Elsevier

Biological Psychiatry

Volume 55, Issue 3, 1 February 2004, Pages 320-322
Biological Psychiatry

Short communication
Milnacipran: a comparative analysis of human monoamine uptake and transporter binding affinity

https://doi.org/10.1016/j.biopsych.2003.07.006Get rights and content

Abstract

Background

Though selective serotonin reuptake inhibitors have revolutionized the field of psychiatry with demonstrated efficacy in affective and anxiety disorders with minimal side effects, norepinephrine-serotonin reuptake inhibitors may provide efficacy similar to tricyclic antidepressants without the adverse side effects associated with tricyclic antidepressants.

Methods

The affinity and selectivity of milnacipran, duloxetine, venlafaxine, citalopram, amitriptyline, and nortriptyline were determined for the human serotonin, norepinephrine, and dopamine transporters.

Results

Both milnacipran and duloxetine were potent inhibitors of serotonin and norepinephrine uptake. Unlike duloxetine and venlafaxine, milnacipran appears serotonin transporter selective in binding (ratio = 2.61) and norepinephrine transporter selective in uptake (ratio = .45).

Conclusions

Milnacipran's binding and uptake inhibition profile more closely resembles that of the tricyclic antidepressants than that of duloxetine. Whether these differences observed in vitro manifest themselves in vivo is not clear.

Section snippets

Methods and materials

Assays and data analyses were performed as previously described in detail Owens et al., 1997, Owens et al., 2001. All competition assays utilized 12 concentrations of competing ligands in triplicate samples over a maximum concentration range of 10−13 to 10−4.67 mol/L. The chosen concentration of competing ligands was adjusted for each assay. For uptake assays, cells were incubated with competing ligand for 10 minutes before addition of radiolabeled transmitter. After 10 minutes of incubation

Results

Table 1 lists the affinities (Ki; nmol/L) of the various antidepressants for the transporters assayed. All data are shown as geometric mean ± SE in nmol/L. Milnacipran bound to both serotonin and norepinephrine transporters with high affinity (Ki = 8.44 and 22 nmol/L, respectively), as did duloxetine, amitriptyline, and nortriptyline (Ki < 20 nmol/L in all cases). Venlafaxine and citalopram, in contrast, selectively bound to the SERT, but not the norepinephrine transporter (NET), with high

Discussion

The binding affinity of a drug for various transporters and/or receptors can theoretically predict both clinical efficacy and side effect profile. Potent antagonists of SERTs or NETs (or both) are clinically effective antidepressants. In agreement with previous in vitro human monoamine transporter studies, all drugs tested were potent antagonists of the SERT Owens et al., 2001, Tatsumi et al., 1997, Moret et al., 1985. Though the relevance of dopamine transporter (DAT) inhibition to

Acknowledgements

This research was supported by a research grant from Cypress Biosciences, San Diego, California.

Dr. Nemeroff is a paid consultant and stockholder of Cypress Biosciences. Drs. Rao and Kranzler are employees of Cypress Biosciences. At the time the research was performed, Dr. Owens was also a consultant for Cypress Biosciences; however, he is no longer a consultant at this time or at the time the manuscript was submitted.

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