Venlafaxine hydrochloride is a synthetic derivative of phenethylamine^[1] and a prescription antidepressant first introduced by Wyeth in 1993, and marketed under the trade names EffexorВ® for tablets and Effexor XRВ® for extended-release capsules. EfexorВ® and Efexor XRВ® / EfexorВ® Depot are alternate trade name spellings used in some countries. Since venlafaxine is under patent, under current United States law, a generic will not be available to U.S. citizens until 2008. The European patent on the drug will hold until 2017.

Uses

Venlafaxine is used primarily for the treatment of depression, generalized anxiety disorder, and social anxiety disorder in adults. It is known as one of the most activating or energizing of the newer antidepressants. While this can be helpful to some, as many depressed patients report feeling exhausted and unmotivated, to others it poses the risk of increased anxiety and agitation.

Venlafaxine is an effective antidepressant for many persons; however, it seems to be especially effective for those with treatment-resistant depression. Some of these persons have taken two or more antidepressants prior to venlafaxine with no relief. It has also been found to reduce the severity of 'hot-flashes' in menopausal women^[2]. In addition, a September 2004 Consumer Reports study ranked venlafaxine as the most effective among six commonly prescribed antidepressants. (However, this should not be considered a definitive finding, and responses to psychiatric medications vary significantly from individual to individual.)

Off-label / Investigational Uses

Substantial weight loss in patients with major depression, generalized anxiety disorder, and sozial phobia has been noted, but the manufacturer does not recommend the use as anorectical drug either alone or in combination with phentermine or other amphetamine-like drugs.

Description of Compound

The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (В±)-1-[a [О±- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride and it has the empirical formula of C₁₇H₂₇NO₂ В· HCl. It is a white to off-white crystalline solid, distributed in pentagon-shaped peach-colored tablets of 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg. There is also an extended-release version distributed in capsules of 37.5 mg (gray/peach), 75 mg (peach), and 150 mg (brownish red).

Mechanism of Action

Venlafaxine is a bicyclic antidepressant, and is usually categorized as a serotonin-norepinephrine reuptake inhibitor, but it has been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor.^[3] It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active in the synapse. At low dosages, venlafaxine blocks serotonin reuptake alone, similarly to a selective serotonin reuptake inhibitor (SSRI). At medium dosages (about 225mg/day), venlafaxine blocks the reuptake of norepinephrine as well as serotonin. At dosages above 300mg/day, it blocks dopamine reuptake in addition to serotonin and norepinephrine.

Pharmacokinetics

Venlafaxine is extensively metabolized in the liver via the CYP2D6 isoenzyme to O-desmethylvenlafaxine, which is just as potent a serotonin-norepinephrine reuptake inhibitor as the parent compound, meaning that the differences in metabolism between extensive and poor metabolizers are not clinically important.

Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3–4 weeks.

Prescribed dosages are typically in the range of 75–225 mg per day, but higher dosages are sometimes used for the treatment of severe or treatment-resistant depression. Because of its relatively short half-life of 5 hours, venlafaxine should be administered in divided dosages throughout the day. The extended release version eliminates this problem and has largely replaced the original in use.

Side Effects

As with most antidepressants, lack of sexual desire can be a very disturbing side-effect for some persons. Venlafaxine can raise blood pressure at high doses, so it is usually not the drug of choice for persons with high blood pressure. Venlafaxine should not be used in children. Caution should also be used in those with a seizure disorder.

The energizing effect of the drug may come unwanted to some, possibly leading to an increased anxiety / depressed mind state.

Venlafaxine is sometimes used for the treatment of depressive phases of bipolar disorder. However, this has some potential danger, as venlafaxine can induce mania, mixed states, rapid cycling and/or psychosis in some bipolar patients, particularly if they are not also being treated with a mood stabilizer.

Common side effects include:

• Nausea
• Dizziness
• Sleepiness
• Insomnia
• Vertigo
• Dry mouth
• Sexual dysfunction
• Sweating
• Vivid dreams
• Increased blood pressure

Rare to very rare side-effects include:

• Cardiac arrhythmia
• Increased serum cholesterol
• Gas or stomach pain
• Abnormal vision
• Nervousness, agitation or increased anxiety
• Depressed feelings
• Confusion
• Neuroleptic malignant syndrome
• Loss of appetite
• Constipation
• Tremor
• Drowsiness
• Allergic skin reactions
• External bleeding
• Serious bone marrow damage (thrombocytopenia, agranulocytosis)
• Hepatitis
• Pancreatitis
• Seizure

Discontinuation syndrome

Venlafaxine is notorious for its potentially severe withdrawal symptoms upon sudden discontinuation (the recommended discontinuation is a drop of 35 mg per week; sudden stops are usually advised only in emergencies). Wyeth-Ayerst euphemistically refers to these severe withdrawal symptoms in its product literature as a "severe discontinuation syndrome". These have a tendency to be significantly stronger than the withdrawal effects of other antidepressants including the tricyclic antidepressants, but are similar in nature to those of SSRIs such as Paroxetine (PaxilВ® or SeroxatВ®).

These effects may include irritablility, headache, nausea, fatigue, and "brain shivers". Rarer withdrawal symptoms include shaking legs, dizziness and dysphoria. "Brain shivers" have been described as electric-like shocks in the brain causing pounding headaches and disorientation, increasing over time before abating. Although "brain shivers" are not painful per se, they can be severe enough to be disabling. Antidepressant withdrawal effects do not indicate addiction, but are rather the results of the brain attempting to reach neurochemical stability. These can be minimalized or avoided by tapering off of the medication over a period of weeks.

Studies by Wyeth-Ayerst and others have reported occasional cases of withdrawal symptoms severe enough to require permanent use. In some of these cases, successful discontinuation was eventually achieved by the addition of fluoxetine, which was later discontinued itself without difficulty.

External links

• Detailed Effexor Consumer Information: Uses, Precautions, Side Effects
• PubChem Substance Summary: Venlafaxine National Center for Biotechnology Information.
• Effexor XR Prescribing Information Wyeth Laboratories (PDF).