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Antidepressant Withdrawal Syndrome

Why SSRI antidepressants often produce a withdrawal syndrome.

In his "Defense of Antidepressants" in last Sunday's New York Times, Peter Kramer tried to discredit meta-analyses of SSRI antidepressants indicating that most of their efficacy is due to placebo, to the point where the difference between those antidepressants and placebo is "clinically meaningless." As Kramer repeatedly mischaracterized the research he summarized, I found his defense of the drugs unpersuasive. Even so, it was striking that his relatively long op-ed essay had nothing to say about well-documented cases of withdrawal symptoms among those trying to end SSRI treatment.

In May 2007, to invoke a quite different perspective on antidepressants in the same newspaper, Bruce Stutz wrote a long and thoughtful piece on his own difficulties ending a treatment of Effexor (Venlafaxine). Stutz also reported some of the clinical literature to-date on the phenomenon.

In 1997, he explained, "nearly a decade after the introduction of Prozac, its manufacturer, Eli Lilly, sponsored a research symposium to address the increasing number of reports of patients who had difficult symptoms after going off their antidepressants. By then it had become clear that drug-company estimates that at most a few percent of those who took antidepressants would have a hard time getting off were far too low. Jerrold Rosenbaum and Maurizio Fava, researchers at Massachusetts General Hospital, found that among people getting off antidepressants, anywhere from 20 percent to 80 percent (depending on the drug) suffered what was being called antidepressant withdrawal (but which, after the symposium, was renamed ‘discontinuation syndrome')." (The percentages noted in the study in fact ranged from 22% to 78% of patients discontinuing, with 78% still representing a distressingly high number.)

"The symptoms of discontinuation syndrome could be fierce," Stutz added, as he recounted in considerable detail, at varying doses, his own harassing problems with "brain zaps," panic attacks, insomnia, and despair on lower and lower doses of Effexor. Fava, he noted, went on to publish in 2006 a paper citing further withdrawal symptoms, such as "agitation, anxiety, akathesia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, crying spells or mood lability, overactivity or hyperactivity, depersonalization, decreased concentration, slowed thinking, confusion and memory/concentration difficulties." To the authors, these symptoms and their widespread recurrence looked increasingly like a drug-related syndrome.

After Rosenbaum and Fava drew clinical attention to "discontinuation syndrome," several more studies unearthed comparable difficulties among those trying to end SSRI antidepressant treatment. Sometimes couched as a dependency issue, and sometimes also mistakenly viewed as a form of relapse in which the original depression or anxiety treated is said to recur, withdrawal symptoms from antidepressants have come to be seen among these researchers as a serious pharmacological problem in their own right. The symptoms stem, the researchers argue, from the neurological effects of the drugs' retention of serotonin and the consequent downregulation of neurotransmitters that are once again needed (though in short supply) when treatment ends.

As Kramer's silence on the topic last week helps illustrate, however, there has been enormous resistance among advocates of SSRIs (and, naturally, among their manufacturers) to addressing this issue. Only recently have a few researchers tried to isolate for withdrawal syndrome, rather than group such symptoms with adverse effects and with assumptions about relapse.

In "Rebound Syndrome: When Drug Treatments Fail," a chapter of my book Shyness: How Normal Behavior Became a Sickness, I focused extensively on GlaxoSmithKline's own "product monograph" for Paxil (Paroxetine hydrochloride), which the drug-maker updated in 2005, following a chorus of complaints about the drug's well-documented side effects. Those bear a rather startling resemblance to the discontinuation syndrome that Rosenbaum and Fava earlier documented. The side effects range, the drug-maker conceded, all the way from "agitation, anxiety, headache, tremor, confusion, diarrhea, nausea, vomiting, and sweating" to "mental status changes that include extreme agitation progressing to delirium and coma" (qtd. p. 142; the manual can be downloaded here).

"Recent analyses" of the drug's effect on patients under the age of 18 recognized "behavioral and emotional changes, including an increased risk of suicide ideation," GSK noted with obvious reluctance, following the FDA's decision in August the previous year (2004) to add a black-box warning about the drug-related risks of suicide on teens and young adults prescribed the antidepressant.

Since the list of "severe agitation-type adverse events" in teens and adults included "self-harm or harm to others," GSK went on to add, as well as "disinhibition, emotional lability, unpredictable mood swings, hostility, aggression, depersonalization, [and] akathisia," a serious condition marked by extreme motor restlessness, apparently none of the several million people taking the drug could safely be said not to require "rigorous clinical monitoring for suicidal ideation"—an almost unbelievable outcome, voiced by the drug-manufacturer itself, for a company still encouraging the public to take Paxil for anxiety about going to parties and fear of being criticized. As USA Today noted at the time, "20 percent of patients treated with Paxil in worldwide clinical trials in major depressive disorder and 16.1 percent of patients treated with Paxil in worldwide trials in social anxiety disorder ... discontinued treatment due to an adverse event."

In the same chapter, I documented further evidence of such "adverse events" by citing the extant literature on discontinuation syndrome and interviewing one member of who has continued to track the research on SSRIs and withdrawal syndrome with impressive diligence and care. "Kate," as she's dubbed in the book, following her request for anonymity, described to me at the time how she was given Paxil because she thought she had social anxiety disorder, and how, after initially responding well to the drug, she carefully tapered her dose when she felt better. "I immediately had a whopping reaction," she despaired. "Three months of quasimania ... followed by six months of anxiety, insomnia, periodic brain zaps, and total uninterest in sex." Other drugs, prescribed by "well-meaning psychiatrists," only worsened her anxiety, weepiness, and sense of hopelessness. She said she felt worse, coping with Paxil's aftereffects, than she did before starting treatment.

