Pharmacokinetic considerations for current state-of-the-art antidepressants

ABSTRACT

Introduction: Nowadays, the first-line medications in depression include SSRIs, SNRIs, NDRIs, NaSSAs, SMSs, or a melatonin (M1/M2) receptor agonist and a 5-HT_2C receptor antagonist. These drugs have quite similar antidepressant efficacy and safety profiles, but they differ in chemical structure, receptor affinity, and pharmacokinetics.

Areas covered: Pharmacokinetic properties of first-line antidepressant drugs and factors influencing their pharmacokinetic processes are presented. Alterations in pharmacokinetics of newer antidepressants in special populations are summarized. In addition, the significance of therapeutic drug monitoring (TDM) and pharmacogenetic testing in dose optimization for the treatment of depressive disorders using newer antidepressants is discussed.

Expert opinion: Due to the fact that 30-40% of depressive patients do not respond to the therapy and that the incidence of depression is constantly growing, the search for new more effective and safer antidepressant therapies is becoming an urgent need. More well-designed clinical studies under naturalistic conditions are needed to establish/refine therapeutic ranges for older and current state-of-the-art antidepressant drugs. The pharmacogenetic testing with concomitant application of TDM seems to be the best way for implementing personalized dosing of current state-of-the-art antidepressants metabolized by polymorphic CYPs, especially when co-administered with strong inhibitors or other substrates of CYP2D6 or CYP2C19.

KEYWORDS:

• CYP2C19
• CYP2D6
• antidepressants
• P-glycoprotein
• pharmacogenetics
• pharmacokinetics
• TDM

Article highlights

• Newer antidepressants share several common features, such as a good absorption from the gastrointestinal tract, CYP-mediated metabolism, or an extensive tissue distribution, whereas the occurrence of nonlinearity or stereoselectivity in pharmacokinetics, duration of elimination half-life, and pharmacological activity of metabolites are drug-specific.

• They are poor substrates of Pg-p and have a low potential for drug–drug interactions at therapeutic doses when coadministered with P-gp modulators.

• The newest antidepressants, i.e. levomilnacipran, vilazodone, and vortioxetine rarely require dosage adjustment in special populations (e.g. the elderly, patients with liver diseases, or CYP2D6 and CYP2C19 poor metabolizers). This also applies to vilazodone and vortioxetine in patients with renal diseases.

• The available data do not clearly suggest that substantial benefits may be obtained from routine monitoring of plasma levels of newer antidepressants. However, TDM may be useful in certain situations, e.g. when poor compliance is suspected, serious drug–drug interactions are likely to develop, or therapeutic failure or toxic events occur at clinically relevant doses.

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Declaration of interest

E. Wyska receives research support from Jagiellonian University Medical College under the Statutory Activity (N42/DBS/000073). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.