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Venlafaxine, sold under the brand name Effexor among others, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.
A comparative meta-analysis of 21 major antidepressants found that venlafaxine, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, and vortioxetine were more effective than other antidepressants although the quality of many comparisons was assessed as low or very low.
The rate of life-threatening or lethal outcomes for suicidal overdoses of venlafaxine is lower than for the TCAs, MAOIs, and bupropion but higher than almost all of the SSRIs, and equal to citalopram.
In 2007, venlafaxine was the sixth most commonly prescribed antidepressant on the U.S. retail market, with 17.2 million prescriptions.
Contents
1 Medical uses
1.1 Depression
2 Adverse effects
2.1 Suicide
2.2 Discontinuation syndrome
2.3 Serotonin syndrome
2.4 Contraindications
2.4.1 Glaucoma
2.4.2 Pregnant women
2.5 Drug interactions
2.6 Bipolar disorder
2.7 Other/adverse results
3 Overdose
4 Mechanism of action
4.1 Pharmacology
4.2 Pharmacokinetics
5 Chemistry
6 Society and culture
7 References
8 External links
Medical uses
Venlafaxine is used primarily for the treatment of depression, general anxiety disorder, social phobia, panic disorder, and vasomotor symptoms.
Some doctors may prescribe venlafaxine off label for the treatment of diabetic neuropathy (in a similar manner to duloxetine ) and migraine prophylaxis (in some people, however, venlafaxine can exacerbate or cause migraines). Studies have shown venlafaxine’s effectiveness for these conditions,
Due to its action on both the serotoninergic and adrenergic systems, venlafaxine is also used as a treatment to reduce episodes of cataplexy, a form of muscle weakness, in patients with the sleep disorder narcolepsy.
Depression
Multiple double blind studies show venlafaxine’s effectiveness in treating depression. Venlafaxine has similar efficacy to the tricyclic antidepressants amitriptyline (Elavil) and imipramine, and is better tolerated than amitriptyline. Its efficacy is similar to or better than sertraline (Zoloft) and fluoxetine (Prozac), depending on the criteria and rating scales used. Higher doses of venlafaxine are more effective, and more patients achieved remission or were “very much improved”. The efficacy was similar if the number of patients who achieved “response” or were “improved” was considered. A meta-analysis comparing venlafaxine and combined groups of SSRI or tricyclic antidepressants showed venlafaxine’s superiority.
Adverse effects
See also List of adverse effects of venlafaxine
Suicide
The US Food and Drug Administration body (FDA) requires all antidepressants, including venlafaxine, to carry a black box warning with a generic warning about a possible suicide risk.
A 2014 meta analysis of 21 clinical trials of venlafaxine for the treatment of depression in adults found that compared to placebo, venlafaxine reduced the risk of suicidal thoughts and behavior.
A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk by 60% (statistically significant), as compared to no treatment. At the same time, fluoxetine (Prozac) halved the suicide risk.
In another study, the data on more than 200,000 cases were obtained from the UK general practice research database. At baseline, patients prescribed venlafaxine had a greater number of risk factors for suicide (such as prior suicide attempts) than patients treated with other anti-depressants. The patients taking venlafaxine had significantly higher risk of completed suicide than the ones on fluoxetine or citalopram (Celexa). After adjusting for known risk factors, venlafaxine was associated with an increased risk of suicide relative to fluoxetine and dothiepin that was not statistically significant. A statistically significant greater risk for attempted suicide remained after adjustment, but the authors concluded that it could be due to residual confounding.
An analysis of clinical trials by the FDA statisticians showed the incidence of suicidal behaviour among the adults on venlafaxine to be not significantly different from fluoxetine or placebo.
Venlafaxine is contraindicated in children, adolescents and young adults. According to the FDA analysis of clinical trials
Discontinuation syndrome
Main article: SSRI discontinuation syndrome
People stopping venlafaxine commonly experience discontinuation symptoms such as dysphoria, headaches, nausea, irritability, emotional lability, sensation of electric shocks, and sleep disturbance.
The higher risk and increased severity of discontinuation syndrome symptoms relative to other antidepressants may be related to the short half-life of venlafaxine and its active metabolite.
Serotonin syndrome
The development of a potentially life-threatening serotonin syndrome (also more recently classified as “serotonin toxicity”)
Contraindications
Studies of venlafaxine in children have not established its efficacy.
Glaucoma
Venlafaxine can increase eye pressure, so those with glaucoma may require more frequent eye checks.
Pregnant women
There are few well-controlled studies of venlafaxine in pregnant women. A study released in May 2010 by the Canadian Medical Association Journal suggests use of venlafaxine doubles the risk of miscarriage.
Drug interactions
Venlafaxine should be taken with caution when using St John’s wort.
Bipolar disorder
Venlafaxine is neither recommended nor approved for the treatment of major depressive episodes in bipolar disorder as it can induce mania or mixed episodes. Venlafaxine appears to be more likely than the SSRIs and bupropion to induce mania and mixed episodes in bipolar patients.
Other/adverse results
There have been false positives reported for phencyclidine (PCP), cocaine and amphetamine with routine urine-based drug tests. Although rare these instances typically occur with higher doses of Venlafaxine, more than 150 mg per day, when used for extended periods of time.
