Achieving remission from depression with venlafaxine and venlafaxine extended release: a literature review of comparative studies with selective serotonin reuptake inhibitors.

OBJECTIVE: To evaluate data supporting the ability of venlafaxine, an antidepressant with a dual mechanism of action, to produce remission from depression. METHOD: Review of multicentre, double-blind, randomized studies comparing venlafaxine or venlafaxine extended release (XR) with a selective serotonin reuptake inhibitor (SSRI), using Hamilton Depression Rating Scale total scores in the range of < or = 7 and < 10 as the final outcome measure, to evaluate the ability of venlafaxine/venlafaxine XR to produce full remission from depression. RESULTS: Venlafaxine/venlafaxine XR demonstrated higher rates of remission than did the SSRIs and placebo. CONCLUSION: With full remission rather than response as the measure of outcome, venlafaxine/venlafaxine XR demonstrated more robust antidepressant efficacy than the SSRIs and placebo. This finding suggests that venlafaxine/venlafaxine XR are appropriate standard-of-care therapies for the treatment of patients with major depressive disorder.

Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors.

BACKGROUND: It had been suggested that the antidepressant venlafaxine, which inhibits reuptake of both serotonin and (at higher doses) noradrenaline, may result in better outcomes than treatment with selective serotonin reuptake inhibitors (SSRIs). AIMS: To compare remission rates during treatment with SSRIs or venlafaxine. METHOD: Data from eight comparable randomised, double-blind studies of major depressive disorder were pooled to compare remission rates (Hamilton Rating Scale for Depression score < or = 7) during treatment with venlafaxine (n = 851), SSRIs (fluoxetine, paroxetine, fluvoxamine; n = 748) or placebo (four studies; n = 446). RESULTS: Remission rates were: venlafaxine, 45% (382/851); SSRIs, 35% (260/748); placebo, 25% (110/446) (P: < 0.001; odds ratio for remission is 1.50 (1.3-1.9), favouring venlafaxine v. SSRIs). The difference between venlafaxine and the SSRIs was significant at week 2, whereas the difference between SSRIs and placebo reached significance at week 4. Results were not dependent on any one study or the definition of remission. CONCLUSIONS: Remission rates were significantly higher with venlafaxine than with an SSRI.

Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial.

CONTEXT: Generalized anxiety disorder (GAD) is a chronic disorder that is associated with debilitating psychic and somatic symptoms. Venlafaxine extended-release (XR) capsules have been shown to be effective in short-term treatment of patients with GAD without major depressive disorder (MDD), but long-term data are needed to establish whether this agent confers persistent benefits. OBJECTIVE: To compare the 6-month efficacy and safety of a flexible dosage of venlafaxine XR in outpatients with GAD without associated MDD. DESIGN: Six-month, randomized, double-blind, placebo-controlled, parallel-group trial conducted May 1996 to October 1997. SETTING: Fourteen outpatient clinics and private psychiatric practices in the United States. PARTICIPANTS: A total of 251 outpatients aged 18 years or older who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for GAD, had sufficient symptoms to require treatment, and did not have coexisting MDD. INTERVENTIONS: Participants were randomly assigned to receive either placebo (n=127) or venlafaxine XR (75, 150, or 225 mg/d, as required to control symptoms; n=124) for 28 weeks. MAIN OUTCOME MEASURES: Changes from baseline in the Hamilton Rating Scale for Anxiety (HAM-A) total score, the HAM-A psychic anxiety factor score, and the Clinical Global Impressions (CGI) scale Severity of Illness and Global Improvement scores, compared by intervention group. RESULTS: During weeks 6 through 28, response rates in the venlafaxine XR group were 69% or higher compared with rates of 42% to 46% in the placebo group (P<.001). By an evaluable-patient analysis, venlafaxine XR compared with placebo significantly improved anxiety scores from week 1 or 2 through week 28 on all primary efficacy measures, including the HAM-A total (P<.001), the HAM-A psychic anxiety factor (P<.001), and the CGI scale scores (P<.001). Adjusted mean changes from baseline to week 28 using last-observation-carried-forward methods were for HAM-A, venlafaxine XR -13.4, placebo -8.7 (P<.001); for HAM-A psychic anxiety score, venlafaxine XR -7.4, placebo -4.2 (P<.001); and for CGI-Improvement, venlafaxine XR 2.2, placebo 3.0 (P<.001). The most common treatment-emergent adverse event was nausea, followed by somnolence and dry mouth. CONCLUSIONS: This study is the first placebo-controlled demonstration of the long-term efficacy of any drug class in treating outpatients with DSM-IV-diagnosed GAD. Venlafaxine XR is an effective, rapidly acting, safe, once-daily agent for both the short- and long-term treatment of anxiety and may provide an important alternative to currently available anxiolytics. JAMA. 2000.

