Venlafaxine is comparable to paroxetine, and each is superior to placebo for the treatment of social anxiety disorder (SAD), according to the results of a randomized study published in the February issue of the Archives of General Psychiatry.

“Evidence has shown that the serotonin-norepinephrine reuptake inhibitor venlafaxine hydrochloride extended release (ER) is also effective for ameliorating symptoms of anxiety, including generalized anxiety disorder, symptoms of anxiety in patients with major depressive disorder, and comorbid major depressive disorder and generalized anxiety disorder,” write Michael R. Liebowitz, MD, from New York State Psychiatric Institute in New York, and colleagues. “This study is one of a series of studies designed to determine if serotonin-norepinephrine reuptake inhibitors are also a viable treatment option for symptoms of social anxiety.”

At 26 U.S. centers, 440 adult outpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria for generalized SAD for at least six months were randomized to receive venlafaxine hydrochloride ER (75-225 mg/day), paroxetine (20-50 mg/day), or placebo for 12 weeks or less. The primary outcome was the total Liebowitz Social Anxiety Scale (LSAS) score; and secondary outcomes were response rates as determined by the Clinical Global Impression-Improvement (CGI-I) score of 1 or 2, Clinical Global Impression (CGI)-Severity of Illness, and Social Phobia Inventory (SPI) scores.

Of 440 patients treated, 413 (93.9%) were included in the last-observation-carried-forward efficacy analysis. Of 429 patients evaluated for safety, 318 (74.1%) completed the study. Mean daily doses were 201.7 ± 38.1 mg for venlafaxine ER and 46.0 ± 7.9 mg for paroxetine.

Compared with placebo, venlafaxine ER treatment was superior at weeks 1 through 12 on the LSAS and SPI, and at week 2 and weeks 6 through 12 for CGI-Severity of Illness and responder status (P < .05 for all). Compared with paroxetine treatment, venlafaxine ER treatment was superior at weeks 1 and 2 for the SPI (P < .05 for both).

Paroxetine treatment was superior to placebo at weeks 3 through 12 on the LSAS, the CGI-Severity of Illness scale, and the SPI, and at weeks 4 through 12 for response (P < .05 for all). Response rates at week 12 were greater for venlafaxine ER and for paroxetine (58.6% and 62.5%, respectively) than for placebo (36.1%; P < .001 for both).

Study limitations include the 12-week duration, and exclusion of patients with comorbid psychiatric disorders.

“Venlafaxine ER is effective in the short term treatment of generalized social anxiety disorder, with efficacy and tolerability comparable to paroxetine,” the authors write. “In addition to its established efficacy in the treatment of depression and generalized anxiety disorder, the results indicate that venlafaxine ER is a viable first-line treatment option for patients with generalized SAD.”

Wyeth, maker of venlafaxine, supported this study, and has financial arrangements with its three authors, who also report various financial arrangements with Bristol-Myers Squibb, GlaxoSmithKline, maker of paroxetine, Pfizer, Novartis, Forest, Eli Lilly, UCB Pharma, Pharmacia, Novartis, Pherin Pharmaceuticals, Cephalon, Vela Pharmaceuticals, Best Practice, AstraZeneca, Cyberonics, Roche, and/or ZARS, Inc.

Arch Gen Psych. 2005;62:190-198

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:

• Compare the efficacy and safety of venlafaxine ER vs placebo for the treatment of SAD.
• Compare venlafaxine vs paroxetine in the treatment of SAD.

Clinical Context

SAD is characterized by persistent fear and avoidance of a wide variety of social situations, significantly impairing social functioning. Twelve-month and lifetime prevalence have been estimated at 7.9% and 13.3%, respectively. It is the third most common psychiatric diagnosis after major depression and alcohol dependence. Age of onset is around 15 years, with infrequent presentation after 25 years. Psychiatric comorbidity is common with estimates ranging from 43% to 69%, and SAD tends to precede the comorbid condition. Individuals present mainly to the primary care physician with symptoms that may remain unrecognized as SAD. Involvement of the serotonergic, dopaminergic, and possibly noradrenergic systems have been postulated. Antidepressants, such as paroxetine, have been shown to be efficacious in treatment compared with placebo. Venlafaxine has been shown to be helpful in ameliorating the effects of generalized anxiety disorders, anxiety in patients with depression, and comorbid major depression and anxiety.

