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CNS Drugs

, Volume 15, Issue 8, pp 643–669 | Cite as

Venlafaxine Extended-Release

A Review of its Use in the Management of Major Depression
  • Keri Wellington
  • Caroline M. Perry
Adis Drug Evaluation

Summary

Abstract

Venlafaxine inhibits presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). Venlafaxine extended-release (XR) has been investigated in patients with major depression and in patients with major depression with associated anxiety in randomised, double-blind, multicentre trials. A therapeutic response in patients with major depression was evident at week 2 of treatment with venlafaxine XR 75 to 225 mg/day in a placebo-controlled trial. By week 4, the drug was significantly more effective than placebo at reducing both the Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores. Furthermore, cumulative relapse rates were lower among recipients of venlafaxine XR 75 to 225 mg/day than placebo recipients after 3 and 6 months in another trial. Venlafaxine XR 75 to 150 mg/day was significantly more effective than venlafaxine immediate-release (IR) 75 to 150 mg/day or placebo during a 12-week study. Reductions from baseline in all 4 efficacy parameters (HAM-D, MADRS, HAM-D depressed mood item and the Clinical Global Impression Severity of Illness scale) were significantly higher among patients treated with venlafaxine XR than venlafaxine IR or placebo at week 12 (using an intent-to-treat, last observation carried forward analysis)

Venlafaxine XR 75 to 225 mg/day was compared with fluoxetine 20 to 60 mg/day in patients with major depression in 2 randomised, double-blind, placebo-controlled, multicentre studies. Remission rates were significantly in favour of venlafaxine XR recipients in one study: 37, 22 and 18% of patients treated with venlafaxine XR, fluoxetine or placebo, respectively, achieved full remission (HAM-D total score ≤7 at end-point). In the other trial, venlafaxine XR and fluoxetine had comparable efficacy in reducing HAM-D and Hamilton Rating Scale for Anxiety (HAM-A) total scores compared with placebo. However, the HAM-A response rate was significantly higher with venlafaxine XR than with fluoxetine at week 12.

In a comparative study involving paroxetine, reductions from baseline in HAM-D and MADRS total scores in patients given venlafaxine XR 75 mg/day or paroxetine 20 mg/day for 12 weeks were significant, but no significant differences between treatment groups were evident.

Discontinuation rates because of unsatisfactory clinical response were similar among patients treated with venlafaxine XR, fluoxetine or paroxetine.

Adverse events pertaining to the digestive (nausea, dry mouth), nervous (dizziness, somnolence, insomnia) and urogenital (abnormal ejaculation) systems as well as sweating were the most frequently reported adverse events during 8 to 12 weeks of treatment in 3 randomised, double-blind, multicentre trials. Comparative studies with fluoxetine and paroxetine demonstrated a similar adverse event profile to venlafaxine XR.

Conclusion: Venlafaxine XR has shown efficacy in the treatment of major depression and was at least as effective as fluoxetine or paroxetine and more effective than venlafaxine IR. Furthermore, it is effective at reducing symptoms of anxiety in depressed patients. The incidence of adverse events in recipients of venlafaxine XR is similar to that in patients receiving treatment with well established selective serotonin reuptake inhibitors. As an effective and well tolerated antidepressant, venlafaxine XR should be considered as a first-line pharmacological treatment in patients with major depression.

Pharmacodynamic Properties

Venlafaxine and its major active metabolite O-desmethylvenlafaxine (ODV) both inhibit presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). Venlafaxine has been referred to previously as a serotonin noradrenergic reuptake inhibitor (SNRI). Venlafaxine also weakly inhibits dopamine reuptake. The drug has no significant affinity for α1-adrenergic, muscarinic cholinergic, H1 histaminergic, benzodiazepine or opioid receptors and does not inhibit monoamine oxidase.

Venlafaxine 75 to 150 mg/day did not impair psychomotor performance to any clinically significant degree in healthy volunteers. Although the drug impaired vigilance, it did not affect driving ability after administration of 75 to 150 mg/day for 2 weeks. Venlafaxine did not exacerbate the detrimental effects on psychomotor performance when coadministered with diazepam or alcohol. However, the drug markedly suppressed rapid eye movement (REM) sleep and increased wake time in healthy volunteers and patients with depression.

Although dosages ≤300 mg/day are not associated with a significant risk of sustained diastolic blood pressure (DBP) elevation, venlafaxine extended-release (XR) may elevate BP in some patients.

Pharmacokinetic Properties

The absolute bioavailability of venlafaxine XR (≈45%) is not affected by food or the time of administration, and plasma concentrations of the drug are not affected by gender or age. Maximum plasma concentrations of venlafaxine and ODV occur approximately 5.5 and 9 hours, respectively, after administration of venlafaxine XR, and steady-state concentrations are reached within 3 days with ongoing administration. Proportionality between the dose and plasma concentrations of venlafaxine has been demonstrated. Plasma protein binding is minimal for venlafaxine (27%) and ODV (30%).

