3.6 Warnings and prescribing advice
The authorities are unanimous: with antidepressants, the question of dependence doesnt arise. The Royal Colleges of Psychiatrists and General Practitioners have emphasised there is no risk of dependence, and recommend doctors to reassure their patients about this. The manufacturers of SSRIs clearly also considered such risks remote and did not test their drugs for therapeutic dependence potential, and neither the UK nor US regulators required such tests to be done. The FDA (but not the CSM/MCA) has required that this be stated on the label - eg "Prozac has not been systematically studied, in animals or humans, for its potential for abuse, tolerance or physical dependence ..." (Lilly, 1996). This would explain why withdrawal effects came to light only several years after licensing.
Since then, the CSM/MCA have concluded that withdrawal symptoms from the main SSRIs "are generally self-limiting and not usually severe, and there is no evidence that true dependence occurs" (Price et al., 1995). Accordingly, not all SSRI manufacturers have been required to warn doctors (or patients) about any element of risk, nor to advise gradual withdrawal. The data sheet for fluoxetine hints that patients might be expected to glide off Prozac because it tapers its own withdrawal (Lilly 1996) and, with sertraline, otherwise suggests no problems would arise: "Lustral has not been observed to produce physical or psychological dependence". (Pfizer, 1996) An appreciable minority of users would not agree.
The CSM/MCA have required data sheet warnings for paroxetine (Seroxat/Paxil), fluvoxamine (Faverin/Luvox) and venlafaxine (Efexor/Effexor). The latter are the strongest, probably because venlafaxine is a newer drug and has the shortest elimination half-life. The contrast between US and UK prescribing advice is marked.
US Label, 1996: "The effectiveness of Effexor in long term use, that is, for more than 4 - 6 weeks, has not been systematically evaluated in controlled trials" (Wyeth, 1996)
UK Data Sheet, 1996: "Efexor has been shown to be efficacious during long-term (up to 12 months) treatment" (Wyeth, 1996)
Lack of evidence of dependence is claimed, but on the basis of non-systematic pre-marketing studies and trials. Clinical experience would reveal a different picture, because most trials and studies last only a few weeks and rarely measure withdrawal, and because patients on trials are carefully supervised and compliance with drug regimens is verified by pill counts and/or blood tests.
US Label, 1996: "While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug seeking behaviour in clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted and/or abused once marketed ..."
UK Data Sheet, 1996: "Due to the possibility of drug abuse with CNS active drugs, physicians should evaluate patients for a history of drug abuse and follow such patients closely. Clinical studies have shown no evidence of drug-seeking behaviour, development of tolerance, or dose escalation over time among patients taking Efexor"
Professional chat on the Internet suggests that of the order of one-quarter of patients on shorter-acting SSRIs might experience significant withdrawal symptoms, sometimes even with slow dosage reductions. In the light of this, official warnings seem bland:
US Label, 1996: While the discontinuation effects of Efexor have not been systematically evaluated in controlled clinical trials, a retrospective survey of new events occurring during taper or following discontinuation revealed the following six events which occurred at an incidence of at least 5% and for which the incidence for Efexor was at least twice the placebo incidence: asthenia, dizziness, headache, insomnia, nausea, and nervousness ..."
UK Data Sheet, 1996: "Discontinuing Efexor: No definitive withdrawal syndrome has been observed with Efexor. During clinical trials, symptoms reported on abrupt discontinuation ... included fatigue, nausea and dizziness and one episode of hypomania ..."
No warnings appear about the risk of mistaking withdrawal symptoms for relapse, and no suggestion is made that patients might need to be informed. There is reference to the possible need for gradual withdrawal:
US Label, 1996: "When discontinuing Efexor after more than one week of therapy, it is generally recommended that the dose be tapered to minimise the risk of discontinuation symptoms. Patients who have received Efexor for six weeks or more should have their dose tapered gradually over a two week period."
UK Data Sheet, 1996: "Discontinuation effects are well known to occur with antidepressants; therefore when Effexor has been administered for more than one week and is then stopped, it is generally recommended that the dose be reduced gradually over a few days and the patient monitored in order to minimise the risk of discontinuation symptoms. Patients who have received Effexor for six weeks or more should have their dose reduced gradually over at least a one-week period"
In UK patient information leaflets, which are also subject to regulatory approval, the recommendation for gradual withdrawal comes down to this: "Do not stop taking your tablets without the advice of your doctor. If your doctor thinks you no longer need Efexor, he may ask you to reduce your dose before stopping altogether". (Wyeth, 1996)
Advice to patients taking paroxetine (Seroxat/Paxil) goes into more detail, albeit to push the serotonin deficiency model of depression for much more than it is worth: "These tablets are not addictive. Everyone has a substance caused serotonin in their brain. Low levels of serotonin are thought to be a cause of depression, and other related conditions. This medicine works by bringing the levels of serotonin in your brain back to normal". (SmithKline Beecham, 1996) The leaflet goes on as follows:
"Do not suddenly stop taking your tablets without discussing this with your doctor. Some people find that if they suddenly stop taking these tablets, they feel dizzy, shaky, sick, anxious, confused or have tingling sensations. They may also have difficulty sleeping and vivid dreams when they do sleep. But these symptoms are unusual and generally disappear after a few days. To avoid these symptoms your doctor may tell you to take smaller doses or to spread doses further apart before you stop taking the tablets altogether ... If you stop taking your tablets too soon, your symptoms may return. Remember that you cannot become addicted to Seroxat."
In short, warnings in patient information leaflets and in the data sheet/label have to be read closely and between the lines. They might be strong enough to protect manufacturers and regulators, if problems were to arise, but offer limited help to doctors and patients who would want to prevent them.
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