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July 5, 2019 by Henricus G Ruhe | The Lancet Psychiatry

Tapering of SSRI treatment to mitigate withdrawal symptoms

Henricus G Ruhe, Annemieke Horikx, Mariëlle J P van Avendonk, Bart F Groeneweg, Hèlen Woutersen-Koch, on behalf of theDiscontinuation of Antidepressants Taskforce

(The Lancet Psychiatry) – In their excellent manuscript, published in The Lancet Psychiatry, Mark Horowitz and David Taylor share their personal view on tapering of SSRI treatment to mitigate antidepressant withdrawal symptoms. In the Netherlands, this topic has been raising debate as well, which urged representatives of the Dutch college of General Practitioners, the Royal Dutch Pharmacists Association, the Dutch Association for Psychiatry, and the patient organisation MIND to develop multidisciplinary recommendations for the discontinuation of SSRIs and serotonin–norepinephrine reuptake inhibitors (SNRIs; appendix pp 1–15).

Independent of Horowitz and Taylor, but with identical reasoning, we proposed reducing doses of SSRIs or SNRIs hyperbolically, and we also advocated the strategy of mini-tapering (tableappendix pp 3–6).

Table Steps in dosing to discontinue SSRIs and SNRIs in case of one or more risk factors for acute withdrawal syndrome
Citalopram (mg/day) Escitalopram (mg/day) Fluvoxamine (mg/day) Paroxetine (mg/day) Sertraline (mg/day) Duloxetine (mg/day) Venlafaxine (mg/day)
Step 1 20·0 10·00 50·0 20·0 50·00 60·0 75·0
Step 2 10·0 5·00 30·0 10·0 25·00 30·0 37·5
Step 3 6·0 3·00 20·0 7·0 15·00 15·0 20·0
Step 4 4·0 2·00 15·0 5·0 10·00 10·0 12·0
Step 5 3·0 1·50 10·0 3·0 7·50 6·0 7·0
Step 6 2·0 1·00 5·0 2·0 5·00 4·0 5·0
Step 7 1·0 0·50 2·5 1·0 2·50 2·0 3·0
Step 8 0·5 0·25 0·0 0·5 1·25 1·0 2·0
Step 9 0·0 0·00 .. 0·0 0·00 0·0 1·0
Step 10 .. .. .. .. .. .. 0·0
Hyperbolic reductions are calculated based on a desired 10% reduction in serotonin transporter occupancy per step, following the Michaelis–Menten equation: Dose = (Occupancy/Bmax) × (ED50/(1-Occupancy/Bmax), where Bmax is the maximal occupancy possible, ED50 is the dose with 50% occupancy, and both are determined per drug on the basis of PET data (appendix pp 14). Depending on occurrence and tolerability of antidepressant withdrawal symptoms, which might still be occurring when following these steps, the interval between steps (or dosages) can be adjusted via shared decision making by the patient and physician. This Taskforce does not consider prolonged use of any dosage of these discontinuation steps without further attempts of discontinuation as being rational pharmacotherapy. SNRI=serotonin–norepinephrine reuptake inhibitor.

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Because the prevalence of antidepressant withdrawal symptoms is unknown,  and not all patients require hyperbolic dose reductions to discontinue antidepressants, we identified three risk-factors that are consistently reported in the literature to indicate an increased risk of antidepressant withdrawal symptoms: (1) dosing above the minimal effective dose to reach efficacy, (2) antidepressant withdrawal symptoms when a dose was missed or during strategic treatment interruption, and (3) earlier failed attempts to discontinue the SSRI or SNRI. Although other risk factors have been proposed, these three factors might indicate a need to apply hyperbolic dose decreases instead of halving the minimal effective dose and stopping immediately therafter.

Instead of recommending reductions in steps of 1 month, which might be both very effective but also too conservative and time-consuming in a substantial number of patients who nevertheless require hyperbolic dose reductions, we propose initial steps of 1 week and observation of the emergence of antidepressant withdrawal symptoms. Such symptoms might either be bearable or, if not, would prompt a return to the dosage of a step earlier when no antidepressant withdrawal symptoms were noticed, followed by a slower discontinuation. This policy resembles the nomogram provided by Horowitz and Taylor, which is clinically very helpful.

Because of paucity of evidence to exactly guide clinical recommendations, we strongly advocate shared decision making and careful, repeated evaluation of the hyperbolic dosing steps. Advocating shared decision making could have been more explicit in the manuscript.

In 2018, Bockting and colleagues showed that the combination of preventive cognitive therapy (PCT) and maintenance antidepressants was superior (in terms of relapse prevention) to antidepressant maintenance therapy or PCT with discontinuation of antidepressants. In the same study, relapse rates were similar between antidepressant maintenance therapy and PCT with discontinuation of antidepressants. In a meta-analysis of four studies, Kuyken and colleaguesshowed that mindfulness-based cognitive therapy was superior to maintenance antidepressants. These publications emphasise the need for careful evaluation of the risk of recurrence or relapse before antidepressants are discontinued, and for initiating preventive psychotherapy to reduce risk of recurrence.

We agree with Horowitz and Taylor that empirical evidence regarding the discontinuation of antidepressants is urgently needed. Research should address: (1) the prevalence of antidepressant withdrawal symptoms in clinical populations discontinuing antidepressants, (2) systematic identification of risk factors for antidepressant withdrawal symptoms and their relevance being determined in prospective studies, and (3) the relative advantages of different dose-reduction regimens (eg, comparing mini-tapering and micro-tapering, and different timings of dose steps). In the ongoing OPERA project, the first two of these issues will be addressed, for the third, large collaborative randomised trials still need to be initiated.

For more on the OPERA project please see https://opera-project.nl

References

  1. Horowitz MA, Taylor D. Tapering of SSRI treatment to mitigate withdrawal symptoms. Lancet Psychiatry. 2019; 6538-546
  2. Groot PC, Consensusgroep Tapering. Taperingstrips voor paroxetine en venlafaxine. Tijdschr Psychiatr. 2013; 55789-794
  3. Davies J, Read J. A systematic review into the incidence, severity and duration of antidepressant withdrawal effects: are guidelines evidence-based?. Addict Behav. 2018; published online Sept 4. DOI:10.1016/j.addbeh.2018.08.027
  4. Bockting CLH, Klein NS, Elgersma HJ, et al. Effectiveness of preventive cognitive therapy while tapering antidepressants versus maintenance antidepressant treatment versus their combination in prevention of depressive relapse or recurrence (DRD study): a three-group, multicentre, randomised control. Lancet Psychiatry. 2018; 5401-410
  5. Kuyken W, Warren FC, Taylor RS, et al. Efficacy of mindfulness-based cognitive therapy in prevention of depressive relapse. JAMA Psychiatry. 2016; 73565-574
Source: TheLancet.com/journals/lanpsy/article/PIIS2215-0366(19)30182-8/fulltext

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