Venlafaxine undergoes extensive cytochrome P450 (CYP) 2D6-mediated first-pass oxidative metabolism to produce ODV. In most individuals, plasma concentrations of ODV are approximately 2- to 3-fold higher than those of the parent drug; in poor metabolisers (determined by genetic polymorphism in CYP2D6 activity), venlafaxine concentrations are higher than ODV concentrations.

The terminal elimination half-lives of venlafaxine and ODV are 5 and 11 hours, respectively, and within 48 hours of administration, 87% of a dose of venlafaxine is recovered in urine.

Clearance of venlafaxine is reduced and dosage adjustments are warranted in patients with mild to moderate renal impairment, in those undergoing haemodialysis and in patients with hepatic cirrhosis.

The results of in vitro and volunteer studies suggest that venlafaxine has a low potential to interfere with the metabolism of other drugs. However, concomitant administration of venlafaxine and diphenhydramine in 9 healthy volunteers with the CYP2D6 extensive metaboliser phenotype resulted in the oral clearance of venlafaxine being decreased by 59% and a more than 2-fold increase in the area under the concentration-time curve. Cimetidine also inhibited the metabolism of venlafaxine, but not ODV, in healthy volunteers; however, the interaction may not be of clinical significance.

Therapeutic Efficacy

The clinical potential of venlafaxine XR, administered once daily, has been investigated in patients with major depression and in patients with major depression with associated anxiety, as defined by DSM-IV or DSM-III-R criteria, in randomised, double-blind, multicentre trials. All studies used an intent-to-treat, last observation carried forward analysis to determine efficacy.

Venlafaxine XR 75 to 225 mg/day produced consistent and significant reductions in all primary outcome measures compared with placebo during an 8-week flexible dose study in patients with major depression. A therapeutic response was evident after 2 weeks of treatment with the drug. By week 4, venlafaxine XR was significantly more effective than placebo at reducing both the Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores. Significantly fewer venlafaxine XR-treated patients discontinued treatment because of lack of therapeutic response than placebo recipients.

Venlafaxine XR 75 to 150 mg/day was significantly more effective than venlafaxine immediate-release (IR) 75 to 150 mg/day or placebo during a 12-week flexible dose study. Reductions from baseline in HAM-D total and Clinical Global Impression Severity of Illness (CGI-S) rating scores were significantly higher among patients treated with venlafaxine XR than venlafaxine IR at week 8. A therapeutic response to venlafaxine XR compared with that to placebo was evident after 2 weeks with respect to reductions in HAM-D total scores and the HAM-D depressed mood item. Furthermore, mean reductions in all primary efficacy variables [HAM-D and MADRS total scores, HAM-D depressed mood item and the CGI-S] were significantly greater among recipients of venlafaxine XR than venlafaxine IR or placebo at week 12.

In a subanalysis of the 2 aforementioned flexible dose studies, venlafaxine XR 75 to 150 mg/day significantly reduced HAM-D psychic anxiety scores compared with placebo. Apooled analysis of both studies involving the HAM-D item scores from the anxiety somatisation cluster (psychic anxiety, somatic anxiety, somatic gastrointestinal and somatic general items) showed that mean score reductions were significantly higher in patients who received venlafaxine XR than placebo or venlafaxine IR at week 12.

Venlafaxine XR has been compared with fluoxetine and placebo in patients with major depression in 2 randomised, double-blind, placebo-controlled, multi-centre studies. In an 8-week study, reductions in HAM-D total scores among patients treated with venlafaxine XR 75 to 225 mg/day or fluoxetine 20 to 60 mg/day were not significantly different to those in placebo recipients. However, whereas venlafaxine XR significantly reduced the MADRS, CGI-S and HAM-D depressed mood scores compared with placebo, fluoxetine significantly reduced only the HAM-D depressed mood item compared with placebo. Remission rates were significantly in favour of venlafaxine XR recipients: 37, 22 and 18% of patients treated with venlafaxine XR, fluoxetine or placebo, respectively, achieved full remission (HAM-D total score ≤7 at end-point). Furthermore, in a 12-week flexible dose study in patients with major depression and associated anxiety, venlafaxine XR and fluoxetine both significantly reduced HAM-D and Hamilton Rating Scale for Anxiety (HAM-A) total scores compared with placebo. There were no significant differences between active treatment groups in any of the measured parameters (total scores of the HAM-D, HAM-A, Hospital Anxiety and Depression Scale and Covi Scale or remission rates). However, the HAM-A response rate was significantly higher (p < 0.05) with venlafaxine XR than with fluoxetine at week 12. Reductions in HAM-A total scores in venlafaxine XR recipients were significantly greater than those in placebo recipients after 8 weeks. Among recipients of fluoxetine, HAM-A total score reductions were higher than those of patients given placebo only at week 12. Both venlafaxine XR and fluoxetine significantly reduced HAM-D total scores compared with baseline values from week 2 to week 12.

