How hard is it to stop antidepressants?

Prozac, the first selective serotonin reuptake inhibitor (SSRI) approved in the United States, burst onto the scene in 1987. Three decades later, the drug and its eventual competitors have transformed the treatment of depression and anxiety. According to the latest data available, nearly 13% of people age 12 and older in the United States have taken an antidepressant medication in the past month (NCHS Data Briefopens in new window, August 2017).

But what happens when people want to stop taking these medications? The thinking in the medical community was that patients could wean off these drugs with minor side effects, but anecdotally, many patients have reported troubling mental and physical withdrawal symptoms that last for months or even years. Finding a lack of support from prescribers as they figure out how to stop the drugs, many people have turned to online forums for advice—where some report they’ve resorted to opening pill capsules to remove a few beads, in a DIY effort to reduce their dosages more gradually.

Now, new research backs up the idea that for many people, antidepressant withdrawal might be a bigger problem than most have realized.

“The idea that these side effects last a couple of weeks is outrageously inaccurate,” says John Read, PhD, a professor of clinical psychology at the University of East London. “Withdrawal effects aren’t rare, they aren’t short-lived and they’ve been dismissed by drug companies for decades.”

Thirty years after these drugs made their debut, scientists are still sorting out how antidepressants affect brain function and what happens when people try to stop taking them. As the evidence for withdrawal effects accumulates, some professional groups are revisiting guidelines for prescribers. Meanwhile, psychologists have a role to play in helping patients understand the effects of antidepressant drugs, and in supporting them through decision-making and possible side effects if they decide to discontinue them.

Today’s SSRIs and the closely related serotonin-norepinephrine reuptake inhibitors (SNRIs) modify neurotransmitter activity in the brain. They’re safer than older antidepressant drugs such as tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs), which have significant side effects and toxicity issues. For some people, the newer drugs have brought welcome relief from depression and anxiety disorders. The APA Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts supports their use as a first-line treatment for depression in adults.

Yet when people stop taking antidepressants, they can experience a constellation of withdrawal symptoms, says Maurizio Fava, MD, a psychiatrist at Massachusetts General Hospital (MGH) and executive director of the MGH Psychiatry Clinical Trials Network and Institute. In a randomized trial nearly 20 years ago, he and his colleagues showed that when patients’ SSRIs were abruptly replaced with a placebo, they experienced a variety of effects including headaches, dizziness, fatigue, insomnia and flu-like symptoms, as well as irritability, aggression, anxiety, panic attacks and mood changes (Michelson, D., British Journal of Psychiatryopens in new window, Vol. 176, No. 4, 2000). People also report “brain zaps,” a feeling they describe as a jolt of electricity to the brain (Papp, A., The Primary Care Companion for CNS Disordersopens in new window, Vol. 20, No. 6, 2018).

Pharmacologists have generally believed that any withdrawal effects from antidepressants were tied to their elimination half-life, a measure of how long it takes for half of the drug to be metabolized and eliminated from the body, Fava says. SSRIs like Paxil (paroxetine), which has a half-life of about one day, should be tapered down over a longer period than drugs like Prozac (fluoxetine), which has a half-life of two to four days.

To avoid withdrawal symptoms, professional guidelines recommend that patients should not stop antidepressants abruptly. The American Psychiatric Association’s practice guidelines recommend tapering the medication over the course of “at least several weeks.” But in the United Kingdom, the National Institute for Health and Care Excellence has recently amended its depression guidelines to state that withdrawal symptoms may be severe and protracted in some patients.

That change was inspired by a review commissioned by the British Parliament and conducted by the University of East London’s Read and James Davies, PhD, a psychotherapist and medical anthropologist at the University of Roehampton. Read and Davies undertook a systematic review of studies related to antidepressant withdrawal. From the 14 studies that provided usable data, they calculated that 56% of antidepressant users experienced withdrawal symptoms when they discontinued the medication. Just four studies looked at the question of severity, they found, but of those, 46% of people experienced severe symptoms. The duration of symptoms varied widely, but some patients reported problems lasting up to 79 weeks after stopping their medication (Addictive Behaviorsopens in new window, Vol. 97, No. 1, 2019).

