T tt

10 50 100 300 ng/mL

Paroxetine log [M]

Copyright © American Psychiatric Publishing, Inc., or American Psychiatric Association, unless otherwise indicated in figure legend. All rights reserved,

Standard curves for paroxetine inhibition of NE (A) and 5-HT (B) resulting from NET and 5-HTT antagonism, respectively. Note that at 100 ng/mL of paroxetine, which represents a typical therapeutic dose, there is a 15% decrease in NE uptake and a 90% decrease in 5-HT uptake. Transporter inhibition occurs in a dose-dependent manner. 5-HT = serotonin; 5-HTT = serotonin transporter; NE = norepinephrine; NET = norepinephrine transporter.

Source.Gilmor et al. 2002.

Paroxetine's role as a norepinephrine reuptake inhibitor (NRI) has implications for interpreting the results of head-to-head comparisons with other antidepressants. The minimal NET activity observed at more conventional doses of paroxetine necessitates that clinical trials comparing it with established SNRIs (Goldstein et al. 2004; Shelton et al. 2005) would have to employ doses much higher than 20 mg in order to be considered a valid comparison. It currently remains somewhat controversial whether the combination of 5-HTT and NET inhibition is associated with greater antidepressant efficacy (J. C. Nelson 1998; J. C. Nelson et al. 1991, 2004; Seth et al. 1992; Thase et al. 2001). Additionally, it remains to be discovered what magnitude of NE reuptake inhibition would result in increased efficacy and/or decreased latency of antidepressant effect.

Paroxetine has no appreciable affinity for the dopamine transporter (DAT) or for dopamine], (D1), dopamine2 (D2), serotoniniA (5-HTia), serotoniri2A (5-HT2a); «i- and «2-adrenergic, and histamine! (H1) receptors, indicating that it is a relatively "clean" drug, particularly when compared with the older generation of antidepressants, such as TCAs and MAOIs (Hyttel 1994; Owens et al. 1997). It is distinguished from sertraline by its high affinity for the NET and low affinity for the DAT. Sertraline, in contrast, has a very high affinity for the DAT but no affinity for the NET (Tulloch and Johnson 1992). The affinity of paroxetine for the muscarinic cholinergic receptor is approximately 22 nmol, which is similar to that of desipramine, though paroxetine is used in lower doses than desipramine and is therefore less anticholinergic than this TCA. However, this property may account for its mild anticholinergic side effects, including dry mouth, blurry vision, and constipation (Owens et al. 1997). However, compared with nortriptyline, paroxetine has virtually no measurable anticholinergic activity in geriatric patients treated for depression (Pollock et al. 1998). Table 15-1 shows a comparison of paroxetine and other available antidepressants in terms of their affinity for various neurotransmitter receptors and monoamine transporters.

TABLE 15-1. Inhibition constants (Ki, nmol/L) of various antidepressants for various transporters and receptors in human and animal cells

Compound

5-HTTa

NETa

Hib

la

2a

Muscarinic0

Paroxetine

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