Effects of Venlafaxine in Patients with MDD

CNS Spectrums | 2024, Vol. 29, No. 3, p. 206–214

Effect of Venlafaxine on Anhedonia and Amotivation in Patients with Major Depressive Disorder

Roger S. McIntyre; Department of Psychiatry, UniversityofToronto, Toronto, Canada

Ofer Agid; Department of Psychiatry, CAMH and University of Toronto, Toronto, Canada

Egbert Biesheuvel; Biometrics, Viatris, Amstelveen, Netherlands

Pradeep Purushottamahanti; Global Medical Affairs, Viatris, Bangalore, India

Objective: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD).

Methods: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data.

Results: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: 2.73 [3.63, 1.82], p < 0.0001) and amotivation scores (mean, 95%CI: 0.78 [ 1.04, 0.52], p<0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time.

Conclusion: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Anhedonia; amotivation; venlafaxine XR; SNRI; SSRI; MADRS 5-item anhedonia subscale; HAM-D17 derived measure

“Major depressive disorder (MDD) is a highly prevalent and often debilitating mental disorder associated with low mood, anhedonia, alterations in behavior and emotional processing, and significant impairments in social and occupational functioning. Anhedonia and motivational deficits (amotivation) are core symptoms of MDD, present in the majority of patients. These two symptoms are principal indicators of functional impairment and non-recovery. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision criteria (DSM-5-TR), anhedonia and depressed mood are key diagnostic criteria for MDD. Evidence indicates that disturbances in motivation (and cognition) are continuing deficits in MDD that mediate poor functional outcomes” (p. 206).

“Venlafaxine, an SNRI, has been available in the United States since 1993 and its extended-release (XR) formulation has been approved for the treatment of MDD since 1997. Venlafaxine has been reported to have an action on serotonin, norepinephrine, and dopamine in a dose-dependent manner. Therefore, venlafaxine may have an effect on symptoms mediated by norepinephrine and dopamine, such as anhedonia, amotivation, and low energy. However, there is limited information about the effect of venlafaxine on motivational deficits. This study aimed to conduct a post hoc pooled analysis of clinical trials of venlafaxine XR to assess its effect on the symptoms of anhedonia and amotivation” (p. 207).

“The data set selected for our pooled analysis was based on the meta-analysis by Thase et al., which evaluated the efficacy of venlafaxine XR (75–225 mg/day) in adult patients with MDD, utilizing HAM-D17 and MADRS as efficacy measures. The patient-level data required for our study that made use of derived measures from HAM-D17 and MADRS for evaluating amotivation and anhedonia was available in this data set, and thus, it was deemed a good fit…Anhedonia was measured with the Montgomery–Åsberg Depression Rating Scale (MADRS) 5-item anhedonia subscale… Amotivation was evaluated using three items from the HAM-D17” (p. 207 - 208).

“The current study is one of the first studies assessing the impact of venlafaxine XR on anhedonia and amotivation in patients with MDD. In this analysis, statistically significant change from baseline in the MADRS anhedonia sub-scale score and in amotivation measure derived from HAM-D17 with venlafaxine XR was observed at week 2 and at all subsequent assessments compared with placebo. An assessment of the effect of baseline severity of anhedonia or motivational deficits on efficacy outcomes in patients treated with venlafaxine XR or placebo showed an association between the severity of baseline score and the probability of achieving improvement. The magnitude of change from baseline in the anhedonia or amotivation scores was prominent in patients with severe disease or higher baseline scores” (p. 210).

“The baseline severity by treatment interaction was not significant. Comparison between the treatment groups for the degree of improvement, based on baseline severity score, showed that the improvement was greater with venlafaxine XR compared with placebo, although the baseline severity score by treatment interaction was not statistically significant. The methods adopted in our analysis have been validated in previously published studies” (p. 211). 

“These derived measures can be positioned as a potential way of assessing anhedonia and motivational deficits in a clinical setting. They may also be useful in implementing measurement-based care (MBC). MBC has been reported to offer the advantages of improved outcomes, better monitoring and control of symptoms, improvement in overall functioning and quality of life, enhancing collaborative care and aiding communication and relationship between patients and care providers. It may enhance the accuracy of decision making and clinical judgment and may provide more opportunities for treatment individualization. Due to the ease of use of derived measures for patient care, MBC could be applied in a larger population. Additionally, they may also aid in evaluating the functional recovery in patients with MDD” (p. 211).

“The limitations of this analysis should be considered in the discussion of results. Although this was a post hoc analysis of data from clinical trials which were not designed to assess the symptoms of anhedonia or amotivation, validated derived measures were used for their measurement, and the results obtained were statistically significant. Due to its post hoc character, no statistical correction for multiple comparisons has been applied. Another limitation of this analysis is the heterogeneity of the five pooled trials. These studies had enrolled different populations based on inclusion criteria, different study designs, use of fixed versus flexible dosing, dosages evaluated, and duration of the trials. However, basic statistical assumptions like residual and QQ plots were checked,and first-order interaction terms,including the study by treatment interaction, were added to the MMRM model and did not reveal any concern. We recognize the limitations of the LOCF approach while dealing with missing data, as it might introduce methodological bias. Hence, the results of the MMRM model have to be considered as well, because, in general, MMRM models are less prone to bias. This study included short-term clinical trials, with the studies being conducted for 8 to 12 weeks. It might limit the generalizability of the findings for long-term effects of venlafaxine XR on anhedonia and amotivation. Another limitation that needs to be considered is the absence of a control treatment group. Therefore, a comparison with another antidepressant cannot be made. While it is not the intent of this analysis, it can be explored in future studies. While analyzing derived measures could be considered a limitation, we believe that these validated measures are important for clinicians in assessing anhedonia and motivational deficits. The current study does not assess the impact of the dose of venlafaxine XR on its efficacy in anhedonia and amotivation, and this could be an interesting subject for future studies” (p. 212).