Venlafaxine, sold under the brand name Effexor among others, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.[4][5][6] This means it increases the concentrations of the neurotransmitters serotonin and norepinephrine in the body and the brain. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder, and social phobia.[7][8] A comparative meta-analysis of 12 major antidepressants found that venlafaxine, mirtazapine, escitalopram, and sertraline were significantly more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine for MDD.[9] 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.[10] It is metabolised in the body into another antidepressant drug called desvenlafaxine (O-desmethylvenlafaxine) which is also sold as an antidepressant, under the brand name Pristiq.[11] In 2007, venlafaxine was the sixth most commonly prescribed antidepressant on the U.S. retail market, with 17.2 million prescriptions.[12] Venlafaxine is used primarily for the treatment of depression, general anxiety disorder, social phobia, panic disorder, and vasomotor symptoms.[13] At low doses (<150 mg/day), it acts only on serotonergic transmission. At moderate doses (>150 mg/day), it acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day), it also affects dopaminergic neurotransmission.[14] 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,[15] although agents that are marketed for this purpose (like pregabalin or duloxetine) are likely preferred. It has also been found to reduce the severity of 'hot flashes' in menopausal women and men on hormonal therapy for the treatment of prostate cancer.[16][17] 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.[18] Some open-label and three double-blind studies have suggested the efficacy of venlafaxine in the treatment of attention deficit-hyperactivity disorder (ADHD).[19] Clinical trials have found possible efficacy in those with post-traumatic stress disorder (PTSD).[20] 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.[21][needs update] Judged by the same criteria, venlafaxine was similar in efficacy to the atypical antidepressant bupropion (Wellbutrin); however, the remission rate was significantly lower for venlafaxine.[22] In a double-blind study, patients who did not respond to an SSRI were switched to venlafaxine or citalopram. Similar improvement was observed in both groups.[23] See also List of adverse effects of venlafaxine 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.[24] 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.[25] 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.[26] 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.[27] Venlafaxine is contraindicated in children, adolescents and young adults. According to the FDA analysis of clinical trials[27] venlafaxine caused a statistically significant 5-fold increase in suicidal ideation and behaviour in persons younger than 25. In another analysis, venlafaxine was no better than placebo among children (7–11 years old), but improved depression in adolescents (12–17 years old). However, in both groups, hostility and suicidal behaviour increased in comparison to those receiving a placebo.[28] In a study involving antidepressants that had failed to produce results in depressed teenagers, teens whose SSRI treatment had failed who were randomly switched to either another SSRI or to venlafaxine showed an increased rate of suicide on venlafaxine. Among teenagers who were suicidal at the beginning of the study, the rate of suicidal attempts and self-harm was significantly higher, by about 60%, after the switch to venlafaxine than after the switch to an SSRI.[29] People stopping venlafaxine commonly experience discontinuation symptoms such as dysphoria, headaches, nausea, irritability, emotional lability, sensation of electric shocks, and sleep disturbance.[30] Venlafaxine has a higher rate of moderate to severe discontinuation symptoms relative to other antidepressants (similar to the SSRI paroxetine).[31] 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.[32] After discontinuing venlafaxine, the levels of both serotonin and norepinephrine decrease, leading to the hypothesis that the discontinuation symptoms could result from an overly rapid reduction of neurotransmitter levels.[33] The development of a potentially life-threatening serotonin syndrome (also more recently classified as "serotonin toxicity")[34] may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited to SSRIs and SNRIs, many hallucinogens such as tryptamines and phenethylamines (e.g., LSD/LSA, DMT, MDMA, mescaline), dextromethorphan (DXM), tramadol, tapentadol, pethidine (meperidine) and triptans and with drugs that impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). Venlafaxine-induced serotonin syndrome has also been reported when venlafaxine has been taken in isolation in overdose.[35] An abortive serotonin syndrome state, in which some but not all of the symptoms of the full serotonin syndrome are present, has been reported with venlafaxine at mid-range dosages (150 mg per day).[36] A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5 mg per day) has also been reported.[37] Studies of venlafaxine in children have not established its efficacy.[38] Venlafaxine is not recommended in patients hypersensitive to it, nor should it be taken by anyone who is allergic to the inactive ingredients, which include gelatin, cellulose, ethylcellulose, iron oxide, titanium dioxide and hypromellose. It should not be used in conjunction with a monoamine oxidase inhibitor (MAOI), as it can cause potentially fatal serotonin syndrome.[2][3][39] Venlafaxine can increase eye pressure, so those with glaucoma may require more frequent eye checks.[40] 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.[41][42] Consequently, venlafaxine should only be used during pregnancy if clearly needed.[40] A large case-control study done as part of the National Birth Defects Prevention Study and published in 2012 found a significant association of venlafaxine use during pregnancy and several birth defects including anencephaly, cleft palate, septal heart defects and coarctation of the aorta.[43] Prospective studies have not shown any statistically significant congenital malformations.[44] There have, however, been some reports of self-limiting effects on newborn infants.[45] As with other serotonin reuptake inhibitors (SRIs), these effects are generally short-lived, lasting only 3 to 5 days,[46] and rarely resulting in severe complications.[47] Venlafaxine should be taken with caution when using St John's wort.[48] Venlafaxine may lower the seizure threshold, and coadministration with other drugs that lower the seizure threshold such as bupropion and tramadol should be done with caution and at low doses.[49] 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.[50] 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 150mg per day, when used for extended periods of time. In rare cases, drug-induced akathisia can occur after use in some people.[51] Venlafaxine should be used with caution in hypertensive patients. Venlafaxine must be discontinued if significant hypertension persists.[52][53][54] It can also have undesirable cardiovascular effects.[55] 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.[56] Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcome compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Healthcare professionals are advised to prescribe Effexor and Effexor XR in the smallest quantity of capsules consistent with good patient management to reduce the risk of overdose.[57] It is usually reserved as a second-line treatment for depression due to a combination of its superior efficacy to the first-line treatments like fluoxetine, paroxetine and citalopram and greater frequency of side effects like nausea, headache, insomnia, drowsiness, dry mouth, constipation, sexual dysfunction, sweating and nervousness.[9][58] 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.[59] 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).[60][61] It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitters in the synapse. The neurotransmitters affected are serotonin and norepinephrine. Additionally, in high doses it weakly inhibits the reuptake of dopamine,[62] with recent evidence showing that the norepinephrine transporter also transports some dopamine as well, since dopamine is inactivated by norepinephrine reuptake in the frontal cortex. The frontal cortex largely lacks dopamine transporters, therefore venlafaxine can increase dopamine neurotransmission in this part of the brain.[63][64] 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.[65] 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 a 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.[67] Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the kidneys.[40] The half-life of venlafaxine is relatively short, so patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed dose can result in withdrawal symptoms.[68] 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.[69] A 2007 study[70] found that carriers of at least one C allele (variant CC or CT) are 7.72 times more likely than non-carriers to achieve remission after 4 weeks of treatment with amitriptyline, citalopram, paroxetine or venlafaxine (all P-gp substrates). The study included patients with mood disorders other than major depression, such as bipolar II; the ratio is 9.4 if these other disorders are excluded. At the 6-week mark, 75% of C-carriers had remitted, compared to only 38% of non-carriers.[citation needed] The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride, and it has the empirical formula of C17H27NO2. It is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioid analgesic tramadol, and more distantly to the newly released opioid tapentadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or RIMAs.[71] 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.[72] 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.[73] 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.[1]