Higher venlafaxine serum concentrations necessary for clinical improvement? Time to re-evaluate the therapeutic reference range of venlafaxine

Abstract

Background: The therapeutic reference range for venlafaxine in antidepressant treatment has been defined as 100 to 400 ng/mL. However, in an everyday setting active moiety concentrations above the therapeutic reference range were often reported. Aim: The aim of this study was to re-evaluate the therapeutic reference range of venlafaxine. Methods: In-patients (⩽60 years) with major depressive episodes receiving antidepressant monotherapy with venlafaxine during routine clinical treatment were included in this observational study. Depressive symptom severity was evaluated on a weekly basis using the Hamilton Depression Rating Scale (HAMD-21), and therapeutic drug monitoring analyses were performed. Resting electrocardiograms were analyzed in week 3, week 5 and week 7 of study participation. Results: Clinical improvement from baseline to week 4 was significantly associated with increasing serum concentrations of the active moiety of venlafaxine ( N = 23, Pearson correlation, p = 0.009), but not with the dose of venlafaxine. Patients achieving remission showed significantly higher serum concentrations than patients achieving response/non-response (Kruskal–Wallis test, p = 0.019). Moreover, in patients with serum concentrations above 400 ng/mL time to remission and time to response was significantly shorter than in patients with concentrations below 400 ng/mL (Mantel–COX test, p = 0.001; p = 0.010). QTc time was below the upper limit of a normal QTc time (450 ms) for all patients. Conclusion: The serum concentration of the active moiety and not the dose determined the effect of venlafaxine. Shorter remission times without ECG alterations in patients with serum concentrations above the therapeutic reference range suggest a re-evaluation of the therapeutic reference range for venlafaxine in larger studies.

Automated Interlaboratory Comparison of Therapeutic Drug Monitoring Data and Its Use for Evaluation of Published Therapeutic Reference Ranges

“…However, Shams et al used 25–75 percentiles, which may be the primary reason why the upper limit is considerably lower than the therapeutic analytical ranges in our study, which is on average from 550 to 2555 nmol/L when applying 10–90 percentiles ( Table 2 ). A higher upper limit than the one presented in the guideline was suggested by Reis et al [ 8 ], and Scherf-Clavel et al also argued for a higher therapeutic reference range for the total moiety of venlafaxine and the active metabolite o-desmethyl-venlafaxine [ 12 ].…”

“…Commonly, these studies relied on a single laboratory test developed in-house, and verification using modern techniques is therefore necessary. The continual re-evaluation of therapeutic reference ranges is also important as the treatment paradigm of a drug may change over time [ 12 ]. For these reasons, a ratification is warranted before a published range can be used in the clinic, and the agreement with current laboratory methods needs to be ensured.…”

Role of JNK in the Regulation of Xenobiotic Metabolizing Function of Hepatocytes

“…In general, our data show the participation of JNK-mediated MAPK-pathway [10,15] in the regulation of xenobiotic metabolism in liver cells. In particular, the role of this second messenger in relation to the biochemical transformation of one of the most effective antidepressants venlafaxine [7] is reduced to inhibition of its transformation. At the same time, the results of experiments indicate that the JNK inhibitor accelerated metabolism of this drug.…”

“…Moreover, this effect of protein kinase blocker is obviously mediated via its participation in the regulation of activity not only of CYP2D6 (responsible for the formation of O-DVLF), but also CYP2C19, CYP3A4, and CYP2C9 (catalyzing the formation of inactive metabolites N,O-didesmetylvenlafaxine and their glucuronide conjugates) [4,9]. The discovered properties of the JNK inhibitor can be used to develop a fundamentally new approach to personification and increase the effectiveness of venlafaxine antidepressant therapy [7,8]. Based on the identified phenomena, JNK inactivation in liver cells can increase the level of drug transformation in low metabolizers (persons with low CYP2D6 expression, or in patients with liver diseases [3,4,6]) to the normal level (i.e.…”

“…In 30 min, the venlafaxine (Aarti Industries) was added to the homogenate in a dose of 100 ng/ml and the cell suspension was incubated at 37°C in a TS-100 thermoshaker (Biosan). In 30 min, 1, 2, and 4 h, the content of the main venlafaxine metabolite O-desmethylvenlafaxine (O-DVLF) was evaluated [6,7]. The control was liver homogenate containing equivalent amounts of venlafaxine and solvent (DMSO, final concentration of 0.15%).…”