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

Abstract

Background: As many patients with unipolar depression do not respond sufficiently to initial antidepressant monotherapy, a dose increase of the current administered antidepressant (dose escalation, high-dose treatment) is frequently carried out as next treatment measure. Methods: We conducted a meta-analysis which included all double-blind randomized controlled trials (RCTs) comparing a dose increase of antidepressants directly to continuation of standard-dose treatment in unipolar depressive patients who were non- responders to standard-dose pharmacotherapy. A mean change in the Hamilton Rating Scale for Depression (HAM-D) total score was the primary outcome. Secondary outcomes were response rates and discontinuation rates due to any reason, inefficacy, and adverse effects. Hedges g and risk ratios were calculated as effect sizes. Results: Seven double-blind RCTs (8 study arms) representing 1,208 participants were included. Fluoxetine (N [number of studies] = 2, n [number of patients] = 448), sertraline (N = 2, n = 272), paroxetine (N = 2, n = 146), duloxetine (N = 1, n = 255), and maprotiline (N = 1, n = 87) were investigated. Dose escalation was not more efficacious in HAM-D total score reduction than maintaining standard-dose treatment, neither for the pooled antidepressant group (N = 7, n = 999; Hedges g = -0.04, 95% CI: -0.20 to 0.12; p = 0.63) nor the individual antidepressants. No differences could be determined for response rates, all-cause discontinuation, and drop-outs due to inefficacy. Significantly more patients in the dose escalation group dropped out due to adverse effects than in the standard-dose continuation group. The metaregressions indicate no influence of baseline symptom severity or amounts of dose increments on effect sizes. Conclusions: According to our meta-analytic findings, dose escalation after initial non-response to standard-dose pharmacotherapy cannot be regarded as general evidence-based treatment option in unipolar depression.

Predicting antidepressant response by monitoring early improvement of individual symptoms of depression: individual patient data meta-analysis

“…Hence, although lack of early improvement can identify a group of high-risk patients that may need to be monitored more intensively or benefit from additional counselling, a degree of caution in adapting pharmacological treatment may be warranted, especially because the evidence for alternative treatment strategies is scarce. Switching antidepressants is no more effective than continuing the same antidepressant, 26 and there is also little evidence in favour of the effectiveness of early dose escalation, although escalation is clearly associated with reduced tolerability 27 , 28 . This may, however, be different for non-SSRI/SNRI antidepressants like mirtazapine, 29 or for escalating from very low dosages to standard dosages 30 .…”

“…Switching antidepressants is no more effective than continuing the same antidepressant, 26 and there is also little evidence in favour of the effectiveness of early dose escalation, although escalation is clearly associated with reduced tolerability. 27,28 This may, however, be different for non-SSRI/SNRI antidepressants like mirtazapine, 29 or for escalating from very low dosages to standard dosages. 30 Other strategies, such as augmentation, may be more successful but also result in decreased tolerability.…”

Clinical correlates of augmentation/combination treatment strategies in major depressive disorder

“…Therefore, treatment resistance represents one of the most important clinical challenges in the pharmacological management of MDD. As dose escalation of the current antidepressant and a switch to another, new antidepressant compound after insufficient response to a previous antidepressant cannot be generally recommended as evidence‐based treatment option, augmentation and/or combination strategies are commonly applied in the clinical routine care to improve treatment response . Usually, combination treatment is defined by the simultaneous administration of two drugs of the same substance group such as two antidepressants and augmentation by the concomitant use of two drugs of different substance classes, for example, the coadministration of an antidepressant together with an antipsychotic drug.…”

A register-based approach to identifying treatment-resistant depression—Comparison with clinical definitions

“…This much shorter duration is most likely the reason for yielding higher proportions than the ESM (12-16 weeks). Regarding the parameter of increasing the dosage above the recommended starting dose, this was not included in the KIM as it is in general does not increase likelihood of treatment response [28].…”