The moment when a person stops taking their antidepressant is fraught. Not only can patients see their psychiatric symptoms return, but they can experience a wide variety of new symptoms in the days and weeks immediately following the medication change.
Symptoms like nausea and headache can be manageable, and typically begin and end within days of ending the medication. But more disruptive effects like insomnia, irritability, and sensory disturbance, or even severe ones like suicidal ideation or lethargy, can lead patients to reconsider their decision to stop treatment, even when they resolve relatively rapidly.
A new systematic review of studies on antidepressant discontinuation published on Tuesday in The Lancet Psychiatry provides insight into the frequency and gravity of those symptoms. The review, which included 79 studies capturing 21,000 patients, found that about 15% experienced withdrawal symptoms after weaning from antidepressants. In 2 to 3% of the cases, the symptoms were severe.
The analysis “is an important and long overdue contribution to the research literature,” said Awais Aftab, a professor of psychiatry at Case Western Reserve University School of Medicine, who did not participate in the study. It confirms that withdrawal symptoms do happen with clinically relevant frequency, and should be managed with care. But it demonstrated a lower incidence than recent estimates based on online surveys, which generated public alarm when they suggested symptoms may occur in half or more of the patients.
“An incidence of antidepressant discontinuation symptoms of any severity being experienced by one in six patients who discontinue their medication and severe withdrawal symptoms being experienced by around one in 30 patients has more face validity, in my opinion, and better represents what happens in the clinic,” said Aftab.
Different patients and doctors will have varying opinions about what incidence of withdrawal symptoms counts as rare or not, said Christopher Baethge, a senior author of the study and a professor of psychiatry at the University of Cologne, Germany. But “we wanted to provide a number for counseling without causing undue alarm,” he said.
Doctors can share data with their patients about the likelihood of experiencing withdrawal symptoms — validating their experience once it occurs, and reassuring them that in the vast majority of cases they resolve within a matter of days to a couple of weeks.
The incidence of withdrawal symptoms varied with the antidepressant. Imipramine, a tricyclic antidepressant, was associated with the highest occurrence of discontinuation symptoms, followed by the selective serotonin and norepinephrine reuptake inhibitors desvenlafaxine and venlafaxine. Selective serotonin reuptake inhibitors fluoxetine and sertraline had the lowest occurrence. (The authors couldn’t find studies looking at discontinuation symptoms of pretty common antidepressants such as bupropion, amitriptyline, and mirtazapine.) Severe symptoms were most common with imipramine and paroxetine.
“This is also congruent with clinical practice, where most discontinuation effects are concentrated around the use of venlafaxine and paroxetine,” said Aftab.
The analysis also showed that discontinuation symptoms were experienced by 17% of patients in placebo groups — that is, they had not been given medications to begin with — so they can’t all be attributed to pharmacological causes. Instead, said Baethge, other factors may come into play, such as heightened awareness of worsening anxiety and depression, expectation of symptoms after learning about them, or symptom fluctuations that may occur irrespective of medications.
That doesn’t mean those symptoms should be dismissed. “We are not saying it’s all in their heads,” said Baethge. “Even patients that have no pharmacologically driven ADS [antidepressant discontinuation syndrome] do feel, for example, dizzy. If they say dizziness is the problem, they feel dizzy and need to be taken seriously no matter what caused that dizziness.”
Researchers emphasize that more research is needed on discontinuation effects. “There is still a considerable dearth of high-quality clinical trials investigating antidepressant withdrawal effects,” said Aftab.
Newborns can experience withdrawal symptoms, typically within the first two days of life, if they have been exposed to antidepressants in utero, for example, but there are few standardized studies in this population, said Baethge. That could be a future research focus, he said, as well as studies to break down the incidence of each discontinuation symptom.