In the comparative study involving paroxetine, reductions from baseline in HAM-D and MADRS total scores in patients given venlafaxine XR 75 mg/day or paroxetine 20 mg/day for 12 weeks were both significant, but no significant differences between treatment groups were evident. Similarly, there were no significant between-group differences in response rates based on HAM-D, MADRS or Clinical Global Impression Global Improvement (CGI-I) scales, or in the number of patients achieving remission (defined as a HAM-D score of <7).

Discontinuation rates because of unsatisfactory clinical response were similar among patients treated with venlafaxine XR, fluoxetine or paroxetine.

According to the results from 2 meta-analyses, venlafaxine XR is associated with a significantly higher mean success rate than the selective serotonin reuptake inhibitors fluoxetine, fluvoxamine, sertraline, paroxetine or citalopram, or the tricyclic antidepressants (TCAs) amitriptyline, imipramine, desipramine or nortriptyline. A retrospective pooled analysis also demonstrated significantly higher rates of remission and absence of depressed mood in recipients of venlafaxine compared with paroxetine. However, it was not specified whether patients received venlafaxine XR or IR.

A pharmacoeconomic analysis based on the results from one of these meta-analyses concluded that venlafaxine XR is the most cost-effective antidepressant for the initial treatment of major depression in both inpatients and outpatients.

Tolerability

Among venlafaxine XR recipients, adverse events pertaining to the digestive (nausea, dry mouth), nervous (dizziness, somnolence, insomnia) and urogenital (abnormal ejaculation) systems as well as sweating were the most frequently reported adverse events during 8 to 12 weeks of treatment in 3 randomised, double-blind, multicentre trials.

The proportion of patients withdrawing from these studies because of adverse effects was approximately 11 and 6% in patients receiving venlafaxine XR and placebo, respectively. Nausea (4 vs <1%), dizziness (2 vs 1%) and somnolence (2 vs <1%) were the most common events that resulted in discontinuation of treatment among patients in the 3 studies.

The frequency of nausea associated with venlafaxine XR was highest during the first week of treatment and decreased thereafter.

In one comparative study, dizziness and sweating were reported by a greater proportion of venlafaxine XR recipients (38 and 28% of patients, respectively) than those receiving fluoxetine (18 and 17%), whereas in another study, dizziness and nausea were more prevalent in venlafaxine XR recipients (26 and 36%) than those receiving fluoxetine (6 and 20%). There were no significant between-group differences in adverse events among patients receiving venlafaxine XR or paroxetine, although the mean duration of nausea was twice as long in paroxetine-treated patients (10 days) than in patients treated with venlafaxine XR (5 days).

Venlafaxine can cause some cardiovascular effects in overdose but is markedly less hazardous than the TCAs. Two patients with depression who took overdoses of the drug during clinical trials recovered without serious complication. Nonetheless, the manufacturer advises that fatalities have been reported in patients taking overdoses of venlafaxine, predominantly in combination with alcohol or other drugs. Serotonin syndrome has been reported in patients receiving venlafaxine concomitantly or within ≤16 days of discontinuation of monoamine oxidase inhibitors. This combination is contraindicated. Serotonin syndrome has also been seen in patients taking venlafaxine alone, although rarely.

Dosage and Administration

Venlafaxine XR is indicated for the treatment of depression as defined by DSM-IV criteria. The recommended initial dosage of the drug in patients with depression is 75mg once daily, taken with food at the same time each day. In patients who do not improve with 75 mg/day, the dosage may be titrated in increments of ≤75 mg/day, at intervals of ≥4 days, to a maximum dosage of 225 mg/day. Venlafaxine XR has recently been approved for the prevention of relapse and the prevention of recurrence of depression. Although the optimum duration of treatment in patients with depression has not been determined, international guidelines recommended that, following remission, patients receive venlafaxine XR therapy for 16 to 20 weeks. The manufacturer recommends regular BP monitoring during treatment. Dosage adjustments are not required in elderly patients, but are necessary in those with renal or hepatic dysfunction. When discontinuing venlafaxine XR after more than 1 week’s treatment, the manufacturer recommends that the dosage be tapered in order to minimise the risk of discontinuation symptoms, which include asthenia, dizziness, headache, insomnia, nausea and nervousness.

Keywords

Fluoxetine Major Depression Paroxetine Venlafaxine MADRS Total Score 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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© Adis International Limited 2001

Authors and Affiliations

  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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