Antidepressant efficacy is correlated with plasma levels: mega-analysis and further evidence

Abstract

The debate around optimal target dose for first-line antidepressants (ADs) is still ongoing. Along this line, therapeutic drug monitoring (TDM) represents one of the most promising tools to improve clinical outcome. Nevertheless, a few data exist regarding the concentration-effect relationship of first-line ADs which limits TDM implementation in routine clinical practice. We conducted the first patient-level concentration-response mega-analysis including data acquired by us previously and explored the concentration dependency of first-line AD (206 subjects). Further, new data on mirtazapine are reported (18 subjects). Hamilton Depression Rating Scale-21 administered at baseline, at month 1 and month 3 was used as the measure of efficacy to assess antidepressant response (AR). When pooling all four first-line ADs together, normalized plasma levels and AR significantly fit a bell-shaped quadratic function with a progressive increase of AR up to around the upper normalized limit of the therapeutic reference range with a decrease of AR at higher serum levels. Our results complement the available evidence on the issue and the recent insights gained from dose-response studies. A concentration-dependent clinical efficacy, such as previously demonstrated for tricyclic compounds, also emerge for first-line ADs. Our study supports a role for TDM as a tool to optimize AD treatment to obtain maximum benefit.

Is Therapeutic Drug Monitoring Relevant for Antidepressant Drug Therapy? Implications From a Systematic Review and Meta-Analysis With Focus on Moderating Factors

“…However, in higher concentration ranges, a negative direction could be observed, indicating a decline in efficacy with increasing concentrations. This biphasic concentration-efficacy relationship has already been shown for TCAs in systematic reviews (11,12) and in a recent mega-analysis including four newer antidepressants (mirtazapine, escitalopram, duloxetine, and venlafaxine) (46).…”

Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability

“…Such amounts of ADs tend to evoke pleiotropic effects, ranging from disruption of lipid homeostasis [13], inhibition of acid sphingomyelinase [54], direct binding to neurotrophin receptors [55], to blockade of membrane trafficking [39,56], as well as widespread cytotoxicity [13,57,58]. In contrast, our study has focused on the lower end of therapeutic concentration range, which is characterized by high tolerability and strong dose-response relationship in the clinic [21]. In the light of the emerging importance of therapeutic drug monitoring for balancing AD efficacy and sideeffect burden [59,60], future investigation of concentrationdependent SSRI action will need to consider complexities of their tissue distribution, metabolism, and clearance [23,61,62].…”

“…While SSRIs are generally considered safer and better tolerated than earlier ADs, they are associated with multiple short and longterm side effects [18,19], affecting adherence [20]. Association between dosage, plasma concentration, clinical efficacy, and side effects of SSRIs remains incompletely understood [21,22], further obfuscated by their complex metabolism and tissue distribution profile [23]. Lack of knowledge regarding mechanisms of SSRI action across the body continues to hamper their definitive appraisal not only for MDD treatment but also for drug repurposing.…”

Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions

“…Furthermore, blood levels should be monitored in non-responding persons receiving some TCAs (i.e., imipramine, desip ramine, nortriptyline), as therapeutic levels/win dows have been established for these agents [175][176][177] .…”