Lancet,Jul/19:Authors' reply - Tapering of SSRI treatment to mitigate withdrawal

[[La...]]

https://www.ncbi.nlm.nih.gov/pubmed/31230678

 

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(19)30219-6/fulltext 

 

We thank Sudhakar Selvaraj and colleagues1 for their interest in our work. They offer several critiques of the relevance of PET occupancy data to withdrawal effects. However, we think their claim that changes in plasma levels of drug would not be associated with withdrawal symptoms has little evidential support. The more abrupt reduction in plasma levels of antidepressants with shorter half-lives is understood to cause their more severe and quick-onset withdrawal symptoms.2 Selvaraj and colleagues state that a study by Michelson and colleagues3 shows no correlation between change in blood concentration and withdrawal symptoms for any individual SSRI; however, they also found “percentage reduction in plasma concentrations across drug groups was statistically significantly correlated with new adverse events.”3 This suggests that the study was underpowered to find an effect for individual agents—an effect which became clear when the three SSRIs were grouped together.3

Additionally, reduced brain receptor exposure to antidepressants is likely to be the key factor in withdrawal symptoms, and plasma concentration might not accurately reflect brain exposure because of a number of individual pharmacokinetic effects, another limitation to this analysis.3

 

Selvaraj and colleagues claim that a hyperbolic relationship between antidepressant dose and serotonin transporter occupancy, obtained by PET, would not hold with long-term treatment. We concur that neuroadaptation to long-term use of antidepressants is likely2 (which, in turn, is the probable basis of withdrawal symptoms). However, the law of mass action would not be suspended by such a change; it would simply entail a right-shifting of the dose-response curve, while maintaining its overall hyperbolic shape. The law of mass action is a foundational pharmacological principle describing a steep increase in effect at small doses of drug, flattening out as receptors become increasingly saturated. Log transformation of the x-axis in older textbooks, yielding linear-appearing graphs for intermediate doses, can obscure this fact.

 

Selvaraj and colleagues question the analogy to benzodiazepine tapering: but as the law of mass action applies across species, drug classes and receptor targets, we hold that the principle of tapering according to the biologically meaningful unit of receptor activity, as for benzodiazepines, makes more sense than tapering linearly according to dose.

 

We agree that such a paucity of research into withdrawal symptoms is regrettable, so that potentially non-representative samples are the best data available on severity of the symptoms. Nonetheless, uncertainty over the exact incidence of withdrawal effects is perhaps exaggerated: the meta-analysis cited found an incidence of 44%,1 compared with 56% in a previous analysis.2

 

We welcome Henricus Ruhe and colleagues'4 thoughts on our paper, and concur with many of their conclusions—rate of tapering should be jointly decided with patients, some patients might tolerate intervals shorter than one month (which might be determined empirically) and preventative psychotherapy should certainly have a role in the process.

 

Golo Kronenberg and colleagues5 suggest that so-called nocebo effects might have a role in antidepressant withdrawal. Although this notion cannot be discounted, the presence of withdrawal effects in double-blind trials, as well as the presence of quite particular symptoms such as electric shocks suggest the contribution might be small.

 

Minimisation of the scale and severity of withdrawal alongside somewhat vague prescriptions for tapering1 is not a rational way forward. Instead, further study of the incidence, nature, timing, and severity of withdrawal symptoms and testing of plausible tapering regimens, and ways to individualise them, is required. If regulators do not require manufacturers to do such studies for licenced products, the government and independent researchers will have to step in. Energetic leadership in this area will assure patients that their concerns are being heard and addressed; an approach that will help to maintain, or regain, trust.

 

MAH declares no competing interests. DT reports personal fees from Lundbeck, and grants and personal fees from Janssen, outside the submitted work.