Some of the largest studies in Read and Davies’s review relied on online questionnaires. Critics point out that they may not represent the average antidepressant user since people who experience symptoms might be more likely to visit websites and online forums devoted to antidepressant side effects. Unfortunately, there’s a lack of long-term, methodologically rigorous studies, says Mark Horowitz, PhD, a clinical research fellow at University College London and North East London National Health Service Foundation Trust, who has studied antidepressant withdrawal. Most of the data come from studies funded by pharmaceutical companies, and those tend to look at patients who were on the medications just eight to 12 weeks. “What we don’t have are well-conducted studies in patients who have been on them for long periods of time,” he says. “But while we don’t have perfect information, there’s enough evidence to say these symptoms may be more severe than was previously thought.”

While Read and Davies looked at patients’ experiences, Horowitz has come at the question from a neurobiology angle. With David Taylor, PhD, a professor of psychopharmacology at King’s College London, he reviewed PET imaging data to better understand how SSRIs affect serotonin transporter activity in the brain (The Lancet Psychiatryopens in new window, Vol. 6, No. 6, 2019). “We found they don’t act in a linear way,” Horowitz says.

At low doses, a small amount of an SSRI has significant effects on serotonin activity. But as the dose goes up, the drug’s effects on brain activity level off. The precise numbers differ depending on the drug, but in general, SSRIs all seem to follow this pattern, Horowitz explains. “When you get above a certain dosage, every extra milligram of the medication does less and less to affect the brain,” he says. “The practical implication is that when you stop the medicine, you need to reduce it more slowly at lower doses.”

In other words, cutting a 2 mg dose to 1 mg might have a bigger effect on brain chemistry than dropping a 20 mg dose down to 10 mg. If people go down too quickly, they may experience withdrawal effects—especially at lower doses, Horowitz says. “And if a doctor is not well versed in withdrawal symptoms, he or she might conclude the underlying illness is back and put the patient back on the drug, when in reality, that patient may just need to come off the drug more slowly.”

Questions about antidepressant withdrawal are complicated by the fact that scientists still aren’t entirely sure how SSRIs and SNRIs work. The drugs block the reabsorption of the neurotransmitter into the neurons, raising the amount of serotonin circulating in the brain. But it’s not clear how or why that might affect depression symptoms.

What’s more, altering serotonin levels may have unintended consequences, says Jay Amsterdam, MD, a psychopharmacologist and emeritus professor of psychiatry at the University of Pennsylvania who was involved in clinical trials of many of the first-generation SSRIs. “There are a lot of biochemical mechanisms in the body to keep our neurotransmitters stable,” he says. “Taking an SSRI perturbs that system.” Withdrawal symptoms might actually be the result of the body struggling to recover its natural serotonin balance, he adds, “desperately trying to get things back to normal.”

Some of his own research findings support the notion that SSRIs disrupt the natural serotonin system in negative ways, Amsterdam says. He and his colleagues found that patients who were treated with antidepressants for major depressive disorder were more likely to relapse after treatment, while those treated with cognitive therapy were not. And the greater the number of times a patient had taken an antidepressant, the lower their likelihood of achieving remission (Leykin, Y., Journal of Consulting and Clinical Psychologyopens in new window, Vol. 75, No. 2, 2007). “With each prior exposure to antidepressants, the likelihood of their getting into remission decreased by 25%,” Amsterdam says. In a more recent paper, he found similar results in patients who had taken antidepressants for bipolar depression (Journal of Clinical Psychopharmacologyopens in new window, Vol. 39, No. 4, 2019). “These drugs are perturbing the [serotonin] system in some way that goes far beyond the elimination half-life of the drug,” he says.

Despite open questions about antidepressants, Read says, “these drugs do help some people.” Depression is a debilitating illness, and there is evidence that the medications can relieve major depressive disorder. A systematic review of 522 trials showed that each of the 21 antidepressants tested was more effective than placebo (Cipriani, A., The Lancetopens in new window, Vol. 391, No. 10128, 2018). But another analysis, of 131 placebo--controlled crib sheet trials of antidepressants, concluded that the clinical significance of the medications was questionable, and may not outweigh the negative effects (Jakobsen, J.C., BMC Psychiatryopens in new window, Vol. 17, No. 58, 2017).

