Major Depressive Disorder
Venlafaxine hydrochloride is used in the treatment of major depressive disorder. Efficacy of venlafaxine conventional tablets for the management of major depression has been established in several placebo-controlled studies in outpatient settings in patients who had major depression and in 1 placebo-controlled study in a hospital setting in patients who had major depression with melancholia. Efficacy of venlafaxine extended-release capsules for the treatment of major depression also has been established by controlled studies of 8-12 weeks' duration in outpatient settings; however, the safety and efficacy of venlafaxine extended-release capsules in hospitalized patients with major depression have not been adequately evaluated.
In 4 studies of 6 weeks' duration in adult outpatients with major depression, venlafaxine in dosages of 75-225 mg daily administered in 2 or 3 divided doses as conventional tablets was found to be superior to placebo on at least 2 of the following 3 clinical measures of depression: Hamilton Depression Rating Scale (HAM-D) total score, HAM-D depressed mood item, and the Clinical Global Impression (CGI) Severity of Illness Scale. In these studies, higher dosages (i.e., dosages exceeding 225 mg daily) were not associated with greater response. In 2 short-term (8 or 12 weeks), placebo-controlled, flexible-dose (75-225 mg daily) studies with venlafaxine extended-release capsules in adult outpatients, venlafaxine was found to be superior to placebo on the same clinical measures of depression that were used in the studies of venlafaxine conventional tablets, as well as on the Montgomery-Asberg Depression Rating Scale (MADRS) total score and certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, the retardation factor, and the psychic anxiety score.
Venlafaxine also has been shown to be superior to placebo in the management of major depression with melancholia in a hospital setting. In a study of 4 weeks' duration, 65% of hospitalized patients with major depressive disorder and melancholia who received venlafaxine 150-375 mg daily (mean dosage of 350 mg daily) administered in 3 divided doses as conventional tablets had at least a 50% reduction in MADRS total score compared with 28% of those who received placebo. Patients who participated in this study had a mean baseline MADRS total score of 35 (range: 26-48); those with a baseline score of 4 or greater on the suicidal thought item of the MADRS were excluded from the study.
Results of long-term, relapse prevention studies in outpatients with major depression indicate that venlafaxine's antidepressant effects are maintained for up to 1 year. In these studies, patients who responded to an initial 8-week course of venlafaxine 75-225 mg once daily (as extended-release capsules) or an initial 26-week course of venlafaxine 100-200 mg daily in 2 divided doses (as conventional tablets) were randomized to receive either venlafaxine (same dosage range) or placebo. Patients receiving venlafaxine experienced substantially lower relapse rates than those receiving placebo. Relapse was defined in clinical studies with venlafaxine conventional tablets as a score of 4 or greater on the CGI Severity of Illness Scale and in clinical studies with venlafaxine extended-release capsules as a reappearance of major depressive disorder as defined by DSM-IV criteria and a CGI Severity of Illness score of 4 or greater (i.e., moderately severe depression), 2 consecutive scores of 4 or greater on the CGI Severity of Illness Scale, or a final CGI Severity of Illness score of 4 or greater for any patient who withdrew from the study for any reason.
For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risk, .
Generalized Anxiety Disorder
Venlafaxine hydrochloride is used in the treatment of generalized anxiety disorder. Efficacy of venlafaxine extended-release capsules for the management of generalized anxiety disorder has been established in 4 randomized, multicenter, placebo-controlled studies of 2 or 6 months' duration in adult outpatients who met DSM-IV criteria for generalized anxiety disorder. Three studies employed fixed venlafaxine dosages, and the other employed a flexible dosing schedule. In the flexible-dose study, approximately 69% of patients receiving venlafaxine (75-225 mg daily as extended-release capsules) were categorized as responders (defined as a 40% or greater reduction from baseline in the Hamilton Rating Scale for Anxiety [HAM-A] total score or a score of 1 [''very much improved''] or 2 [''much improved''] on the Clinical Global Impressions [CGI] Global Improvement Scale) during weeks 6-28 of therapy compared with 42-46% of those receiving placebo. In separate clinical studies of 2 or 6 months' duration employing fixed dosages of venlafaxine (37.5, 75, 150, or 225 mg daily as extended-release capsules), venlafaxine was shown to be substantially more effective than placebo on HAM-A total score, both the HAM-A anxiety and tension items, and the CGI Scale. While a relationship between dosage (over the dosage range of 75-225 mg daily) and efficacy in generalized anxiety disorder has not been definitively established, dosages of 37.5 mg daily were not as consistently effective in one study as dosages of 75 or 150 mg daily.
Venlafaxine hydrochloride is used in the treatment of social phobia (social anxiety disorder). Efficacy of venlafaxine extended-release capsules in the treatment of social phobia has been established in 2 multicenter, placebo-controlled studies of 12 weeks' duration in adult outpatients who met DSM-IV criteria for social phobia. In these studies, venlafaxine (75-225 mg daily administered as extended-release capsules) was substantially more effective than placebo, as determined by change from baseline in the Liebowitz Social Anxiety Scale (LSAS) total score.