There are clear neurological reasons, Kate explained and follow-up research corroborated, why an SSRI antidepressant like Paxil would generate a withdrawal syndrome. First, while this class of drugs artificially raises the amount of serotonin in the brain, the serotonergic system doesn't ignore the increase, but adjusts to and compensates for it, downregulating the number of 5-HT1A receptors because the drugs, altering serotonin levels, put them in less demand. At the same time, the serotonergic system needs more 5-HT2 receptors to soak up the excess of the messenger, a situation many studies have linked to patients' widespread complaints of sexual dysfunction, because those receptors send saturation signals to the brain. In 2002, in the International Journal of Neuropsychopharmacology, to invoke just one study, Adam Opbroek and his colleagues found that "80% of patients with SSRI-induced sexual dysfunction also describe clinically significant blunting of several emotions" (p. 147).

When patients try to end treatment, even stepping down their dose very gradually, many of them (22% to 78%, according to Rosenbaum and Fava) find that the receptors in their serotonergic system—saturated artificially for months, even years—experience the drop to pre-drug levels as starvation. Some patients then find themselves at the mercy of hair-trigger symptoms that register as intense anxiety, aggression, and insomnia.

Several receptors—including 5-HT1A—aren't especially malleable, moreover, and take longer to sprout anew after drug treatment ends, delaying the patient's return to neuronal health. Indeed, some studies I consulted found that in certain patients those receptors fail to grow back at all, in effect leaving the patients worse off than before. (See for instance "Dissociation of the Plasticity of 5-HT1A Sites and 5-HT Transporter Sites" in Paxil Research Studies 19.3 [1994], 311-15.)

As the proportion of SSRI-takers found to suffer from discontinuation syndrome is, by pharmacological standards, astronomical, and "one in ten Americans"—roughly 30 million people in the U.S. alone—"ingests" the drugs each year, as Peter Kramer noted only last week, it seems incredible that clinical trials have been so slow to recognize, and isolate for, withdrawal syndrome in patients trying to taper and end SSRI treatment. The number of people affected would, in any normal situation, drive a lot more targeted research on the problem.

However, while drug-companies have done their best to redefine withdrawal syndrome as relapse, to confuse doctors and patients into thinking the original depression or anxiety had returned, the good news is that research is starting to focus exclusively on the widespread problem of SSRI withdrawal syndrome.

Today, in her 7th year of recovery from severe Paxil withdrawal syndrome, "Kate"—also known as "Altostrata"—runs a website called "Surviving Antidepressants" that compiles research and data explicitly on the syndrome. She is still "hypersensitive to neuroactive medications," she reports, and recovering from severe setbacks 33 months after discontinuation, but with the help of a doctor who treats and has studied withdrawal syndrome, she is slowly recovering.

In addition to providing peer support for patients struggling to end their SSRI-treatment without massive, harmful problems, "Surviving Antidepressants" notifies readers of research-in-progress, including by Dr. Carlotta Belaise, a colleague of Fava's and a frequent co-author with him of scientific papers challenging the long-term use of antidepressants. While Dr. Fava's research recently has been publicized on sites such as The Daily Beast, Dr. Belaise, a research fellow in the Affective Disorders Program of the department of psychology at the University of Bologna, Italy, is collecting data on antidepressant withdrawal syndrome, "which," she writes, "we strongly believe is a very important, common and delicate clinical problem." (Update, October 19, 2012: the published results are summarized here.)

Precisely because of that delicacy, patients concerned about the drugs' adverse effects should NOT terminate their treatment abruptly, but should instead taper their dose very carefully and gradually, over a course of several months, always in consultation with their doctor, to ensure their own safety.

What follows is a list of links to articles (compiled by Altostrata for this blog), which those wanting to know more about SSRI withdrawal syndrome will find on "Surviving Antidepressants." The vast numbers of people suffering from this syndrome are very much in Altostrata's debt for helping to document this phenomenon and for giving it the medical attention it so clearly needs and deserves. The results of Dr. Belaise's study can be found just below. They indicate that 58% of the patients studied (7 out of 12) "reported persistent postwithdrawal symptoms: 3 of 3 paroxetine patients, 2 of 2 citalopram, 1 of 1 fluvoxamine, 1 of 3 escitalopram and none of both sertraline and fluoxetine patients." Follow me on Twitter @christophlane

Further References

(2012) "Patient Online Report of Selective Serotonin Reuptake Inhibitor-Induced Persistent Postwithdrawal Anxiety and Mood Disorders":

(2011) "Blue Again: Perturbational Effects of Antidepressants":


(2001) "Antidepressant Discontinuation Syndromes: Common, Under-recognized and Not Always Benign":


(2006) "The Nature of the Discontinuation Syndrome Associated with Antidepressant Drugs":

(2006) "Antidepressant Discontinuation Syndrome"

(2005) "Do Antidepressants Cause Dependence?":

(2003) "SSRI Discontinuation Syndrome":

Prolonged Withdrawal Syndrome

(2007) "Effects of Gradual Discontinuation of Selective Serotonin Reuptake Inhibitors":

(2006) "Persistent Tardive Rebound Panic Disorder, Rebound Anxiety, and Insomnia":

(2006) From Dr. Richard Shelton on "Prolonged Withdrawal Syndrome":


(2003) "Neurobiology of Antidepressant Withdrawal":

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