In rare cases, drug-induced akathisia can occur after use in some people.
Venlafaxine should be used with caution in hypertensive patients. Venlafaxine must be discontinued if significant hypertension persists.
Overdose
Most patients overdosing with venlafaxine develop only mild symptoms. Plasma venlafaxine concentrations in overdose survivors have ranged from 6 to 24 mg/l, while postmortem blood levels in fatalities are often in the 10–90 mg/l range.
There is no specific antidote for venlafaxine, and management is generally supportive, providing treatment for the immediate symptoms. Administration of activated charcoal can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with benzodiazepines or other anticonvulsants. Forced diuresis, hemodialysis, exchange transfusion, or hemoperfusion are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug’s high volume of distribution.
Mechanism of action
Pharmacology
Venlafaxine is usually categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI), but it has been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI).
Venlafaxine indirectly affects opioid receptors (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) as well as the alpha2-adrenergic receptor, and was shown to increase pain threshold in mice. When mice were tested with a hotplate analgesia meter (to measure pain), both venlafaxine and mirtazapine induced a dose-dependent, naloxone-reversible antinociceptive effect following intraperitoneal injection. These findings suggest venlafaxine’s seemingly superior efficacy in severe depression as opioids become increasingly used as a measure of last resort for refractory cases.
Pharmacokinetics
Venlafaxine is well absorbed, with at least 92% of an oral dose being absorbed into systemic circulation. It is extensively metabolized in the liver via the CYP2D6 isoenzyme to desvenlafaxine ( O-desmethylvenlafaxine ), which is just as potent an SNRI as the parent compound, meaning that the differences in metabolism between extensive and poor metabolisers are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe in CYP2D6 poor metabolisers.
Venlafaxine is a substrate of P-glycoprotein (P-gp), which pumps it out of the brain. The gene encoding P-gp, ABCB1, has the SNP rs2032583, with alleles C and T. The majority of people (about 70% of Europeans and 90% of East Asians) have the TT variant.
Chemistry
The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a
Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release (controlled release) version distributes the release of the drug into the gastrointestinal tract over a longer period than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of nausea as a side effect, resulting in better compliance.
Society and culture
Effexor XR 75 mg and 150 mg capsules
Generic 75mg (top) and 150mg (bottom) venlafaxine capsules by Krka
Venlafaxine was originally marketed as Effexor in most of the world; generic venlafaxine has been available since around 2008 and extended release venlaxafine has been available since around 2010.
As of June 2017 venlafaxine was marketed under many brand names worldwide, many with alternative extended release forms (not shown): Adoxa, Alfaxin, Alventa, Alventa, Amfax, Anapresin, Ansifix, Arafaxina, Argofan, Arvifax, Axone, Axyven, Blossom, Calmdown, Conervin, Convalemin, Dalium, Defaxine, Depant, Depefex, Depressa, Depretaxer, Deprevix, Deprexor, Deprixol, Depurol, Desinax, Dislaven, Dobupal, Easyfor, Ectien, Eduxon, Efaxin, Efaxine, Efectin, Efegen, Efetrin, Efevelon, Efexiva, Efexor, Effegad, Effexine, Effexor, Elafax, Elify, Enlafax, Falven, Faxigen, Faxine, Faxiprol, Faxiven, Faxolet, Flaxen, Fobiless, Foraven, Ganavax, Genexin, Idixor, Idoxen, Illovex, Ivrix, Ivryx, Ixilania, Jarvis, Lafactin, Lafaxin, Lanvexin, Levest, Mazda, Melocin, Memomax, Mezine, Mollome, Nefexyl, Nervix, Norafexine, Norezol, Norezor, Norpilen, Novidat, Noviser, Odiven, Olwexya, Oriven, Paxifar, Politid, Pracet, Pramina, Prefaxine, Quilarex, Rafax, Senexon, Sentidol, Sentosa, Serosmin, Seroxine, Sesaren, Subelan, Sunveniz, Sunvex, Symfaxin, Tedema, Tifaxin, Tonpular, Trevilor, Tudor, Valosine, Vandral, Velaf, Velafax, Velahibin, Velaxin, Velept, Velpine, Ven-Fax, Venax, Venaxibene, Venaxol, Venaxx, Vencontrol, Vendep, Venegis, Venex, Venexor, Venfalex, Venfax, Venfaxime, Venforspine, Veniba, Veniz, Venjoy, Venla, Venlabacher, Venlabax, Venlabrain, Venlaburg, Venladex, Venladoz, Venlaf, Venlafab, Venlafaxin, Venlafaxina, Venlafaxine, Venlafaxinum, Venlafectin, Venlagamma, Venlalic, Venlamax, Venlamylan, Venlaneo, Venlanofi, Venlapine, Venlasand, Venlatif, Venlatrin, Venlax, Venlaxin, Venlaxine, Venlaxor, Venlectine, Venlexor, Venlifax, Venlift, Venlix, Venlobax, Venlofex, Venlor, Venoxor, Venozap, Venxin, Venxor, Vexamode, Vfax, Viepax, Voxafen, Xadevil, Xapnev, Zacalen, Zanfexa, Zaredrop, Zarelis, Zarelix, and Zenexor.

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