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Venlafaxine Extended-Release

A Review of its Clinical Potential in the Management of Generalised Anxiety Disorder

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Sumamry

Abstract

Venlafaxine inhibits presynaptic reuptake of both serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). Dysregulation of one or both of these neurotransmitters has been implicated in anxiety disorders, which often co-exist with depressive disorders.

Venlafaxine extended release (XR) formulation has been evaluated in patients with generalised anxiety disorder (GAD) as defined in the DSM-IV without comorbid major depression. In randomised, double-blind, placebo-controlled, multi-centre studies, venlafaxine XR 75 to 225 mg/day produced greater improvements in Hamilton Rating Scale for Anxiety (HAM-A) total scores than placebo. A therapeutic effect was evident within 1 week of the initiation of treatment with venlafaxine XR and improvements were sustained over ≤28 weeks. In 2 long term (6 month) studies all dosages of venlafaxine were significantly better than placebo. In an 8-week study venlafaxine XR 225 mg/day (but not lower dosages) was significantly better than placebo with respect to reductions in HAM-A total scores. Discontinuation because of an unsatisfactory clinical response was consistently less common among recipients of venlafaxine XR than placebo in the long term studies.

Venlafaxine XR 75 and 150 mg/day was at least as effective as buspirone 30 mg/day and diazepam 15 mg/day in 2 randomised, double-blind, placebo-controlled multicentre trials. Reductions in HAM-A total scores in patients receiving active treatment exceeded those in placebo recipients, but were not statistically significant in either study.

Adverse events pertaining to the digestive (nausea, dry mouth), nervous (insomnia, somnolence, dizziness) and urogenital systems (abnormal ejaculation) were the most frequently reported adverse events in venlafaxine recipients during 8 weeks of treatment in 2 randomised, double-blind, placebo-controlled, multi-centre studies.

In conclusion venlafaxine XR is the only antidepressant presently approved for, and shown to be effective, in the long term management (i.e. ≤6 months) of GAD.

Pharmacology

Venlafaxine and its major active metabolite, O-desmethylvenlafaxine (ODV), inhibit presynaptic reuptake of both serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). The drug does not interact significantly with adrenergic, muscarinic, cholinergic, histamine H1, benzodiazepine or opioid receptors or inhibit monoamine oxidase.

Venlafaxine has a marked suppressive effect on REM sleep in healthy volunteers and patients with depression; it reduced the absolute power and increased beta and decreased alpha activity on the EEG in healthy volunteers. At dosages of ≤150 mg/day, venlafaxine did not have any clinically significant adverse effects on psychomotor performance. Although the drug impaired vigilance, it did not impair driving ability at a dosage of ≤150 mg/day for 2 weeks. Venlafaxine did not exacerbate the detrimental effects of diazepam or alcohol on psychomotor performance.

At high dosages venlafaxine may elevate blood pressure (BP) in some patients. Dosages >300 mg/day are not associated with a significant risk of sustained BP elevation.

Pharmacokinetic Properties

The absolute bioavailability of venlafaxine XR (45%) is not affected by food or the time of administration. Plasma concentrations of the drug are not affected by gender or age. Maximum plasma concentrations (Cmax) of venlafaxine and ODV occur approximately 5.5 and 9 hours, respectively, after administration of venlafaxine XR. Proportionality between the dosage and plasma concentrations of venlafaxine has been demonstrated. Steady-state concentrations in plasma are achieved after 3 days of administration. 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 of the drug (determined by genetic polymorphism in CYP2D6 activity) plasma concentrations of venlafaxine are higher. Terminal elimination half-lives of venlafaxine and ODV were 5 and 11 hours, respectively, in healthy volunteers. Venlafaxine and its metabolites are excreted primarily by the renal route (87% of a dose).

Clearance of the 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. Cimetidine inhibited metabolism of venlafaxine, but not ODV, in healthy volunteers; the interaction may not be of clinical significance.

Clinical Potential

The clinical potential of once daily venlafaxine XR has been investigated in patients with generalised anxiety disorder (GAD) who did not have comorbid major depressive disorder (MDD), as defined in DSM-IV, in randomised, double-blind, placebo-controlled, multicentre trials.

Within 1 week of the initiation of treatment with venlafaxine XR, a therapeutic effect was evident. After 7 days of treatment with venlafaxine XR 75 mg/day in a flexible dose study, significant reductions in all primary efficacy variables [mean Hamilton Rating Scale for Anxiety (HAM-A) total, HAM-A Psychic Anxiety Factor and Clinical Global Impression (CGI)-Severity scores] were evident. During each week of this 28-week study, HAM-A total scores and scores on each of the HAM-A subscales, and CGI-Severity scores were significantly lower among recipients of venlafaxine XR 75 to 225 mg/day than placebo.

Throughout 2 fixed dose studies, mean reductions in HAM-A total and HAM-A Psychic Anxiety Factor scores were greater in each of the venlafaxine XR dosage groups compared with placebo. These differences were statistically significant after 24 weeks of treatment with venlafaxine XR 37.5 to 150 mg/day in one study. At the end of the other study (8 weeks), statistically significant reductions in HAM-A total scores were obtained in patients treated with venlafaxine XR 225 mg/day, but not lower dosages.

