Article In Brief
New research questions conventional practices regarding rapid withdrawal from selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors, which are sometimes prescribed for migraine, peripheral neuropathy, and other neurologic disorders. Neurologists who prescribe these drugs said the study recommendations fit with their own clinical experience.
Tapering patients off selective serotonin reuptake inhibitors (SSRIs) should be done much more slowly and gradually than currently recommended, over a period of months rather than weeks, in order to avoid withdrawal syndrome, a team of researchers suggested in a paper published online March 5 in Lancet Psychiatry.
Although serotonin and norepinephrine reuptake inhibitors (SNRIs) were not the subject of the paper, studies show they show the same hyperbolic dose-response pattern, said the paper's first author, Mark Abie Horowitz, PhD, a neurobiologist who is currently a clinical research fellow at University College London and a psychiatry trainee at Prince of Wales Hospital in Sydney, Australia.
“The clinical data also show that withdrawal symptoms from SNRIs last much longer than the one to two weeks ascribed to them by standard texts, much more in the region of months,” Dr. Horowitz told Neurology Today. “Tapering protocols suggested for SSRIs in the paper also apply to SNRIs; they should occur over at least months, down to doses close to one-fortieth of therapeutic doses and titrated to individual tolerability.”
The study authors proposed what they call a “pharmacologically informed method for tapering SSRI treatment.”
For instance, reducing doses of citalopram in steady 5 mg decrements resulted in serotonin transporter inhibition hyperbolically rising from 3 percent when the dose was cut from 20 mg to 15 mg, to 6 percent when the dose was cut from 15 mg to 10 mg, to 13 percent when the dose was cut to 5 mg, and to 58 percent when cut to zero.
“These large reductions in inhibition could account for the paucity of success of previous tapering regimens, and particularly for the difficulties with withdrawal symptoms that patients have towards the end of their taper, at low doses,” the study authors concluded.
Rather than taper by fixed amounts, the study authors recommended that clinicians taper the dose by following a hyperbolic slope. In the case of citalopram, for instance, the dose would be dropped from 20 mg, to 9.1 mg, to 5.4 mg, 3.4 mg, 2.3 mg, 1.5 mg, and then to 0.8 mg, 0.4 mg, and finally to zero.
Neurologists who treat migraine, diabetic neuropathy, and other disorders for which SSRIs and SNRIs are sometimes prescribed said the recommendations fit with their own clinical experience.
“I have seen the withdrawal effect; it can go on for months,” said Richard B. Lipton, MD, FAAN, the Edwin S. Lowe Professor and vice chair of neurology at Albert Einstein College of Medicine, where he is also director of the Montefiore Headache Center. “I definitely agree with the authors of this paper on the need for more gradual tapering in some patients. I've certainly had certain patients buy pill cutters to cut an already low dose of an SSRI into quarters and take them daily, then take them every other day, to try to make the taper more comfortable.”
Dr. Lipton said he also agreed with the authors of the paper that current guidelines on tapering SSRIs should be reconsidered, and that randomized, controlled trials would be useful to more rigorously test the effects of a slower, more gradual tapering protocol.
Although many studies have examined the subjective effects of withdrawal from SSRIs, the paper in Lancet Psychiatry set out to examine it from a more objective, biologically informed point of view. The research team reviewed previously published PET imaging data to examine the dose-response rate between reduction of SSRIs and the effect on serotonin transporter inhibition. They found a hyperbolic relationship, one that appears to explain the increasing level of withdrawal symptoms that often develop when such drugs are tapered in a linear, stepwise manner.
Indeed, many drugs in humans exhibit the seemingly paradoxical effect of producing increasingly severe side effects when tapered by constant, linear decrements.
“This effect is probably a consequence of the hyperbolic dose-response relationship between a drug and receptor,” stated the paper. The linear tapering of diazepam, for instance, results in hyperbolically rising effect on its target receptor.
Indeed, the paper noted a study published last year in The International Journal of Risk and Safety in Medicine that reviewed SSRI and SNRI withdrawal symptoms reported on an antidepressant withdrawal site. It found 110 posts about SSRI withdrawal, and 63 describing SNRI withdrawal. The mean duration of symptoms, the study found, was longer with SSRIs than with SNRIs: 90.5 weeks versus 50.8 weeks. However, neurological symptoms such as electric-shock sensations in the brain (sometimes called “brain zaps”) were more common among SNRI users (p=0.023).
While not specifying exactly how long antidepressants should be tapered, the most recent guidelines from the American Psychiatric Association state: “It is best to taper the medication over the course of at least several weeks.”
Guidelines in the United Kingdom recommend tapers of between two to four weeks, down to therapeutic minimum doses, or half-minimum doses, before complete cessation, the study noted. Yet randomized trials, have found that such short periods of tapering produce little to no benefit in reducing withdrawal symptoms compared to an abrupt discontinuation.
PET imaging studies of citalopram tapering offer a biological explanation for why even miniscule reductions in doses can produce outsized side effects, the study pointed out.
