The relationship between dose and serotonin transporter occupancy of antidepressants—a systematic review

Abstract

Brain imaging techniques enable the visualization of serotonin transporter (SERT) occupancy as a measure of the proportion of SERT blocked by an antidepressant at a given dose. We aimed to systematically review the evidence on the relationship between antidepressant dose and SERT occupancy. We searched PubMed and Embase (last search 20 May 2021) for human in vivo, within-subject PET, or SPECT studies measuring SERT occupancy at any dose of any antidepressant with highly selective radioligands ([11C]-DASB, [123I]-ADAM, and [11C]-MADAM). We summarized and visualized the dose-occupancy relationship for antidepressants across studies, overlaying the plots with a curve based on predicted values of a standard 2-parameter Michaelis–Menten model fitted using the observed data. We included seventeen studies of 10 different SSRIs, SNRIs, and serotonin modulators comprising a total of 294 participants, involving 309 unique occupancy measures. Overall, following the Michaelis–Menten equation, SERT occupancy increased with a higher dose in a hyperbolic relationship, with occupancy increasing rapidly at lower doses and reaching a plateau at approximately 80% at the usual minimum recommended dose. All the studies were small, only a few investigated the same antidepressant, dose, and brain region, and few reported information on factors that may influence SERT occupancy. The hyperbolic dose-occupancy relationship may provide mechanistic insight of relevance to the limited clinical benefit of dose-escalation in antidepressant treatment and the potential emergence of withdrawal symptoms. The evidence is limited by non-transparent reporting, lack of standardized methods, small sample sizes, and short treatment duration. Future studies should standardize the imaging and reporting procedures, measure occupancy at lower antidepressant doses, and investigate the moderators of the dose-occupancy relationship.

Clinical practice guideline recommendations on tapering and discontinuing antidepressants for depression: a systematic review

“…This has been suggested to be the case for antidepressants when tapering using standard available doses, especially for the last reductions before cessation due to the large biological effects even at very low and subtherapeutic doses. 12 , 16 , 49 Withdrawal symptoms have thus been reported even after very small dose reductions, especially in the lower dose range, 12 which would not be mitigated by even the slowest taper, as what is needed is smaller dose reductions, not longer time. The hyperbolic relationship between antidepressant dose and occupancy of their primary target receptor, the serotonin transporter, 49 suggests that the gradual reduction in the biological effect likely necessary to mitigate withdrawal symptoms requires a hyperbolic dose-reduction regimen.…”

“… 12 , 16 , 49 Withdrawal symptoms have thus been reported even after very small dose reductions, especially in the lower dose range, 12 which would not be mitigated by even the slowest taper, as what is needed is smaller dose reductions, not longer time. The hyperbolic relationship between antidepressant dose and occupancy of their primary target receptor, the serotonin transporter, 49 suggests that the gradual reduction in the biological effect likely necessary to mitigate withdrawal symptoms requires a hyperbolic dose-reduction regimen. 12 This requires performing multiple dose reductions even below half of the lowest standard manufactured doses, which is practically impossible using standard available doses, as the pills are simply too potent at very low doses and cannot be evenly split into small enough units.…”

Future Prospects of Positron Emission Tomography–Magnetic Resonance Imaging Hybrid Systems and Applications in Psychiatric Disorders

“…Until now, a majority of PET radioligands targeting neurotransmitter receptors, transporters, and enzymes are labeled with carbon-11 [ 94 , 95 ]. Therefore, in the realm of psychiatry, the routine clinical use of radioligand PET imaging has limitations due to the requirement of an onsite cyclotron facility.…”

“…Therefore, in the realm of psychiatry, the routine clinical use of radioligand PET imaging has limitations due to the requirement of an onsite cyclotron facility. However, PET research with 11-C radioligands probing neurotransmitter receptors and transporters has significantly contributed to unraveling the complex pathophysiology of psychiatric disorders such as schizophrenia (DA hypothesis) and depression (serotonin and catecholamine hypothesis) [ 94 , 96 ]. Therefore, PET imaging studies using 11-C radioligands in psychiatric disorders were mainly reviewed in this paper.…”

ABCB1 variants and sex affect serotonin transporter occupancy in the brain

“…While the effects of dose adjustments need to be investigated in further clinical trials, this approach holds promise to reduce the rate of initial side effects and, thus, increase adherence during SSRI treatment. Our model employing occupied SERT ratio can be directly applied as a guidance in this process if assuming a linear relationship between drug dosage and concentration at target sites [ 69 , 70 ]. As described above, O/U SERT ratio is expected to be directly proportional to the product of drug affinity and concentration.…”