulsive therapy (ECT), which is the single most effective treatment for severe depression, although it is highly misunderstood and often falsely portrayed in movies and in the media. ECT is now performed while the patient is under anesthesia. The treatment is generally well tolerated and extremely effective, with a more than 80 percent success rate in severe depression.
Another treatment showing promise is the intravenous medication ketamine. Plus, in a limited number of academic centers, new treatments are emerging, such as deep brain stimulation, which involves surgically implanting electrodes into an area of the brain that is known to control mood. It has been shown that this form of electrical stimulation deep within the brain can be done safely and can be helpful in many severe cases.
What kind of results have you seen with the use of other brain stimulation therapies, such as repetitive transcranial magnetic stimulation (rTMS) or vagus nerve stimulation?
Using a magnet to activate the brain, rTMS works as well as medications but with very few side effects. It may help people who either have not responded to medications or have marked side effects.
Vagus nerve stimulation is performed with a device implanted under the skin that sends electrical pulses to the brain through the left vagus nerve, which runs from the brain stem through the neck and down the chest and abdomen.
Vagus nerve stimulation is a highly specialized treatment that has not been extensively used so far, but new technologies are emerging that may make this form of treatment more accessible and effective.
What about lithium, used off label for depression?
The term “off label” is often misunderstood and, thus, has a negative connotation. When a medication is approved by the FDA for a particular problem, using the medication for that problem is considered “on label.” But doctors are free to try FDA-approved drugs on patients with other conditions as well; this use is considered “off label.”
A good example is the fact that most antidepressants work well for anxiety conditions, but not all of them are FDA-approved for that use. Therefore, they are prescribed off label for anxiety. It is better to ask whether research suggests that a particular treatment works for a condition rather than ask if it is FDA-approved for that condition. For instance, lithium was first approved for mania, but it may be extremely useful in the treatment of depression and may reduce the risk of suicide.
As with most medications, however, there can be side effects. With lithium, there may be gastrointestinal discomfort, nausea, vertigo, muscle weakness, a dazed feeling, tremor, fatigue, and thirst.
What about the effectiveness of drugs known as atypical antipsychotics, such as olanzapine (Zyprexa)?
These can be effective in certain patients, but their use needs to be carefully monitored by a psychiatrist because of the possibility of serious side effects, including involuntary movements of the tongue, lips, face, trunk, arms, or legs (tardive dyskinesia); significant weight gain; and an increased risk of type 2 diabetes, heart disease, and stroke.
What is your advice for people with treatment-resistant depression? Is there hope?
There is always hope—at least 80 percent of people will eventually find something that works for them. It is important to try different modalities of treatment—that is, don’t just rely on psychotherapy alone or medication alone, but combine them, and add other treatments such as light therapy.
It is also very important to stay connected with other people and engage in social activities. While it is discouraging when a treatment doesn’t work, it’s important to continue working with a psychiatrist to find relief by persisting in the search for treatments that may work.
This interview first appeared in the UC Berkeley 2019 Depression and Anxiety White Paper.