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Venlafaxine

A Review of its Pharmacology and Therapeutic Potential in Depression

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Summary

Synopsis

Venlafaxine is a phenylethylamine derivative which facilitates neurotransmission in the brain by blocking presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). Clinical data from patients with major depression are consistent with the favourable efficacy and tolerability profile of venlafaxine predicted by pharmacodynamic studies.

In patients with major depression, venlafaxine 75 to 375 mg/day administered for 6 weeks was significantly more effective than placebo, and at least as effective as imipramine, clomipramine, trazodone or fluoxetine. Venlafaxine is well tolerated, being associated with fewer anticholinergic and CNS adverse effects than tricyclic antidepressants. Unlike the tricyclic antidepressants, venlafaxine does not appear to significantly affect cardiac conduction, although there have been a few reports of modest increases in blood pressure, particularly after high doses of the drug.

In conclusion, wider clinical experience is required to better characterise and confirm potential advantages of venlafaxine compared with other antidepressant agents. These advantages may include a rapid onset of action and reduced propensity to cause anticholinergic effects and cardiotoxicity compared with tricyclic antidepressants. Nevertheless, at this stage venlafaxine offers a more attractive treatment option than tricyclic antidepressants for patients with major depression, primarily because of its good overall tolerability profile.

Pharmacological Properties

Venlafaxine is a phenylethylamine derivative possessing a neuropharmacological profile which differs from that of tricyclic antidepressant drugs. In vitro, venlafaxine inhibits synaptosomal reuptake of both serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine); the drug is a relatively weak inhibitor of dopamine reuptake. Its potency in inhibiting serotonin reuptake is approximately 5 times that of its noradrenaline reuptake inhibitory activity. The antidepressant potential of venlafaxine has also been demonstrated in in vivo models of depression. Venlafaxine has no significant affinity for adrenergic, muscarinic cholinergic or histamine H1 receptors. Venlafaxine exists as a racemic mixture of (−) and (+) enantiomers. The (−) enantiomer inhibits noradrenaline and serotonin presynaptic reuptake, while the (+) enantiomer primarily inhibits serotonin reuptake. Single and multiple doses of venlafaxine have been shown to produce modest increases in blood pressure in healthy volunteers and patients with depression.

Venlafaxine undergoes extensive first-pass metabolism to the major O-demethyl metabolite, and 2 minor metabolites. O-demethylvenlafaxine inhibits noradrenaline and serotonin reuptake with similar potencies to those of the parent compound. Excretion of venlafaxine and its metabolites is primarily by the renal route, with only 4.7% of an administered dose appearing in urine as unchanged drug. The elimination half-life of venlafaxine is approximately 4 hours and that of O-demethylvenlafaxine is about 10 hours. There were no apparent differences in steady-state pharmacokinetics when 2 and 3 times daily regimens were compared. Clearance of venlafaxine and O-demethylvenlafaxine was reduced by 55% in patients with severe renal impairment and by 33% in patients with cirrhosis.

Therapeutic Efficacy

Available clinical data have demonstrated the antidepressant efficacy of venlafaxine during 6 weeks’ treatment of patients with major depression. Dosages of 75 to 375 mg/day administered as 2 or 3 times daily regimens produced significantly greater improvements in total scores of several depression rating scales versus placebo. In comparisons with other antidepressants generally administered at standard dosages, the efficacy of venlafaxine 75 to 225 mg/day was at least comparable to that of clomipramine, imipramine, trazodone and fluoxetine. Initial data suggest that the onset of action of venlafaxine is about 2 weeks and that its antidepressant activity is maintained for up to 1 year.

Tolerability

Venlafaxine administered at dosages of up to 450 mg/day was well tolerated during short term therapy. Most adverse events were of mild to moderate severity, with many resolving during continued treatment. Venlafaxine 75 to 225 mg/day was better tolerated than clomipramine and imipramine, and as well tolerated as trazodone and fluoxetine. Long term venlafaxine treatment appears to be well tolerated. Generally, venlafaxine does not appear to adversely affect the cardiovascular system; the clinical significance of modest increases in blood pressure reported in a few studies has not been established. The drug does not appear to affect psychomotor performance.

Dosage and Administration

The recommended starting dosage of venlafaxine is 75mg daily administered as a 2 or 3 times daily regimen and this may be increased to a maximum of 375 mg/day administered in 3 divided doses. Regular blood pressure monitoring is recommended. The dosage of venlafaxine should be reduced in patients with hepatic or renal impairment. Concomitant administration of venlafaxine and a monoamine oxidase inhibitor is contraindicated.

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    Stephen M. Holliday & Paul Benfield

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Additional information

Various sections of the manuscript reviewed by: P. Beck, Frederiksborg General Hospital, Psychiatric Institute, Hillerød, Denmark; G. Chouinard, Clinical Psychopharmacology Unit, Allan Memorial Institute, Montreal, Quebec, Canada; C.K. Cohn, Department of Psychiatry, University of Texas, Houston, Texas, USA; J.M. Davis, Illinois State Psychiatric Institute, Chicago, Illinois, USA; M.H. Lader, Institute of Psychiatry, University of London, London, England; B.E. Leonard, Pharmacology Department, University College, Galway, Ireland; S.A. Montgomery, Department of Psychiatry, St Mary’s Hospital Medical School, London, England; C.Q. Mountjoy, St Andrew’s Hospital, Northampton, England; M.A. Nader, Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina, USA; M.E. Newman, Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; T.R. Norman, Department of Psychiatry, University of Melbourne, Heidelberg, Victoria, Australia; K. Pacey, University of Houston, Houston, Texas, USA; K. Rickels, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA; B. Saletu, Department of Pharmacopsychiatry and Sleep Research, School of Medicine, University of Vienna, Vienna, Austria; R. Schreiber, Centre de Recherche de Croissy, Croissy-sur-Seine, France; E. Schweizer, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA; E.K.G. Syvälahti, Department of Pharmacology, University of Turku, Turku, Finland; M.R. Trimble, Institute of Neurology, University of London, London, England.

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Holliday, S.M., Benfield, P. Venlafaxine. Drugs 49, 280–294 (1995). https://doi.org/10.2165/00003495-199549020-00010

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