Subgroup analysis of these controlled studies in adult outpatients with social anxiety disorder did not reveal any evidence of gender-related differences in treatment outcome; there was insufficient information to determine the effect of age or race on outcome in these studies.
Venlafaxine hydrochloride is used in the treatment of panic disorder with or without agoraphobia. Efficacy of venlafaxine extended-release capsules in the treatment of panic disorder has mainly been established in 2 multicenter, double-blind, placebo-controlled studies of 12 weeks' duration in adult outpatients who met DSM-IV criteria for panic disorder with or without agoraphobia. Venlafaxine was given in a fixed dosage of 75 or 150 mg once daily as extended-release capsules in one study and in a fixed dosage of 75 or 225 mg once daily as extended-release capsules in the other study. Venlafaxine was found to be substantially more effective than placebo, as determined by percentage of patients free of full-symptom attacks on the Panic and Anticipatory Anxiety Scale (PAAS), mean change from baseline on the Panic Disorder Severity Scale (PDSS) total score, and the percentage of patients rated as responders on the Clinical Global Impressions (CGI) Improvement Scale. While a relationship between dosage (over the dosage range of 75-225 mg daily) and efficacy in panic disorder has not been definitively established, efficacy was established for each dosage studied in these 2 trials.
Subgroup analysis of these controlled studies in adult outpatients with panic disorder did not reveal any evidence of gender-related differences in treatment outcome; there was insufficient information to determine the effect of age or race on outcome in these studies.
In a longer-term study, patients meeting DSM-IV criteria for panic disorder who had responded during the 12-week open phase of a clinical trial with venlafaxine (75, 150, or 225 mg once daily as extended-release capsules) were randomly assigned to either continue receiving venlafaxine in the same dosage range or be switched to placebo and observed for relapse. Relapse was defined as having 2 or more full-symptom panic attacks per week for 2 consecutive weeks or having discontinued therapy due to loss of effectiveness as determined by the study investigators. Patients who continued receiving venlafaxine therapy experienced a significantly longer time to relapse than those receiving placebo in this study.
Venlafaxine has been used for the management of vasomotor symptoms in women with breast cancer and in postmenopausal women. Therapy with the drug has improved both the frequency and severity of vasomotor symptoms (hot flushes [ flashes]) in these women.
Most women receiving systemic antineoplastic therapy for breast cancer experience vasomotor symptoms, particularly those receiving tamoxifen therapy. In a randomized, double-blind, placebo-controlled study in 191 women with breast cancer (69% were receiving tamoxifen) who were experiencing 2 or more episodes of hot flushes daily, the percentage reductions in hot flush severity score at 4 weeks of treatment were 27% for placebo, 37% for venlafaxine 37.5 mg daily, 61% for venlafaxine 75 mg daily, and 61% for venlafaxine 150 mg daily. Comparisons among treatment groups showed that all 3 venlafaxine dosages were associated with a statistically significant reduction in hot flush frequency and severity; in addition, the 75-mg dosage was more effective than the 37. 5-mg dosage, but the 150-mg dosage provided no additional benefit. The role of venlafaxine in managing vasomotor symptoms in women with breast cancer relative to other nonhormonal therapies (e.g., selective serotonin-reuptake inhibitors [SSRIs], gabapentin) remains to be determined. Well-designed, comparative studies are needed to establish optimum nonhormonal therapy, both in terms of efficacy and patient tolerance of adverse effects in these women.
Because of the risks associated with hormone replacement therapy (HRT) for vasomotor symptoms in perimenopausal and postmenopausal women, alternative nonhormonal therapies are being investigated. In a randomized, double-blind, placebo-controlled study in 80 postmenopausal women who were experiencing more than 14 hot flushes weekly, 12 weeks of venlafaxine 75 mg daily was associated with a 51% reduction in hot flush score (patient's perception of hot flush interference with daily living). Although there also was a reduction in hot flush severity, the difference did not reach statistical significance. The role of venlafaxine therapy relative to other nonhormonal therapies (e.g., SSRIs, gabapentin) for postmenopausal vasomotor symptoms, both in terms of efficacy and safety, remains to be established.
Current evidence indicates that venlafaxine is well tolerated in the short-term treatment of vasomotor symptoms associated with breast cancer treatment and with menopause. The principal adverse effects associated with venlafaxine therapy in women with vasomotor symptoms have been dry mouth, decreased appetite, nausea, constipation, and difficulty sleeping. Additional study and experience are needed to further elucidate the role of venlafaxine relative to other nonhormonal therapies and to establish longer-term (i.e., beyond 4-12 weeks) efficacy and safety.
The possible role of venlafaxine in the management of vasomotor symptoms associated with antiandrogenic therapy in men with prostate cancer remains to be determined.
Although substantial changes in appetite and weight have been reported in clinical studies of venlafaxine for the management of major depression, generalized anxiety disorder, social phobia, and panic disorder, the manufacturer states that the drug, alone or in combination with weight loss agents such as phentermine, is not indicated for the management of exogenous obesity. Concomitant use of venlafaxine and weight loss agents also is not recommended by the manufacturer because the safety and efficacy of these agents when used concomitantly have not been established.