Evidence of the dual mechanisms of action of venlafaxine.

BACKGROUND: Indirect evidence suggests that the antidepressant venlafaxine hydrochloride selectively inhibits serotonin (5-HT) uptake at low doses, whereas at high doses, it inhibits both 5-HT and norepinephrine (NE) uptake. We hypothesized that, in vivo, both high and low doses would inhibit the 5-HT uptake of platelets but that the higher dose would differentially blunt the pressor response to tyramine, a marker for NE uptake. METHODS: Healthy male volunteers aged 18 to 45 years received either 75 mg or 375 mg of venlafaxine hydrochloride per day, the 5-HT uptake inhibitor sertraline hydrochloride (50 mg/d), or the NE uptake inhibitor maprotiline hydrochloride (150 mg/d) (n = 8 for each of 4 treatment groups). Changes in platelet 5-HT uptake and the pressor response to intravenous tyramine were assessed following the initial dose and after 1 and 2 weeks of drug administration. RESULTS: Platelet 5-HT uptake was inhibited by venlafaxine across the dose range and by sertraline but not maprotiline. Inhibition was competitive, related to increases in affinity and not related to capacity. Steady-state drug levels were associated with a 5-HT uptake inhibition of 87% or more in subjects taking venlafaxine or sertraline. The pressor response to tyramine differentially distinguished maprotiline from sertraline and the low dose of venlafaxine but not from the high dose of venlafaxine. CONCLUSION: This study provides the first in vivo evidence in healthy humans that both 5-HT uptake and NE uptake inhibition are mechanisms of action sequentially engaged by venlafaxine over its clinically relevant dose range.

A double-blind, randomized, placebo-controlled trial of once-daily venlafaxine extended release (XR) and fluoxetine for the treatment of depression.

BACKGROUND: We compared the efficacy and tolerability of venlafaxine XR with that of fluoxetine in a multicenter, randomized, double-blind, placebo-controlled study in depressed outpatients. METHODS: Outpatients, 18 years and older, who met DSM-IV criteria for major depressive disorder were included (n = 301 randomized; 232 completed). Patients were randomly assigned to eight weeks of treatment with either venlafaxine XR 75-225 mg/day (n = 100), fluoxetine 20-60 mg/day (n = 103), or placebo (n = 98). The primary efficacy outcome measures were the final ratings on the Hamilton Rating Scale for Depression (HAM-D21) total score, HAM-D21 depressed mood item, Montgomery-Asberg Depression Rating Scale total score, and Clinical Global Impressions Scale. RESULTS: Withdrawal from the study due to adverse events occurred in 6% of the patients in the venlafaxine XR group and 9% of the patients in the fluoxetine group. Patients treated with venlafaxine XR, but only rarely those treated with fluoxetine, had statistically significant improvements in their depression ratings compared with placebo at the end of the study. The percentages of patients who achieved full remission of their depression (HAM-D21 total score < or = 7) at the end of treatment were 37%, 22% and 18% for the venlafaxine XR, fluoxetine and placebo groups, respectively. The differences in remission rates between venlafaxine XR and the other groups were statistically significant (p < 0.05). LIMITATIONS: The superior remission outcome observed with venlafaxine XR treatment needs to be replicated in additional studies. CONCLUSION: Venlafaxine XR is a well-tolerated and efficacious treatment for depression. The results of this study suggest that venlafaxine XR is as well-tolerated as fluoxetine but may have some efficacy advantages over fluoxetine.

A meta-analysis of the effects of venlafaxine on anxiety associated with depression.

