Evidence Why Paroxetine Dose Escalation is Not Effective in Major Depressive Disorder: A Randomized Controlled Trial With Assessment of Serotonin Transporter Occupancy

Abstract

Dose escalation is often used in depressed patients who fail to respond to standard doses of selective serotonin reuptake inhibitors, but clinical efficacy is equivocal. We aimed to reassess the efficacy of paroxetine dose escalation and quantify whether paroxetine dose escalation increases occupancy of the serotonin transporter (SERT) more than placebo dose escalation in a randomized controlled trial. We recruited 107 nonpsychotic, unipolar depressed outpatients (18-70 years; Hamilton Depression Rating Scale (HDRS(17)) >18) from primary care and psychiatric outpatient departments. After 6 weeks, open-label paroxetine 20 mg per day (T0), nonresponding patients (HDRS(17) decrease <50%; n=60) were randomized to double-blind paroxetine (30-50 mg per day as tolerable) or placebo dose escalation (paroxetine 20 mg per day+placebo). Patients were followed until 6 weeks after randomization (T1). Forty-nine patients, drug free at study entry, underwent single-photon emission-computed tomography (SPECT) scanning before treatment and were scanned repeatedly at T0 and T1. Paroxetine serum concentrations and SERT occupancy were determined at T0 and T1 (n=32). We terminated the dose-escalation trial after an interim analysis. Thirty nonresponding patients were randomized to paroxetine (46.7+/-5.5 mg per day), 27 to placebo dose escalation. Response rates were 10/30 (33.3%) and 10/27 (37.0%), respectively. Repeated measurement analyses showed no significant effect for treatment (p=0.88, exceeding a priori stopping rules for futility (p>0.5)). Overall dropout was higher for placebo (26.7%) than paroxetine (3.3%; p=0.03). Paroxetine dose escalation increased paroxetine serum concentrations (p<0.001). SPECT measurements (12 patients randomized to paroxetine (46.9+/-4.8 mg) and 14 to placebo dose escalation) showed no significant increase of midbrain SERT occupancy (2.5+/-26.4%, paroxetine; 3.1+/-25.8% placebo; p=0.687) nor in diencephalon (p=0.529). Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation. This is explained by the absence of significant increases of SERT occupancy by paroxetine dose escalation, despite increased paroxetine serum concentrations (ISRCTN44111488).

Dose Escalation of Antidepressants in Unipolar Depression: A Meta-Analysis of Double-Blind, Randomized Controlled Trials

“…The mean patient age was 43.3 ± 2.0 years, and 59.6% of all participants were female. Six RCTs included exclusively outpatients [21,23,24,25,26,27]. Four studies were carried out in North America [21,22,23,27] and 3 in Europe [24,25,26].…”

“…Of the 7 included RCTs, 2 investigated pharmacotherapy with fluoxetine ( n = 448) [21,22], sertraline ( n = 272) [23,24], and paroxetine ( n = 146) [25,26], whereas 1 study examined duloxetine ( n = 255) [27] and maprotiline ( n = 87) [25]. In the individual trials, the number of participants ranged from 60 [26] to 371 [21] (mean = 151.0 ± 112.9 patients), and trial duration varied between 3 [25] and 8 weeks [27] (mean = 5.0 ± 1.6 weeks).…”

“…In the individual trials, the number of participants ranged from 60 [26] to 371 [21] (mean = 151.0 ± 112.9 patients), and trial duration varied between 3 [25] and 8 weeks [27] (mean = 5.0 ± 1.6 weeks). The mean duration of the prospective phase before randomization to the 2 different dose regimes was 4.1 ± 1.6 weeks.…”

Anticipated Outcomes from Introduction of 5-HTTLPR Genotyping for Depressed Patients: An Expert Delphi Analysis

“…To some extent, pharmacoepigenetics inherits all hopes and expectations associated with pharmacogenomics; however, in contrast to pharmacogenomics, pharmacoepigenetics offers another level of understanding of different drug responses among individuals that cannot be explained by variation in DNA sequences [38]. Within the field of antidepressant response, some recent studies have shown that occupancy of the serotonin transporter is modified by 5-HTTLPR and is associated with the response to a SSRI [39,40,41]. Available data indicate that the single marker associations can account only for a small proportion of the variance in antidepressant response and indicate that multiple testing is required for reliable prediction [42].…”

Spectral model of therapy resistant depression

“…Оптимизация дозиров-ки или увеличение продолжительности курса не различаются в баллах с аугментацией или комбини-рованной терапией, в то время как два последних метода предположительно более эффективны [22][23][24].…”