Is sertraline's dopamine transporter inhibition clinically relevant? Is the dopamine reuptake potential of sertraline, which shows unique binding to the dopamine transporter (Ki = 25nM) vs. other SSRI antidepressants clinically relevant? There is debate about the clinical significance of sertraline's dopamine transporter occupancy and whether that becomes clinically relevant in the treatment of depression, particularly at higher doses. Particularly considering the selectivity for sertraline for SERT (Ki = 0.29 nM) over the DAT which is 86-fold and other factors which mean that in theory, DAT occupancy should be low. "Significant inhibition of dopamine reuptake by sertraline at clinical dosages is controversial, and occupation by sertraline of the DAT is thought by many experts to not be clinically relevant" "Single doses of 50 to 200 mg sertraline have been found to result in peak plasma concentrations of 20 to 55 ng/mL (65–180 nM), while chronic treatment with 200 mg/day sertraline, the maximum recommended dosage, has been found to result in maximal plasma levels of 118 to 166 ng/mL (385–542 nM). However, sertraline is highly protein-bound in plasma, with a bound fraction of 98.5%. Hence, only 1.5% is free and theoretically bioactive. Based on this percentage, free concentrations of sertraline would be 2.49 ng/mL (8.13 nM) at the very most, which is only about one- third of the Ki value that Tatsumi et al. found with sertraline at the DAT. A very high dosage of sertraline of 400 mg/day has been found to produce peak plasma concentrations of about 250 ng/mL (816 nM). This can be estimated to result in a free concentration of 3.75 ng/mL (12.2 nM), which is still only about half of the Ki of sertraline for the DAT" [1] In vivo, in animal studies, while all SSRIs increased serotonin, sertraline was unique in it's ability to increase extracellular dopamine, including in the nucleus accumbens [2]. At a dose of 20mg/kg (i.p, rat), significant elevations of dopamine were noted in the nucleus accumbens and striatum. This would correlate with a human equivalent dose of 3.2 mg/kg. That said, it is commonly assumed all SSRIs share the general property of reducing dopaminergic activity in regions of the brain [3]. Sertraline is somewhat unique in increasing spontaneous locomotor activity, assumed to be linked to DAT inhibition, in animal models at doses slightly in excess of usual human therapeutic doses 1 Results from Kitaichi et al. 2010 with SSRIs on NAcc dopamine The major metabolite of sertraline, including desmethylsertraline, seems to be less potent than the parent molecule at DAT (Kd = 129nM vs 25nM) [4]. There is limited human research on the dopaminergic aspects of sertraline, other than case studies of abuse resulting in a dopaminergic-like profile of euphoria, mental overactivity etc at extremely supratherapeutic doses (56 times the normal maximum). Some studies suggest that due to it's dopaminergic effects, it may lack the negative effects on vigilance seen with administration of most SSRIs [5] and may have a cognitive profile superior to other SSRIs through enhanced dopaminergic neurotransmission [6]. References [1] Serotonin-dopamine Reuptake Inhibitor (Wikipedia) https://en.m.wikipedia.org/wiki/Serotonin%E2%80%93dopamine_reuptake_inhibitor [2] Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, Koyama T. Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats.Eur J Pharmacol 2010;647:90–96 https://doi.org/10.1016/j.ejphar.2010.08.026 [3] Di Mascio M, Di Giovanni G, Di Matteo V, Prisco S, Esposito E. Selective serotonin 2 reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area. Brain Res Bull. 1998 Aug;46(6):547-54. https://doi.org/10.1016/s0361-9230(98)00054-9 [4] Tatsumi M, Groshan K, Blakely RD, Richelson E. Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. https://doi.org/10.1016/s0014-2999(97)01393-9 [5] Schmitt JA, Ramaekers JG, Kruizinga MJ, van Boxtel MP, Vuurman EF, Riedel WJ. Additional dopamine reuptake inhibition attenuates vigilance impairment induced by serotonin reuptake inhibition in man. J Psychopharmacol. 2002 Sep;16(3):207-14. https://doi.org/10.1177/026988110201600303 [6] Schmitt JA, Kruizinga MJ, Riedel WJ. Non-serotonergic pharmacological profiles and associated cognitive effects of serotonin reuptake inhibitors. J Psychopharmacol. 2001 Sep;15(3):173-9. https://doi.org/10.1177/026988110101500304 3