This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group comparison of flexible doses of venlafaxine ER and paroxetine in patients with DSM-IV generalized SAD.

Study Highlights

• Inclusion criteria were patients 18 years or older fulfilling DSM-IV criteria for SAD for 6 months or more in at least 4 social situations, LSAS score of 50 or more at baseline, a score of 4 or more on the CGI-I, prestudy Covi Anxiety Scale total greater than the Raskin Depression Scale total score, and prestudy Hamilton Psychiatric Rating Scale for Depression (HAM-D) score of less than 15 with a score of 2 or less on the depression item.
• Exclusion criteria were axis I or II disorder other than SAD, psychotic illness, suicidal, use of medications including antidepressants and herbals with psychotropic effects within 14 days, electroconvulsive therapy within 6 months and psychotherapy within 30 days, and women of childbearing potential who were pregnant, lactating, or not using contraception.
• After a single-blind, 7-day lead-in with placebo, participants from 26 U.S. centers were randomized to receive flexible doses of venlafaxine ER (n = 146) at 75 to 225 mg daily (titrated from 75 mg at 75-mg increments weekly) or paroxetine (n = 147) at 20 to 50 mg daily (starting at 20 mg daily and titrating at 10-mg increments weekly) or placebo (n = 147). Titration was based on anxiety symptom rating and tolerance.
• 74.1% completed the 12-week trial, and 25.9% dropped out. Significantly more (P = .004) in the medication groups withdrew because of adverse events (13.7% for venlafaxine ER, 12.9% for paroxetine vs 4.1% for placebo) while significantly more withdrew in the placebo group because of lack of effect (P = .009).
• Primary outcome was final on-therapy LSAS total score and CGI-I comparing venlafaxine ER with placebo.
• Secondary outcomes were comparisons of venlafaxine ER and paroxetine on the LSAS, SPI, and CGI-I changes from baseline.
• Mean age was 37 years; 48%, women; 70%, white; mean weight, 78 kg; and mean duration of current episode, 23 years. Mean baseline LSAS score was 88, and HAM-D total score was 6.3.
• Reduction of mean LSAS scores was significantly greater in the venlafaxine ER and paroxetine groups vs placebo (P < .05). At end point, the adjusted mean change from baseline was -35.00 for venlafaxine, -39.20 for paroxetine, and -22.20 for placebo, with no significant differences noted between venlafaxine ER and paroxetine.
• At end point, both active groups demonstrated significantly greater secondary efficacy measures vs placebo, with no difference between the two treatment groups.
• On the patient-rated SPI, significantly greater improvement was seen for venlafaxine ER vs baseline at week 1 and from weeks 2 to 12 vs placebo. For paroxetine, significant improvement was seen at week 3, week 4, and from week 6 to 12 vs placebo.
• Significantly greater improvement on the CGI-Severity of Illness scale was seen in the venlafaxine ER vs placebo group at week 2 and from weeks 6 to 12. Similarly, significant improvements were seen for paroxetine compared with placebo at week 3 to 12. The difference between baseline and end point was -0.83 for venlafaxine and -0.73 for the paroxetine group.
• At week 12, more patients in the venlafaxine ER (58.6%) and paroxetine (62.5%) groups were considered responders (CGI-I score, 1 or 2) vs those in the placebo group (36.1%), P < .01 for both comparisons.
• 85.6% of the placebo group, 95.7% of the venlafaxine group, and 91.5% of the paroxetine group reported adverse events. The most common events with incidence of 10% or more in the treatment groups were nausea, insomnia, somnolence, asthenia, and dry mouth.
• Mean weight changes were 0.42, -1.23, and 0.21 kg in the placebo, venlafaxine ER, and paroxetine groups, respectively.

Pearls for Practice

• Venlafaxine ER at flexible doses from 75 to 225 mg daily vs placebo is efficacious and tolerable in the short-term treatment of SAD.
• Flexible doses of venlafaxine ER compared favorably with paroxetine in improving LSAS, CGI-I, and in total number of responders for 12 weeks.