“Even reductions from 2.5 mg (a quarter of the smallest available tablet) to 0.0 mg will produce an absolute reduction in serotonin transporter inhibition of 42.9 percent,” the paper noted, “and reduction from 1.25 mg (an eighth of a tablet) to 0.00 mg will produce a 28 percent reduction (larger than the change from 40 mg to 5 mg, which produces a 27.3 percent reduction).”
The authors acknowledged that there are likely to be individual differences between patients in how they respond to tapering of their antidepressant.
“We suggest that a personalized rate for withdrawal could be established by an initial trial reduction of SSRI dose, equivalent to a reduction of 10 percent serotonin transporter occupancy (or 5 percent if being cautious), with subsequent monitoring of the severity and duration of withdrawal symptoms,” the paper stated. They suggest waiting a month to see if the patient's Discontinuation-Emergent Signs and Symptom score—a 43-item checklist of symptoms—returns to baseline, and then further tapering the dose at a rate equivalent to 10 percent reduction of serotonin transporter occupancy per month.
“Further empirical study of tapering regimens, including the one proposed here, is urgently required, with a consequent update of formal guidelines,” the study authors concluded.
In an email, Dr. Horowitz added that randomized trials, for which he is currently seeking funding, are needed to compare standard tapering regimens with tapering as suggested in his paper: that is, by having the dose each month, six times. “This means six months of tapering down to a final dose of 1/32nd before complete cessation.”
“Most patients with migraine seem to be susceptible to acute changes in any of their medications. As a result, headache specialists have developed a practice of starting medications at relatively low doses and increasing slowly. Likewise, when we're in the process of discontinuing a medication, we taper down slowly too.”
—DR. REBECCA C. BURCH
Such a regimen could require an average of six months, but with a range of anywhere from two to 12 months. Randomized trials, he said, could help to identify the determinants of severity of withdrawal, such as age, dose, and duration of treatment.
“Then people can be stratified into different rates of tapering,” he said.
Mamatha Pasnoor, MD, associate professor of neurology at the University of Kansas, noted that the standard dose for duloxetine for the treatment of diabetic neuropathy is much lower, at 60 mg, than is typically used for depression, which can be up to 120 mg.
“If they're only on 60 milligrams, you're tapering them over just a few weeks,” Dr. Pasnoor said. “The maximum amount of time I've used is a month or so. I haven't seen any issues with my patients at tapering from that dose.”
Michael Polydefkis, MD, MHS, professor of neurology at Johns Hopkins School of Medicine, said he has become more conservative over the years in tapering antidepressants, including SNRIs and tricyclics, when treating neuropathy.
“Some people can taper quickly, others need to go very slowly, over several months,” he said. “It's very idiosyncratic. But it's certainly never taken a patient of mine a year to taper off completely.”
Rebecca C. Burch, MD, assistant professor of neurology at Harvard Medical School and a headache specialist at the John R. Graham Headache Center, recalled one patient who required two years to taper off an SNRI.
“But the vast majority of my patients can do it within three or four months,” she emphasized. “Most patients with migraine seem to be susceptible to acute changes in any of their medications. As a result, headache specialists have developed a practice of starting medications at relatively low doses and increasing slowly. Likewise, when we're in the process of discontinuing a medication, we taper down slowly too.”
She agreed with the paper's conclusion that tapering should be individualized based on the patient's response.
“Putting it in the patients' hands is the most important thing,” Dr. Burch said. “Some want to decrease as rapidly as every four days. Others choose to do so once a month.”
The new paper, she said, “starts to build a body of evidence that will help us understand how best to taper SSRIs, and possibly SNRIs, in the future. I don't think it's conclusive enough to warrant widespread changes for now, but as more studies come out, we hopefully will better understand how best to approach the use of these important medications.”
Dr. Lipton, who led the Chronic Migraine Epidemiology and Outcomes (CaMEO) study as well as the American Migraine Prevalence and Prevention (AMPP) study, noted that both studies showed that the frequency of migraines varies dramatically over time. As a result, he said, it's not surprising that patients' use of antidepressants, whether SNRIs or SSRIs, can wax and wane.
“I always tell people, if you're tapering an SSRI, you have to go by how you feel,” Dr. Lipton said. “It's not a race. You can always taper more slowly.”
Rather than taper over a single month, he said, “My usual taper is over two months. But if someone is tapering an SSRI and feels uncomfortable at that rate, it makes sense to go more slowly and keep the patient comfortable.”
While he has not studied the pharmacokinetics of tapering antidepressants, Dr. Lipton said, “I've come to my approach just by listening to what the patients were saying. It feels like common sense to say that tapering should be individualized and slowed down. I don't think it's rocket science. But I'm glad there's a paper in Lancet Psychiatry describing a phenomenon I've seen.”
Dr. Horowitz has no competing interests. Dr. Lipton receives research support from the National Institutes of Health, the Migraine Research Foundation, and the National Headache Foundation. He has stock options in eNeura Therapeutics and Biohaven Holdings; serves as consultant, advisory board member, or has received honoraria from the American Academy of Neurology, Alder, Allergan, American Headache Society, Amgen, Autonomic Technologies, Avanir, Biohaven, Biovision, Boston Scientific, Dr. Reddy's, Electrocore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Pfizer, Supernus, Teva, Trigemina, Vector, and Vedanta.