Time course of clinical response to venlafaxine: relevance of plasma level and chirality

Objective: Early clinical response to antidepressant treatment is an important therapeutic goal, considering the psychological, social and economic consequences of depression. The aim of the present study was to investigate the relationship between the time course of response and the concentration of venlafaxine (V), its active metabolite O-desmethylvenlafaxine (ODV) and enantiomeric ratios V(+)/V(−) and ODV(+)/ODV(−). Methods: Depressed inpatients (n=35) received V orally at a fixed 300mg daily dose. Accepted comedication included clorazepate (maximum 60mg/day), zopiclone (maximum 15mg/day) and low-dose trazodone (maximum 200mg/day). Severity of depression was assessed on days0, 4, 7, 11, 14, 21 and 28 (Montgomery and Åsberg Depression Rating Scale). Blood samples were taken on day14 and day28 and submitted to stereoselective determination. All measurements reflected trough steady-state values. First, pattern analysis was used to provide a categorical perspective of clinical response (50% improvement from baseline depression score). Patients displaying non-response, transient response, early persistent response and delayed persistent response were compared with respect to racemic concentrations and enantiomeric ratios. Second, in a dimensional perspective, mixed-effects modelling was used to analyse severity of depression versus time curves with respect to the possible influence of concentrations and enantiomeric ratios. Results: Comparison of patients with and without persistent response did not reveal any significant difference for V, ODV, V+ODV plasma levels or enantiomeric ratios. Persistent response was significantly associated with less frequent pre-study antidepressant medication and less frequent comedication with zopiclone (day14) and clorazepate (day28) during the study. Focus on patients with persistent response (n=19, 54.3%) indicated that early response, first observed before day14, was associated with significantly higher V+ODV concentration than delayed response (median 725ng/ml versus 554ng/ml, P=0.023). No difference was found for pre-study medication or comedication during the study. Shorter time to onset of response was significantly associated with lower V(+)/V(−) enantiomeric ratio (rs=0.48, P<0.05). Mixed-effects modelling of depression severity versus time curves in patients with persistent response confirmed that either higher V+ODV plasma level or lower V(+)/V(−) ratio were significantly associated with more rapid decrease of depression score (likelihood ratio tests, P=0.012 and P=0.046, respectively). Conclusion: Considering its modest sample size, naturalistic design and limited observation period, the present study provided preliminary indication that earlier clinical response may occur with higher V+ODV plasma level, extending previous dose-response studies. The hypothesis was also raised that exposure to a more potent noradrenergic therapeutic moiety, as reflected by a lower V(+)/V(−) ratio, may be relevant to early improvement of depressio

Time course of clinical response to venlafaxine: relevance of plasma level and chirality