Venlafaxine is the first member of a novel class of antidepressants that inhibits the reuptake of both serotonin and norepinephrine. Clinical trials of venlafaxine have demonstrated its efficacy and safety in the treatment of patients diagnosed with major depression. Because patients who have depression also often have anxiety, recent investigations have focused on determining whether venlafaxine can relieve symptoms of anxiety in depressed patients. We performed a pooled analysis of six short-term trials of venlafaxine, retrospectively measuring anxiety in anxious depressed patients using the Hamilton Rating Scale for Depression (HAM-D), Anxiety/Somatization factor and Anxiety Psychic item scores. Three studies were placebo-controlled, and three were placebo- and active-drug-controlled; active controls were imipramine in two trials and trazodone in the third trial. Patients were categorized as having anxiety accompanying depression if baseline HAM-D Anxiety Psychic item scores were 2 or greater. Anxious depressed patients treated with venlafaxine showed greater improvement than those treated with placebo beginning at week 3, according to the HAM-D Anxiety/Somatization factor score, and beginning at week 1, according to the Anxiety Psychic item score. Both effects were maintained at week 6 of treatment (and at week 12 in the one study of longer duration). Finally, treatment with venlafaxine resulted in a highly significant (p < or = 0.001) improvement in depression scores in patients who were anxious at baseline, compared with placebo-treated patients. The results of this analysis demonstrate that venlafaxine is more effective than placebo in reducing symptoms of anxiety in depressed patients and suggest that venlafaxine may afford a monotherapy option for treating patients who have a comorbid diagnosis of depression with anxiety.

A randomized, placebo-controlled, dose-response trial of venlafaxine hydrochloride in the treatment of major depression.

BACKGROUND: We examined the efficacy and safety of three different dosages of venlafaxine hydrochloride (75, 225, and 375 mg/day) in a multicenter, randomized, double-blind, placebo-controlled, four-group study. METHOD: Outpatients, 18 to 65 years old, who met DSM-III criteria for major depression were included (N = 358 randomized; 194 completed). Of the total patients completing the trial, 59%, 56%, 51%, and 51% were in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. The primary outcome measures were the Hamilton Rating Scale for Depression (HAM-D21) total, HAM-D21 depression item, Montgomery-Asberg Depression Rating Scale total, and Clinical Global Impressions scale. RESULTS: Each dosage of venlafaxine was associated with statistically significant improvement as compared with placebo, based on the intent-to-treat sample. The two higher dosages were associated with a modestly greater antidepressant response than was the 75-mg dosage. Nausea, dizziness, somnolence, and anorexia were the most common adverse events attributable to venlafaxine. Since headache occurred at a similar frequency in both the drug and placebo groups, we did not consider it to be attributable to venlafaxine use. Withdrawal from the study due to adverse events occurred in 5%, 17%, 24%, and 30% of the patients in the placebo, 75-mg, 225-mg, and 375-mg groups, respectively. CONCLUSION: Venlafaxine, at dosages of 75-375 mg/day, is an effective and well-tolerated antidepressant. With increasing dosage, greater efficacy and possibly more adverse effects will occur.

The use of venlafaxine in the treatment of major depression and major depression associated with anxiety: a dose-response study. Venlafaxine Investigator Study Group.

This 12-week, double-blind, placebo-controlled study evaluated the efficacy and safety of venlafaxine as first-line therapy for the treatment of major depression and major depression associated with anxiety in 384 adult outpatients. Fixed total daily dosages of 75, 150, and 200 mg of venlafaxine were administered in a twice-a-day regimen. Primary efficacy parameters were the Hamilton Rating Scale for Depression (HAM-D) total score, the HAM-D Depressed Mood Item, the Montgomery-Asberg Depression Rating Scale total score, and the Clinical Global Impressions Scale. Overall, a higher percentage of patients responded to venlafaxine than to placebo. Efficacy data indicated a dose-related response, most evident in the onset of clinical improvement; statistically significant improvements in some primary parameters were seen as early as 1 to 2 weeks after initiation of treatment, especially in the 150-and 200-mg/day groups. These dose-related clinical improvements continued through week 12. Venlafaxine-treated patients who had depression associated with anxiety showed significant dose-related improvements compared with placebo-treated patients; improvement was noted by scores on the HAM-D Anxiety-Psychic Item and Anxiety-Somatization Factor. Few clinically significant changes were observed in laboratory values, vital signs, or electrocardiogram tracings. Venlafaxine was generally well tolerated at all dosages. The most common study events included nausea, dizziness, somnolence, insomnia, dry mouth, and asthenia, which are consistent with findings of previous studies. The current study demonstrated that 75 to 200 mg/day of venlafaxine twice daily produced a dose-related improvement in the primary efficacy parameters and in the onset of significant antidepressant effects, which was noted at weeks 1 to 2 with the highest dosage tested (200 mg/day). The study also demonstrated that these dosages of venlafaxine were safe and effective as first-line therapy for major depression and depression associated with anxiety.

Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics.

This single- and multiple-dose, nonrandomized, inpatient study was conducted to determine the effects of age and gender on the pharmacokinetic profiles of the antidepressant venlafaxine and its equally active metabolite, O-desmethylvenlafaxine. The subjects were 18 elderly (age 60-80 yrs) and 18 young (age 21-44 yrs) subjects, 9 men and 9 women per age group. They received a single 50-mg venlafaxine dose followed by 50-mg doses every 8 hours for 5 days. No significant differences in venlafaxine single-dose pharmacokinetics were seen between age groups, but the steady-state half-life increased 24% in the elderly. For O-desmethylvenlafaxine, single doses had a significantly lower apparent clearance in the elderly (0.29 vs 0.38 L/hr/kg), longer half-life (13.2 vs 10.3 hrs), and 14% greater steady-state half-life. For the composite (venlafaxine+O-desmethylvenlafaxine), there was a nonsignificant 16% increase in elderly steady-state area under the curve (AUC* = AUC+activity factor AUCm), and AUC* was linear between doses and age groups. We conclude that venlafaxine dosage adjustments for age or gender are not necessary based on pharmacokinetics.

The safety and tolerability of venlafaxine hydrochloride: analysis of the clinical trials database.

The tolerability and safety of venlafaxine hydrochloride, a new serotonin and norepinephrine reuptake inhibitor, are reviewed in this article. The data presented here are based on a pool of 3,082 patients who were treated with this agent during clinical trials. Of these patients, 2,897 received venlafaxine for depression; 455 of these patients were treated for more than 360 days. The tolerability and safety profiles of venlafaxine were similar to those previously reported for selective serotonin reuptake inhibitors. Patients receiving venlafaxine experienced nausea, insomnia, dizziness, somnolence, constipation, and sweating more often than did patients receiving placebo but reported anticholinergic events less frequently than did patients receiving tricyclics. This is accounted for by the fact that, unlike the tricyclics, venlafaxine lacks significant affinity for muscarinic cholinergic receptors. Resolution of venlafaxine-associated nausea occurred rapidly in the vast majority of the patients who reported it at the start of therapy. Serious adverse events were rare among venlafaxine-treated patients. A small percentage of the patients given venlafaxine experienced modest but significant increases in blood-pressure readings, similar to those observed among imipramine-treated patients. At mean daily venlafaxine dosages of up to 300 mg, the percentage of venlafaxine-treated patients who had sustained elevations in supine diastolic blood pressure during treatment ranged from 2% to 6%, compared with 2% and 5% among the placebo- and imipramine-treated patients, respectively. All of the 14 patients who took an overdose of venlafaxine recovered without sequelae. Tolerability and safety in the elderly did not differ significantly from that observed in younger patients.

Efficacy of venlafaxine and placebo during long-term treatment of depression: a pooled analysis of relapse rates.

The objective of this analysis was to determine the efficacy of venlafaxine in comparison with that of placebo during long-term treatment. A pooled analysis of relapse rates in outpatients with major depression continuing long-term treatment (up to 12 months) after responding to short-term treatment (6 weeks) was performed combining the data from four randomized, double-blind, placebo-controlled clinical trials. Relapses were defined as two consecutive Clinical Global Impression (CGI) severity scores greater than 3 (mildly ill), as a CGI severity score greater than 3 at withdrawal regardless of the reason for withdrawal, or as withdrawal due to lack of efficacy. Data from 304 patients (185 venlafaxine, 119 placebo) well balanced for baseline characteristics were included in the pooled analysis. Percentages of patients completing the long-term phase were 38% venlafaxine and 26% placebo (p = 0.034). Cumulative relapse rates by 6 months of long-term treatment were 11% venlafaxine and 23% placebo (p = 0.019). Cumulative relapse curves for the venlafaxine and placebo groups over the 1-year long-term treatment differed significantly (p = 0.022). The results from this analysis indicate that long-term treatment with venlafaxine in patients with major depressive disorder is effective in maintaining the initial response compared with placebo and suggest that venlafaxine will be effective in the prevention of relapse.

Venlafaxine oxidation in vitro is catalysed by CYP2D6.

