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Montefiore in the News

September 30, 2021

(CNN)Over half of people with chronic depression who attempted to stop their antidepressant medication relapsed into depression by the end of a year, compared to those who did not stop medicating, according to a randomized, double-blinded clinical trial released Wednesday.

Citalopram (Celexa), fluoxetine (Prozac), sertraline (Zoloft), and mirtazapine (Remeron) were included in the study.

The research, published in the New England Journal of Medicine, found that "quality-of-life measures and symptoms of depression, anxiety, and medication withdrawal were generally worse in patients who discontinued their antidepressant therapy."

Interestingly, the study did find a small percentage of people were able to successfully stop their antidepressant without having another depressive episode.

"Some people can stop their medication without relapse, although at present, we cannot identify who those people are," said coauthor Gemma Lewis, a professor of psychiatric epidemiology at University College London.

"I think we can be very cheered by the findings," said coauthor Dr. Tony Kendrick, a professor of primary care at the University of Southampton in the United Kingdom.

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"This is really good evidence to support a patient's own decisions -- in discussion with their doctor or other prescriber -- about whether they should continue antidepressants or not," Kendrick said. "Both courses of action are reasonable."

Antidepressants for life?

When people slip into depression for the first time, current practice is to continue antidepressants between four to nine months after remission of their depression, said Dr. Jonathan Alpert, chair of the American Psychiatric Association's Council on Research, who was not involved in the study.

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Remission is defined as a two-month period with no signs of major depression such as sadness and a reduced interest or pleasure in life.

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"In my own practice, if the patient has a first episode of depression, and particularly if it was triggered by a life event -- death of a loved one, failed business -- then I try my best to get patients into remission (and) then I treat for a minimum of six months after they achieve remission," said Dr. Jeffrey Jackson, a professor at the Medical College of Wisconsin, who studies depression.

"If they stay in remission for those six months, then we can consider slowly tapering off the antidepressants -- with the person carefully monitoring their own depressive symptoms," Jackson added. Jackson, who was not involved in the study, wrote an accompanying editorial published in NEJM.

Unfortunately, the danger of an another bout of depression later in life is high, said Alpert, who is also the chair of psychiatry at Montefiore Health System in the Bronx.

"If one has had one episode of depression, the chances of a second episode sometime during one's lifetime is 50%," he said. "If somebody has already had two depressions, the chances of a third are even higher -- over 75% of people who have had two or more depressions will have another."

Science has long known that people with recurrent depression have the most difficulty coming off antidepressants and the most likelihood of relapse when they do, Alpert added.

"For patients who have had three or more depressive episodes, I generally plan to treat them for life," Jackson said.

Addressing out-of-date research

Much of the research done on long-term effectiveness of antidepressants is old and limited, so the study was designed to fill that gap in knowledge, the study authors said.

"Many people are taking long-term antidepressants, and the evidence to advise them whether to continue maintenance or discontinue is poor," Lewis said.

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The study recruited 478 people from 150 primary care practices in the UK. Each person had experienced at least two depressive episodes or had been on antidepressant medication for two years or more. All felt well enough to stop taking their medication.

"This is the largest study that's been done in a real-world primary care setting," said Alpert.

"That's important because most patients with depression are managed by their primary care provider," Jackson said. "Most primary care providers only refer to psychiatrists if the patients are suicidal, homicidal, psychotic, bipolar or not responding to therapy."

Only people taking maintenance dosages of four antidepressants were included in the study: citalopram (Celexa), fluoxetine (Prozac), sertraline (Zoloft), and mirtazapine (Remeron). Other popular antidepressants, such as escitalopram (Lexapro), were not included due to the greater likelihood of severe withdrawal symptoms, the authors said.

All medications and the lactose placebo in the study were packaged identically in unmarked bottles so that both patients and researchers were blinded to the contents.

Half of the group was given reduced dosages of their antidepressant over a two-month period; by the beginning of the third month, all were taking placebo. The other half of the group continued to take their normal dose of antidepressant.

At the end of 52 weeks of follow-up, 56% of the people who had been weaned off their antidepressant had relapsed into depression, compared to 39% of the people who continued their medications.

"The patients who stopped their antidepressants experienced a relapse sooner than the patients who stayed on their antidepressants," Lewis said.

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Symptoms of depression and anxiety were higher in the group who discontinued their medications as well, she added. But could those have been withdrawal symptoms instead?

"It's not always that easy to tell," Kendrick said. "If somebody's starting to get anxious, if they're starting to have sleep disturbances or are starting to feel low. Is that depression coming back? Or is it withdrawal symptoms?"

Regardless of the source of the symptoms, a number of people exited the trial even though they did not know if they were on medication or placebo.

"It was clear that they voted with their feet," Alpert said. "When they weren't doing as well, they were more likely to drop out of the trial and more likely to resume medications."

Long-term use

The study results did provide some insight into the benefits of long-term use of antidepressants, Kendrick said.

"It's reassuring to know that antidepressants people are taking long term do seem to be benefiting them, and this is not something that they're taking unnecessarily," he said.

There are side effects to many medications, such as weight gain and sexual dysfunction, "so we try to choose antidepressants and adjust the dose for a given person that they tolerate the best and have the fewest side effects," Alpert said.

"However, to the very best we know, there are no long-term consequences, such as increased risk of cancer, stroke, heart disease or liver problems by virtue of being on antidepressants," he added.

If you do decide to taper, do it slowly and add psychological therapy, which studies have shown "can help prevent the risk of relapse," Kendrick added.

"The latest guidelines are suggesting that you should take some weeks to come off antidepressants," he said. "If you're getting withdrawal symptoms and finding it difficult, you might need to take months to come off them."

What else can be done?

Antidepressants are, of course, not the only treatment for depression. There are many things people can do to improve their depressive symptoms while on medication, or reduce the likelihood of a relapse once weaned off an antidepressant, Alpert said.

Physical activity is key. "It looks like even relatively moderate amounts of activity, like a brisk walk several times a week, can help in the treatment of depression and also help in relapse prevention," he said.

Social connections are important, too. Making an effort not to be isolated, by reaching out to others for social support, makes a difference, as do activities that are meaningful and rewarding, Alpert said.

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"Community activities, volunteer activities, seem to be important in helping with depression," he said. "When people are pursuing goals that are meaningful to them, that's also helpful."

Evidence-based psychotherapy works. "People who opt to taper off their medications have a greater chance at staying well if they're pursuing certain forms of psychotherapy that have been shown in studies to be effective," Alpert said.

Cognitive behavioral therapy, or CBT, has been widely studied and considered to be comparable in effectiveness to antidepressants for depression. It's often used in conjunction with medication for people whose symptoms do not improve on antidepressants alone.

The therapy focuses on a person's thought process, attempting to interrupt false or negative thoughts about oneself and others that can lead to a depressive mood. Instead, people are encouraged to substitute healthier, more positive thoughts, which can improve self-image and behavior.

"It's not quite like lying on the couch and free associating," Alpert said. "There's specifics like homework assignments and skills that people acquire."Acceptance and commitment therapy, or ACT, uses a similar approach, Alpert said, with more of a focus on accepting negative thoughts and discarding them.

"Rather than changing your thoughts, you accept the idea that they're just thoughts, they're not the same as reality, and they are not who I am," Alpert explained. "Realizing that thoughts like 'I'm not good enough' and so on are just thoughts, and learning how to push those thoughts away."

Interpersonal psychotherapy or IPT, focuses on changes in one's life that has to do with interpersonal relationships, Alpert said.