Therapeutic responses to venlafaxine XR, defined as ≥40 or ≥50% reductions in HAM-A total scores, were apparent within 2 weeks and were maintained throughout the 2 long term studies. Among those treated with venlafaxine XR 75 to 225 mg/day in these studies, the proportion of responders was approximately 70% or greater after ≥24 weeks of treatment (≤50% of placebo recipients were designated as responders).

Discontinuation of venlafaxine XR because of an unsatisfactory clinical response occurred infrequently during the 8-week study and was consistently less common than in placebo recipients in the long term studies.

Venlafaxine XR 75 and 150 mg/day were at least as effective as buspirone 30 mg/day and diazepam 15 mg/day in 2 randomised, double-blind, placebo-controlled multicentre trials. Reductions in HAM-A total scores in patients receiving active treatment exceeded those in placebo recipients, but were not statistically significant in either study.

In the comparative study which involved buspirone, reductions in psychic anxiety scores, and scores for anxious mood and tension on the HAM-A instrument were all significantly lower among patients treated with venlafaxine XR 75 and 150 than placebo. Similarly CGI-Improvement and CGI-Severity scores were reduced to a significantly greater extent with the lower dosage (vs placebo).

In the comparative study which included a diazepam treatment group, there were no significant differences between active treatments and placebo in the HAM-A total score. In a ‘verum-sensitive’ analysis which excluded results from sites showing no statistically significant difference between HAM-A total scores in diazepam and placebo recipients, venlafaxine XR produced statistically significant reductions in HAM-A total scores versus placebo.

According to the results of a pooled analysis of 2 studies, long term treatment with venlafaxine XR increases the probability of remission, defined as an absolute HAM-A score ≤7, in patients with GAD.

Tolerability

The adverse event profile of venlafaxine XR is similar in patients with depression or GAD. Adverse events pertaining to the digestive (nausea, dry mouth), nervous (insomnia, somnolence, dizziness) and urogenital systems (abnormal ejaculation) were the most frequently reported adverse events in venlafaxine XR recipients during 8 weeks of treatment in 2 randomised, double-blind, placebo-controlled, multicentre studies. The proportion of patients withdrawing from these studies because of adverse effects was approximately 23% and 10% in patients receiving venlafaxine XR and placebo, respectively. Nausea (10 vs ≤1%, respectively) and insomnia (5 vs 2%, respectively) were the most common events causing treatment discontinuation.

In patients with GAD, the frequency of nausea associated with venlafaxine XR decreased over time in long term studies.

Nausea and dry mouth were reported by a greater proportion of venlafaxine XR recipients (≤44 and ≤25% of patients, respectively) than in those receiving buspirone (30 and 5%) or placebo (13 and 5%) in a comparative study. Buspir-one-treated patients were more likely to report dizziness (47%) than were those who received venlafaxine XR (≤21%) or placebo (13%).

Venlafaxine is markedly less hazardous than the tricyclic antidepressants in overdosage. Two patients with GAD who took overdoses of the drug during clinical trials recovered without adverse effects. 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 ≤7 days of discontinuation of monoamine oxidase inhibitors. This combination is contraindicated.

Dosage and Administration

Venlafaxine XR is indicated for the treatment of GAD as defined by DSM-IV criteria. The recommended initial dosage of the drug in patients with GAD is 75mg once daily, taken with or without food, at the same time each day. In patients who do not improve with 75 mg/day, the dosage may be titrated in 37.5 or 75 mg/day increments, at intervals of not less than 4 days, to a maximum dosage of 225 mg/day. The optimum duration of treatment for patients with GAD is not known. 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.

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Authors and Affiliations

  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Julia A. Barman Balfour & Blair Jarvis

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  1. Julia A. Barman Balfour
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  2. Blair Jarvis
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Correspondence to Blair Jarvis.

Additional information

Various sections of the manuscript reviewed by: J-C. Béique, Neurobiological Psychiatry Unit, McGill University, Montreal, Quebec, Canada; W.D. Horst, The Psychiatric Research Institute and The Department of Psychiatry, University of Kansas School of Medicine, Wichita, Kansas, USA; M.H. Lader, Institute of Psychiatry, University of London, London, England; R.H. McAllister-Williams, School of Neurosciences, Division of Psychiatry, The Royal Victoria Infirmary, University of Newcastle, Newcastle upon Tyne, England; K. Rickels, Mood and Anxiety Disorders Section, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA; L. Staner, Service de Psychiatrie Générale, Centre Hospitalier de Rouffach, Rouffache, France; E. Szabadi, Department of Psychiatry, Queen’s Medical Centre, Nottingham, England.

Data Selection

Sources: Medical literature published in any language since 1983 on Venlafaxine XR, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘Venlafaxine XR’ or ‘Venlafaxine extended release’ or ‘Venlafaxine controlled-release-drugs’ and ‘generalised-anxiety-disorders’. Medline search terms were ‘Venlafaxine XR’ or ‘Venlafaxine extended release’. EMBASE search terms were ‘Venlafaxine XR’ or ‘Venlafaxine extended release’. Searches were last updated 23 Oct, 2000.

Selection: Studies in patients with generalised anxiety disorder who received venlafaxine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: venlafaxine, generalised anxiety disorder, pharmacodynamics, pharmacokinetics, therapeutic use.

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Balfour, J.A.B., Jarvis, B. Venlafaxine Extended-Release. CNS Drugs 14, 483–503 (2000). https://doi.org/10.2165/00023210-200014060-00006

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