1. Several selective 5-HT reuptake inhibitors (SSRIs) are inhibitors of the genetically polymorphic drug metabolizing enzyme, CYP2D6. We studied the interaction of venlafaxine, a new SSRI, with CYP2D6 in human liver microsomes. 2. Venlafaxine was a less potent inhibitor of this enzyme activity in vitro than other SSRIs tested. The average apparent Ki values determined using CYP2D6-dependent dextromethorphan O-demethylation were: 33, 52 and 22 microM for rac-venlafaxine, R(+)-venlafaxine and S(-)-venlafaxine, respectively, vs 0.065 to 1.8 microM for paroxetine, fluoxetine, norfluoxetine, fluvoxamine and sertraline. 3. Microsomes from human livers (n = 3) and from yeast transformed with an expression plasmid containing human CYP2D6 cDNA catalyzed the O-demethylation of venlafaxine, which is the major metabolic pathway in vivo. Intrinsic metabolic clearance values (Vmax/Km) indicated that S(-)-venlafaxine was cleared preferentially via this pathway. 4. In microsomes from CYP2D6-deficient livers (n = 2), Vmax/Km of O-demethylation of venlafaxine was one to two orders of magnitude lower and was similar to the rate of N-demethylation. 5. Studies with chemical probes which preferentially inhibit P450 isoforms suggested that CYP3A3/4 is involved in venlafaxine N-demethylation. 6. These in vitro findings predict phenotypic differences in the kinetics of venlafaxine in vivo, although the clinical importance of this is unclear as O-demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.

Effectiveness of venlafaxine treatment in a broad spectrum of depressed patients: a meta-analysis.

The effectiveness of the novel antidepressant venlafaxine was assessed in various subpopulations of depressed patients. Data from six comparable placebo-controlled, double-blind studies were pooled and analyzed (venlafaxine, n = 930; placebo, n = 500). Outcome variables were the Hamilton Rating Scale for Depression total score, Montgomery-Asberg Depression Rating Scale total score, and Clinical Global Impressions severity scores. Venlafaxine had notable antidepressant results in depressed patients regardless of age (although no age differences were apparent, too few patients over age 65 had been enrolled in the six studies to permit definitive conclusions), gender, presence of melancholia, and severity or duration of depression. Our analysis indicates that venlafaxine treatment is effective in a broad range of depressed patients.

Light and electron-microscopic changes in the colon of the guinea pig after treatment with anthranoid and non-anthranoid laxatives.

Male guinea pigs were treated with senna pods, sennosides, danthron or bisacodyl by gastric intubation for 14 consecutive days. The animals were then killed and the intestine was evaluated by light and electron-microscopic techniques. Macroscopically, the mucosa of the cecum and upper colon was brown in color in the animals receiving anthranoid laxatives. No visible changes were detectable in the bisacodyl group. Evaluation by light and electron microscopy revealed cytoplasmic degeneration and increased apoptosis in the colonic surface epithelium after all laxatives. Most of the resulting apoptotic bodies were found in the lamina propria or had been phagocytosed by stromal macrophages, where they had been transformed into dark brown (anthranoids) or grey to light brown (bisacodyl) pigments. The intestinal changes were most pronounced in the cecum and decreased towards the distal part of the colon. It can be concluded that the morphological changes in the large intestine were similar in anthranoid and non-anthranoid treatment, with the exception that the pigments found in macrophages differed in color and were therefore not always detectable macroscopically.

Introduction of a composite parameter to the pharmacokinetics of venlafaxine and its active O-desmethyl metabolite.

Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three-period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O-desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady-state elimination half-life was 3 to 4 hours for venlafaxine and 10 hours for O-desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral-dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O-desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O-desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor.AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high-clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose-proportionality.

Electron microscopical studies on rat intestine after long-term treatment with sennosides.

After gastric administration of daily 100 mg sennosides/kg body weight, no morphological differences could be found between the colon of treated rats and the controls. In particular, no damage to the intramural nerve tissue could be seen under the electron microscope.

Localization of papillomavirus and virus-specific antigens in the skin of tumor-bearing Mastomys natalensis (GRA Giessen).

In skin neoplasms (so-called keratoakanthomas, papillomas, and squamous cell carcinomas) of Mastomys natalensis (GRA Giessen) virus particles and viral antigens were demonstrated in distinct epithelial layers. Nuclei of the upper parts of the stratum granulosum and disintegrated cell parts of the stratum corneum contain viral structures. The localization of virus particles and viral antigens in any skin neoplasms of M. natalensis (GRA Giessen) corresponded to the sites where papillomavirus-specific material had been demonstrated in papillomas of other species.