OBJECTIVE: Early clinical response to antidepressant treatment is an important therapeutic goal, considering the psychological, social and economic consequences of depression. The aim of the present study was to investigate the relationship between the time course of response and the concentration of venlafaxine (V), its active metabolite O-desmethylvenlafaxine (ODV) and enantiomeric ratios V(+)/V(-) and ODV(+)/ODV(-). METHODS: Depressed inpatients ( n=35) received V orally at a fixed 300 mg daily dose. Accepted comedication included clorazepate (maximum 60 mg/day), zopiclone (maximum 15 mg/day) and low-dose trazodone (maximum 200 mg/day). Severity of depression was assessed on days 0, 4, 7, 11, 14, 21 and 28 (Montgomery and Asberg Depression Rating Scale). Blood samples were taken on day 14 and day 28 and submitted to stereoselective determination. All measurements reflected trough steady-state values. First, pattern analysis was used to provide a categorical perspective of clinical response (50% improvement from baseline depression score). Patients displaying non-response, transient response, early persistent response and delayed persistent response were compared with respect to racemic concentrations and enantiomeric ratios. Second, in a dimensional perspective, mixed-effects modelling was used to analyse severity of depression versus time curves with respect to the possible influence of concentrations and enantiomeric ratios. RESULTS: Comparison of patients with and without persistent response did not reveal any significant difference for V, ODV, V+ODV plasma levels or enantiomeric ratios. Persistent response was significantly associated with less frequent pre-study antidepressant medication and less frequent comedication with zopiclone (day 14) and clorazepate (day 28) during the study. Focus on patients with persistent response ( n=19, 54.3%) indicated that early response, first observed before day 14, was associated with significantly higher V+ODV concentration than delayed response (median 725 ng/ml versus 554 ng/ml, P=0.023). No difference was found for pre-study medication or comedication during the study. Shorter time to onset of response was significantly associated with lower V(+)/V(-) enantiomeric ratio (r(s)=0.48, P<0.05). Mixed-effects modelling of depression severity versus time curves in patients with persistent response confirmed that either higher V+ODV plasma level or lower V(+)/V(-) ratio were significantly associated with more rapid decrease of depression score (likelihood ratio tests, P=0.012 and P=0.046, respectively). CONCLUSION: Considering its modest sample size, naturalistic design and limited observation period, the present study provided preliminary indication that earlier clinical response may occur with higher V+ODV plasma level, extending previous dose-response studies. The hypothesis was also raised that exposure to a more potent noradrenergic therapeutic moiety, as reflected by a lower V(+)/V(-) ratio, may be relevant to early improvement of depression

Steady-state concentration of venlafaxine enantiomers: model-based analysis of between-patient variability

OBJECTIVE: To investigate patients treated for depression with respect to steady-state concentration of venlafaxine enantiomers, to quantify within- and between-subject variability and to study the possible influence of individual characteristics such as gender and age. METHODS: Thirty-five inpatients received venlafaxine orally at a fixed 300-mg daily dose. Blood samples were taken on day 14 and day 28 for therapeutic drug monitoring purposes. All measurements reflected steady-state trough values. In a first stage, plasma concentrations of racemic venlafaxine (V) and O-desmethylvenlafaxine (ODV) were measured using a gas chromatography method. In a second stage, (+)/(-) enantiomeric ratios for V and ODV were determined using a stereoselective capillary electrophoresis method. RESULTS: Interindividual variability was 77% and 33% for concentrations of racemic V and ODV, respectively. Intraindividual variability was below 20% for both compounds. Enantiomeric ratios did not statistically differ from unity, with median (+)/(-) ratios of 1.14 for V and 0.97 for ODV. ODV/V metabolite formation ratios for the (+) and (-) enantiomers did not significantly differ from each other (median values 2.85 and 2.37, respectively). However, reduced ODV/V ratio for the (-) enantiomer was strongly associated with decreased (+)/(-) ratio for V (r(S)=0.71, P<0.001) and increased (+)/(-) ratio for ODV (r(S)=-0.79, P<0.001). In contrast, ODV/V ratio for the (+) enantiomer did not significantly correlate with parent compound (+)/(-) ratio and correlated only weakly with metabolite (+)/(-) ratio (r(S)=-0.38, P<0.05). When compared with males, females displayed a significantly lower ODV/V ratio for the (-) enantiomer (median values 1.42 vs 5.08 on day 14, P<0.05) but not for the (+) enantiomer (median values 2.36 vs 3.27, n.s.). Analysis did not reveal any significant association between ODV/V ratios and age, weight, height, creatinine clearance, smoking or co-medication. A pharmacokinetic model at steady state was developed that postulated two different enzyme systems to contribute to O-desmethylation. ODV(-) formation was supposed to largely depend on a single pathway, possibly impaired in a patient subpopulation. ODV(+) formation was postulated to rely on both pathways to a similar extent. Model predictions were in close agreement with observations in patients. CONCLUSION: Observations, together with model-based simulations, suggested that marked stereoselectivity in a patient subgroup may be related with impairment of O-desmethylation greater for (-) than (+) venlafaxine. This hypothesis requires testing against phenotypic and genotypic characteristics of patients