The evidence for venlafaxine to treat generalized anxiety disorder in Japanese patients: fulfilling a significant unmet need

Background

Generalized anxiety disorder (GAD) is highly prevalent worldwide including in Japan and is associated with significant functional impairment. The recognition of GAD as a clinical entity in Japan is scant and there has been no approved treatment until now. A World Mental Health Surveys report noted that more than two-thirds of those with GAD in Japan fail to receive any treatment [1]. This body of work describes the clinical research to demonstrate the evidence for venlafaxine in treating GAD and fulfil the unmet need in Japanese individuals with GAD.

Methods

A placebo-controlled, randomized, double-blind, multicenter study (RCT) was conducted to evaluate the efficacy and safety & tolerability of venlafaxine (75-225mg/day) in Japanese outpatients with generalized anxiety disorder (GAD), using the change from baseline in Hamilton anxiety rating scale (HAM-A) total scores for efficacy [2]. Additional measurement scales evaluated further clinically relevant parameters including remission rates and quality of life. Patients who completed the RCT were followed up to evaluate safety (primary objective) and efficacy of venlafaxine for 52 weeks in an open-label, long-term extension study (OLE) [3].

Results

The evidence for venlafaxine in Japanese patients with GAD (RCT) [2]	N=357 (venlafaxine:179; placebo:178); Duration – 8 weeks 1. Compared to placebo, venlafaxine showed statistically significant reduction in: a. HAM-A total score (p=0.012) b. HAM-A psychic anxiety factor (p=0.022) c. HAM-A somatic anxiety factor (p=0.034) d. CGI-S (p=0.003) e. GAD-7 total score (p<0.001) f. Z‐SAS anxiety index (p=0.007) g. SDS total score (p= 0.012) h. CGI‐I (p=0.019) 2. 21 participants (17 in the venlafaxine group and 4 in the placebo group) discontinued treatment early mostly because of adverse events (12 in the venlafaxine group and 1 in the placebo group). 3. Overall, 197 participants (55.2%)—113 (63.1%) in the venlafaxine group and 84 (47.2%) in the placebo group—experienced at least one treatment‐emergent adverse event.
The evidence for the long-term safety and tolerability of venlafaxine in Japanese patients with GAD (52-week OLE study)[3]	66% of subjects were 100% compliant with treatment all subjects with at least 80% compliance 84% of patients experienced treatment-emergent adverse events (TEAE) - 1 with severe intensity which was not drug related - No serious TEAE - 1.5 % TEAEs led to study discontinuation - 0.7% related TEAEs led to study discontinuation - No death was reported Most TEAEs were nasopharyngitis, somnolence, nausea, weight increased in line with the known safety profile of venlafaxineAdditional mean reduction in HAM-A total score of -8.3 (-7.8 in previous active and -8.7 in previous placebo group) (baseline 15.9)Consistent effects with analog reduction also seen in CGI-S and CGI-I

The evidence for venlafaxine in Japanese patients with GAD (RCT) [2]

N=357 (venlafaxine:179; placebo:178); Duration – 8 weeks 1. Compared to placebo, venlafaxine showed statistically significant reduction in: a. HAM-A total score (p=0.012) b. HAM-A psychic anxiety factor (p=0.022) c. HAM-A somatic anxiety factor (p=0.034) d. CGI-S (p=0.003) e. GAD-7 total score (p<0.001) f. Z‐SAS anxiety index (p=0.007) g. SDS total score (p= 0.012) h. CGI‐I (p=0.019) 2. 21 participants (17 in the venlafaxine group and 4 in the placebo group) discontinued treatment early mostly because of adverse events (12 in the venlafaxine group and 1 in the placebo group). 3. Overall, 197 participants (55.2%)—113 (63.1%) in the venlafaxine group and 84 (47.2%) in the placebo group—experienced at least one treatment‐emergent adverse event.

The evidence for the long-term safety and tolerability of venlafaxine in Japanese patients with GAD (52-week OLE study)[3]

66% of subjects were 100% compliant with treatment all subjects with at least 80% compliance 84% of patients experienced treatment-emergent adverse events (TEAE) - 1 with severe intensity which was not drug related - No serious TEAE - 1.5 % TEAEs led to study discontinuation - 0.7% related TEAEs led to study discontinuation - No death was reported Most TEAEs were nasopharyngitis, somnolence, nausea, weight increased in line with the known safety profile of venlafaxineAdditional mean reduction in HAM-A total score of -8.3 (-7.8 in previous active and -8.7 in previous placebo group) (baseline 15.9)Consistent effects with analog reduction also seen in CGI-S and CGI-I

Conclusions

Together, these findings demonstrated clinical and functional improvement in Japanese patients with GAD who were treated with venlafaxine. The OLE study confirmed the long-term safety and tolerability of the drug. These study results paved the way for the first approved treatment in Japan for individuals with GAD, an unmet clinical need.

References

Stein DJ, Kazdin AE, Ruscio AM, et al. Perceived helpfulness of treatment for generalized anxiety disorder: a World Mental Health Surveys report. BMC Psychiatry. 2021;21(1):392
Otsubo T, Watanabe K, Inoue T, Inagaki A, Kikuchi T, Nomoto K, Higa S, Asami Y, Sun B, Marschall K. A randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of venlafaxine extended release in Japanese patients with generalized anxiety disorder. Psychiatry Clin Neurosci. 2025 Dec;79(12):849-858.
Otsubo T, Watanabe K, Inoue T, Inagaki A, Kikuchi T, Nomoto K, Higa S, Asami Y, Sun B, Marschall K. An open-label, long-term extension, multicenter study to evaluate the safety and efficacy of venlafaxine extended release in Japanese outpatients with generalized anxiety disorder. PCN Rep. in submission