Venlafaxine (Effexor® XR)

Effexor® , Effexor® XR

Classification:
Psychotropic Agents

• Antidepressants
  
  • Serotonin norepinephrine reuptake inhibitors

Description: Venlafaxine is an oral antidepressant agent of the Serotonin-Norepinephrine Reuptake Inhibitor class. Venlafaxine is a ‘dual’ inhibitor; it inhibits serotonin reuptake at select receptors, but unlike the pure SSRIs, it also inhibits the reuptake of norepinephrine. It appears to be effective in treating patients with melancholia, a severe form of depression. Venlafaxine has been studied for the treatment of panic disorder, post-traumatic stress disorder, and the treatment of hot flashes in breast cancer survivors. The side effect and drug interaction profile of venlafaxine is very similar to that of the selective serotonin reuptake inhibitors (SSRIs). While venlafaxine does not exhibit MAO inhibition activity, it should not be used in patients who are receiving or have recently received MAOI therapy. Venlafaxine was approved by the FDA for the treatment adults with major depression in December 1993. An extended-release formulation was first approved in 1997 for the same indication. In 1999, venlafaxine (Effexor XR® ) became the first antidepressant to receive FDA approval for the treatment of generalized anxiety disorder (GAD) in adults. In February 2003, venlafaxine received FDA approval for social anxiety disorder (social phobia). Phase III trials of Effexor XR® are in progress for the treatment of depression in children 8 - 16 years of age. On November 18, 2005 the FDA approved extended-release venlafaxine (Effexor XR® ) for the treatment of panic disorder in adults. On March 22, 2004 the FDA issued a Public Health Advisory for several antidepressants, including venlafaxine, warning of increased risk of worsening depression or suicidal tendency in adults and children (see Contraindications). In September 2003, the UK government urged physicians to stop prescribing Effexor® to children for depression due to an elevated risk for suicide in those children.

On October 15, 2004 the FDA directed manufacturers of all antidepressants to include a Black Box warning, expanded warning statements, and clinical trial results detailing the increased risk of suicidality in children and adolescents. A Patient Medication Guide (MedGuide) will also accompany all prescriptions for antidepressants. The FDA is currently assessing the risk of suicidality in adults taking antidepressants and a final report is expected by mid- to late 2006.

Mechanism of Action: Like the tricyclics, venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), exert their antidepressant effects by inhibiting the reuptake of both serotonin and norepinephrine. In vivo, venlafaxine blocks both reuptake processes, with a potency greater for the 5-HT than for the NE reuptake process. Like the SSRI’s, venlafaxine appears to act preferentially on certain serotonin receptors in vivo, but mechanisms have not been precisley defined. Both venlafaxine and the ODV metabolite have weak inhibitory effects on the reuptake of dopamine. Unlike the tricyclics and similar to SSRIs, venlafaxine and ODV do not exert activity at histaminergic, muscarinic, or alpha1-adrenergic receptors in vitro, which accounts for its lack of anticholinergic, sedative, and cardiovascular side effects frequently observed with the tricyclic antidepressants. However, despite the claims of minimal muscarinic receptor activity, anticholinergic-related side effects may still occur with venlafaxine. Neither parent nor metabolite possess monoamine oxidase inhibiting activity.

Pharmacokinetics: Venlafaxine is administered orally. It is well absorbed from the gastrointestinal tract, with food having no significant effect on venlafaxine absorption or the formation of its active metabolite, O-desmethylvenlafaxine (ODV). After administration of an immediate-release tablet, time to peak serum concentration occurs at approximately 2 and 4 hours for venlafaxine and ODV, respectively; administration of the extended-release formulation results in later times to peak serum concentration (5.5 hours for venlafaxine and 9 hours for ODV). Protein binding is approximately 27% for venlafaxine and 30% for ODV. Metabolism occurs hepatically, with elimination occurring primarily via the urine as unchanged drug, conjugated ODV, ODV, and inactive metabolites. The elimination half-lives of venlafaxine and ODV are 5 and 11 hours, respectively, and are affected by the presence of hepatic and/or renal disease.