Setraline is the chemical name for Zoloft, a commonly prescribed antidepressant. An independent scientist currently unaffiliated with any academic or industrial research entity named Ethan Perlstein has been recently soliciting funds via “crowdsourcing” to continue his studies on the mechanisms by which sertraline is toxic to yeast, with the goal of shedding light on antidepressant function in the human brain.
The experimental foundation for his research plan that he has been soliciting funds to pursue is a paper he published in 2007 in the journal Genetics. This paper describes the isolation and characterization of yeast mutants that are resistant to sertraline-induced toxicity.
In this post, my goal is to enumerate various experimental findings that may be considered germane to the likelihood that his research will succeed at its stated goal of shedding light on antidepressant function in the human brain.
(1) Sertraline is, as pointed out in the Genetics paper, a “cationic amphiphile”. That means that it has both a hydrophobic component and a hydrophilic component that is positively charged under physiological conditions. The paper also points out that cationic amphiphiles “[have] long been recognized [to] interact with phospholipid membranes”. This is, of course, not at all surprising, since cationic amphiphiles are basically detergents.
(2) In human patients, the total concentration of sertraline in plasma at therapeutic doses has been estimated as 80-165 nM, that is bioavailable in the plasma (i.e., unbound to albumin and other proteins) has been estimated as 1.5-3 nM, and that is bioavailable in brain has been estimated as similar to plasma 2-4 nM. This means that in human patients taking sertraline, their brain neurons are probably exposed to a concentration of sertraline somewhere between 1.5 and 4 nM. (These estimates come from this paper.)
(3) According to the Genetics paper, the concentration of sertraline employed in the screen for resistant yeast mutants is “∼45 μm sertraline, which is approximately three times the IC50 of sertraline as determined by dose–response experiments in liquid culture”. The paper also notes that “lowering the selection concentration from ∼45 to ∼42 μm resulted, on average, in a 10-fold increase in the number of resistant colonies”. This indicates that the dose employed is nowhere near saturating with respect to sertraline’s physiological target in yeast cells, and is rather near the lower bound for having any physiological effect.
(4) Since the yeast are plated on a growth medium (YPD) that contains no intact proteins or long peptides, the yeast cells are likely exposed to close to 45 μm sertraline. This means that the yeast cells are likely being exposed to somewhere between 11,250 and 30,000-fold greater concentrations of sertraline than the brain neurons of human patients being treated with sertraline.
(5) As discussed in detail in the Genetics paper, the yeast clones resistant to this dose of sertraline have spontaneous mutations/polymorphisms in genes that encode proteins important for cellular lipid membrane homeostasis and trafficking.
(6) As discussed in detail in the Genetics paper, the dose of sertraline used for the resistance screen induces severe defects in the intracellular membrane structures within the yeast cells.
Based on all of the above, these conclusions follow:
(1) The most parsimonious interpretation of the results of the yeast screen is that mutants resistant to detergent disruption of intracellular membranes have been isolated, and this likely has nothing to do with specific effects of sertraline versus other detergents.
(2) The astronomical difference in effective dose for human therapy versus influencing yeast cellular physiology suggests that the effects of sertraline on yeast cells most likely have absolutely nothing whatsoever to do with its effects on neurons.
(3) Continued study of the effects of sertraline and other amphiphilic compounds at astronomical doses on yeast cells is likely a waste of time and effort vis a vis the goal of elucidating antidepressant actions in the human brain.