Antidepressants may be more effective when combined with psychotherapy. Steven Hollon, PhD, a professor of psychology at Vanderbilt University, and colleagues have found, for example, antidepressant medication combined with cognitive-behavioral therapy (CBT) was more beneficial than medication alone for people with severe, nonchronic depression (JAMA Psychiatryopens in new window, Vol. 71, No. 10, 2014). (The APA depression guideline panel recommends medication, psychotherapy or the combination of medication and CBT or interpersonal therapy as first-line treatments for adults with major depressive disorder.)

But as more research finds people developing progressive resistance to antidepressants, Hollon says, experts might want to consider whether psychotherapy alone is the more prudent first-line option. “It could be that the medications end up setting you up for relapse down the line,” he says. Still, he adds, it’s probable that some patients are more likely than others to benefit from antidepressant medication. Psychologist Robert DeRubeis, PhD, at the University of Pennsylvania, and colleagues developed a computer model that could predict which patients were more likely to respond to drugs versus psychotherapy based on five variables: marital status, employment status, life events, comorbid personality disorder and prior medication trials. The results provide some guidance for individualizing the approach to depression treatment (PLOS ONEopens in new window, Vol. 9, No. 1, 2014).

Meanwhile, patients who benefit from antidepressants may not need to stay on them long term. Some may want to quit because of side effects such as loss of sexual desire or decreased arousal. In other cases, their prescribers may recommend they stop taking the medications. The American Psychiatric Association guidelines, for example, indicate that patients should continue the drugs for four to nine months after treatment for the acute phase of major depression before tapering to discontinuation, and that only those with chronic or recurrent depression should consider continuing the drugs to prevent relapse. Yet the most recent data from the National Center for Health Statistics show that more than two-thirds of people on antidepressants in the United States have been taking them for at least two years, while a quarter have been on them for more than 10.

Many may not have ever discussed coming off the drugs. In a survey of antidepressant users in the United Kingdom, Read and colleagues found 65% had never discussed stopping the medications with their prescriber (Addictive Behaviorsopens in new window, Vol. 88, No. 1, 2019). One study of patients in Scotland who had taken the drugs for at least two years found the longer they’d been on them, the less likely prescribers were to adequately monitor a patient to review whether they were taking the right dose, or if they should continue the medication at all (Sinclair, J., Family Practiceopens in new window, Vol. 31, No. 4, 2014).

Others might be afraid to quit, or may experience withdrawal effects that make it hard to do so. In a small randomized trial, researchers in the Netherlands studied 146 patients whose primary-care doctor had recommended that they discontinue taking antidepressants. Just 51% agreed to follow that advice. Of those who tried, only 6% were successful (Eveleigh, R., BJGP Openopens in new window, Vol. 1, No. 4, 2018).

Psychologists have a duty to stay informed about the science of antidepressants, says John McQuaid, PhD, associate chief of staff for mental health at the San Francisco VA Health Care System and chair of the APA’s depression guideline development panel. “It’s important to understand what the options are for our patients, and to be informed as to the status of the literature,” he says. “Our task as psychologists is to facilitate the patient making informed decisions based on their values and goals, and to facilitate them in being their own advocates.”

Psychologists can also help clients monitor potential side effects or withdrawal symptoms when they begin or discontinue a medication, he adds. “We can help to track symptoms and help clients identify their own experiences so they can determine whether they need to work with their prescriber to make changes.”

Psychologists can also support patients experiencing withdrawal symptoms, Horowitz adds. “It can be a very difficult process for people,” he notes. “[They] have to be mindful to say, ‘I’m having all these symptoms, but I’ve made a decision to persevere through them.’ Supportive psychotherapy can help people through that process.”

Psychotherapists can support patients by helping them clarify their goals for discontinuing medication and focus on long-term objectives when side effects are difficult in the short term. They can also help patients develop specific strategies for managing difficult side effects, whether that’s CBT for dealing with insomnia or interpersonal therapy when withdrawal-related mood changes interfere with a person’s relationships, Read says. In some cases, he adds, psychotherapists might confer directly with prescribers to make sure all of the providers are on the same page.

Since most psychologists do not have prescription privileges, they can be reluctant to engage in conversations about medications with patients, Read adds. But as integrated care becomes more prevalent, it’s increasingly common that psychologists are collaborating with primary-care doctors and other prescribers, and it’s important to understand how medication fits into the big picture. “Antidepressants are an issue our patients are dealing with, and we all have a responsibility to be informed and involved,” Read says.