Lancet, Jul/19: Tapering of SSRI treatment to mitigate withdrawal symptoms - #2

https://www.ncbi.nlm.nih.gov/pubmed/31230676

https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(19)30183-X/fulltext

(See link for references.)

We read with interest the Personal View1 by Mark Horowitz and David Taylor, who suggested that advice on tapering antidepressants should be reconsidered based on the mechanism of action of each SSRI, with PET data. We welcome individualised care for people with depression who have had discontinuation or withdrawal symptoms, and acknowledge this on the precautionary principle that some people can benefit from prolonged tapering from various psychotropics.

Horowitz and Taylor also provide an estimate of the frequency of withdrawal symptoms and suggest that they are related to plasma concentrations and PET occupancy data and can be used to predict withdrawal symptoms when SSRIs are discontinued. Indeed, the authors state that change in plasma concentration of SSRIs correlates with discontinuation or withdrawal symptoms. However, a study2

shows no correlation between change in blood level and withdrawal symptoms for any individual SSRI. Indeed, none of the PET studies that we are aware of show a consistent relationship between individual PET occupancy and therapeutic response at clinical doses.3,  4 Accordingly, a relationship with discontinuation or withdrawal symptoms is even more difficult to predict.

Therefore, the hyperbolic curve in figure 3 of the Personal View1, where serotonin transporter (SERT) is plotted against dose and plasma concentration (with data from healthy volunteers and patients with minimum previous antidepressant exposure), has no relevance to people receiving long-term SSRIs, or who are experiencing longer-term discontinuation or withdrawal symptoms.

It is also unclear how data derived from PET scans on γ-aminobutyric-acid (GABA) occupancy and diazepam dose in non-human primates influences the interpretation of SERT and SSRI dose; actions of an inhibitory neurotransmitter (eg, GABA) are quite different to those of a neuromodulator (eg, serotonin).

The incidence and severity of discontinuation or withdrawal symptoms remains controversial.5

This controversy arises because these symptoms vary markedly between different antidepressants, are less frequent when assessed in placebo-controlled trials, and are typically reported to be severe in open surveys of unblended patient experiences.5 It is perhaps regrettable that Horowitz and Taylor uncritically accept the highest rates claimed in the latter surveys because these are likely to be most affected by attributional bias, and the least likely to reflect the molecular properties of SERT.5

In summary, we agree with tapering treatments for some patients who have depression. The withdrawal regime needs to be personalised and will depend on individual susceptibility to withdrawal symptoms, the medication used, and the precise clinical context in which withdrawal is occurring. However, basing withdrawal on theoretical changes in PET occupancy of doubtful clinical significance is unlikely to assist practitioners in this complex, pragmatic task.

SS has received speaking honoraria from Global Medical Education and honoraria from British Medical Journal Publishing Group. He also owns shares at Flow Med Tech. DSB has attracted research funding (between 1994–2018) from: AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly Ltd, GlaxoSmithKline, Lundbeck, Pharmacia, Pierre Fabre, Pfizer Ltd, Servier, Vernalis Ltd, and Wyeth Ltd. He has also attended advisory boards organised by Grunenthal, Liva Nova, Mundipharma, Roche, and Sumitomo, and has received personal honoraria for lecture engagements organised by AstraZeneca, Bristol-Myers Squibb, Eli Lilly Ltd, GlaxoSmithKline, Janssen, Lundbeck, Pharmacia, Pierre Fabre, Pfizer Ltd, Servier, and Wyeth Ltd. GMG holds shares in P1Vital and has served as consultant, advisor or CME speaker for Allergan, Angelini, Compass pathways, Merck Sharp & Dohme, Lundbeck, Otsuka, Takeda, Medscape, Minervra, P1Vital, Pfizer, Servier, Shire, and Sun Pharma. DJN is an advisor at the British National Formulary and Medical Research Council. He was past president of the British Neuroscience Association, European Brain Council, and European College of Neuropsychopharmacology. He is current chair at DrugScience [uK] and Member International Centre for Science in Drug Policy, current editor of the Journal of Psychopharmacology, and has participated on the following advisory boards: Nalpharm, Mundipharma, Ranvier, Indivior, Opiant. He has received speaking honoraria (in addition to above) at Lundbeck Bristol-Myers Squibb/Otsuka, Janssen, and Martindale. He is also a member of the Lundbeck International Neuroscience Foundation and Chair Campus editorial board. He has received grants or clinical trial payments from the following: Wellcome Trust, Medical Research Council. He has shares in P1Vital and Alcarelle Director Equasy Enterprises. He is an expert witness in a number of legal cases relating to psychotropic drugs, and has edited and written over 32 books (some purchased by pharma companies). AHY has received payment for lectures and advisory boards for the following companies with drugs used in affective and related disorders: AstraZeneca, Eli Lilly, Janssen, Lundbeck, Sunovion, Servier, Livanova. He is also the lead Investigator for Embolden Study (AstraZeneca), the BCI Neuroplasticity study, and the Aripiprazole Mania Study. He has also been an investigator for studies from AstraZeneca, Eli Lilly, Lundbeck, and Wyeth. All other authors declare no competing interests.