RESIDUAL SYMPTOMS IN MAJOR DEPRESSIVE DISORDER: CLINICAL UTILITY OF VENLAFAXINE
Authors: Purushottamahanti *Pradeep , Mcintyre Roger , Agid Ofer , Biesheuvel Egbert 
Published: February 2025

Abstract

Background
Major depressive disorder (MDD) results in functional impairment that reduces quality of life. The current definition of clinical remission in MDD does not encompass functional recovery (Yang 2022). Anhedonia, amotivation, low energy and anxiety are the commonest residual symptoms responsible for functional impairment. Therefore, these should be considered key targets for treatment (Wang 2022). Venlafaxine extended release (XR) is approved worldwide for treating MDD. Its efficacy in comorbid anxiety is well established (Lyndon 2019), but the evidence in other residual symptoms is limited.

Aims and Objectives
Explore the efficacy of venlafaxine XR to address low energy, anhedonia and amotivation.

Methods
A pooled analysis of data from five clinical studies of venlafaxine XR (1087 subjects in total) compared it with placebo across derived measures for its efficacy in low energy (MADRS Item 7 [lassitude] and the sum of work and activities and retardation in HAM-D17); anhedonia (MADRS [anhedonia factor] items 1,2,6,7 and 8) and amotivation (motivational deficits in 3 items of HAM-D).
Primary outcomes were changes from baseline over a study period of 8 weeks. The analysis used Mixed Model Repeated Measures for changes over time and ANCOVA for the change from baseline at week 8 with LOCF employed for missing data.

Results
Efficacy for energy has been demonstrated (Fagiolini 2023). The analysis set for anhedonia included 839 subjects (venlafaxine XR, 456; placebo, 383). The change from baseline in the MADRS anhedonia sub-scale for venlafaxine XR was greater than for placebo after 8 weeks (mean, 95% CI: - 2.73[-3.63, -1.82], p&lt;0.0001), reaching statistical significance at week 2 and increasing over time to week 8 (Figure 1a). The analysis set for amotivation included 1087 subjects (venlafaxine XR, 585; placebo, 502). The change from baseline in the HAM-D amotivation measure was higher for venlafaxine XR compared to placebo after 8 weeks (mean, 95% CI: -0.78[-1.04, -0.52], p&lt;0.0001), reaching statistical significance from week 2 and increasing over time to week 8 (Figure 1b).

Discussion and Conclusion
There was significant improvement across all the derived measures that evaluated low energy, anhedonia and amotivation, demonstrating the efficacy of venlafaxine XR in alleviating symptoms implicated in functional impairment.

References
1.Yang H, Gao S, Li J, Yu H, Xu J, Lin C, Yang H, Teng C, Ma H and Zhang N (2022) Remission of symptoms is not equal to functional recovery: Psychosocial functioning impairment in major depression. Psychiatry 13:915689.
2.Wang Y, Wang G, Zhang N, Huang J, Wu W, Jia F, Liu T, Gao C, Hu J, Hong W, Fang Y. Association between residual symptoms and social functioning in patients with depression. Compr Psychiatry. 2020 Jan 22;98:152164.
3.Lyndon GJ, Prieto R, Wajsbrot DB, Allgulander C, Bandelow B. Efficacy of venlafaxine extended release in major depressive disorder patients: effect of baseline anxiety symptom severity. Int Clin Psychopharmacol. 2019 May;34(3):110-118.
4.Fagiolini A, Cardoner N, Pirildar S, Ittsakul P, Ng B, Duailibi K, El Hindy N. Moving from serotonin to serotonin-norepinephrine enhancement with increasing venlafaxine dose: clinical implications and strategies for a successful outcome in major depressive disorder. Expert Opin Pharmacother. 2023 Sep- Dec;24(15):1715-1723.