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Venlafaxine structure.svg
Systematic (IUPAC) name
Clinical data
Trade namesEfexor, Effexor
Licence dataUS Daily Med:link
Pregnancy cat.B2 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Pharmacokinetic data
Protein binding27±2% (parent compound), 30±12% (active metabolite, desvenlafaxine)[2]
MetabolismHepatic (~50% of the parent compound is metabolised on first pass through the liver)[1][2]
Half-life5±2 hours (parent compound for immediate release preparations), 15±6 hours (parent compound for extended release preparations), 11±2 hours (active metabolite)[1][2]
ExcretionRenal (87%; 5% as unchanged drug; 29% as desvenlafaxine and 53% as other metabolites)[1][2]
CAS number93413-69-5 YesY
ATC codeN06AX16
PubChemCID 5656
ChemSpider5454 YesY
Chemical data
Mol. mass277.402 g/mol
 YesY (what is this?)  (verify)
  (Redirected from Effexor)
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Venlafaxine structure.svg
Systematic (IUPAC) name
Clinical data
Trade namesEfexor, Effexor
Licence dataUS Daily Med:link
Pregnancy cat.B2 (AU) C (US)
Legal statusPrescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Pharmacokinetic data
Protein binding27±2% (parent compound), 30±12% (active metabolite, desvenlafaxine)[2]
MetabolismHepatic (~50% of the parent compound is metabolised on first pass through the liver)[1][2]
Half-life5±2 hours (parent compound for immediate release preparations), 15±6 hours (parent compound for extended release preparations), 11±2 hours (active metabolite)[1][2]
ExcretionRenal (87%; 5% as unchanged drug; 29% as desvenlafaxine and 53% as other metabolites)[1][2]
CAS number93413-69-5 YesY
ATC codeN06AX16
PubChemCID 5656
ChemSpider5454 YesY
Chemical data
Mol. mass277.402 g/mol
 YesY (what is this?)  (verify)

Venlafaxine (brand name: Effexor or Efexor) is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class.[3][4][5] First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder (MDD), as a treatment for generalized anxiety disorder, and comorbid indications in certain anxiety disorders with depression. In 2007, venlafaxine was the sixth most commonly prescribed antidepressant on the U.S. retail market, with 17.2 million prescriptions.[6]

Medical uses[edit]

Venlafaxine is used primarily for the treatment of depression, general anxiety disorder, social phobia, panic disorder and vasomotor symptoms.[7]

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.[8]

Many doctors are starting to 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.[9][10] 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.[11][12]

Substantial weight loss in patients with major depression, generalized anxiety disorder, and social phobia have been noted, but the manufacturer does not recommend use as an anorectic either alone or in combination with phentermine or other amphetamine-like drugs.[13] Venlafaxine hydrochloride is in the phenethylamine class of modern chemicals, which includes amphetamine, methylenedioxymethamphetamine (MDMA), and methamphetamine. This chemical structure likely lends to its activating properties; however, some patients find venlafaxine highly sedating, despite its more common stimulatory effects.

Venlafaxine is not 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.[14]

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.[15]

Venlafaxine was found in one study to be equal to clomipramine (anafranil) in the treatment of Obsessive-compulsive disorder (OCD) with fewer side effects.[16]

Some open-label and three double-blind studies have suggested the efficacy of venlafaxine in the treatment of attention deficit-hyperactivity disorder (ADHD).[17][18][19][20][21]

Due to its tendency to increase blood pressure and its modulative effects on the autonomic nervous system, venlafaxine is often used to treat orthostatic intolerance and postural orthostatic tachycardia syndrome.[22]


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.[23] 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.[24] 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.[25]

Adverse effects[edit]

Incidence of adverse effects[1][2][26]

Very common (>10% incidence) adverse effects include:

Common (1–10% incidence) adverse effects include:

Uncommon (0.1-1% incidence) adverse effects include:

Rare (0.01–0.1% incidence) adverse effects include:

Very rare (<0.01% incidence) adverse effects include:


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.[28]

A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk 1.6-fold (statistically significant), as compared to no treatment. At the same time, fluoxetine (Prozac) halved the suicide risk.[29]

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.[30]

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.[31]

Venlafaxine is contraindicated in children, adolescents and young adults. According to the FDA analysis of clinical trials[31] 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.[32] 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.[33]

Dose dependency of adverse events[edit]

A comparison of adverse event rates in a fixed-dose study comparing venlafaxine 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine use. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one venlafaxine group. Tests for potential dose relationships for these events (Cochran-Armitage test, with a criterion of exact 2-sided p-value ≤0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia (symptom), nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation.[13]

Discontinuation syndrome[edit]

Patients stopping venlafaxine commonly experience SSRI discontinuation syndrome. The high risk of discontinuation syndrome symptoms may reflect venlafaxine's short half-life.[34]

Discontinuation is similar in nature, but not identical to those of SSRIs such as paroxetine (Paxil or Seroxat). Sudden discontinuation of venlafaxine particularly seemed to cause discontinuation symptoms during the first 3 days in a study of 18 patients.[35] As reported in 2001 by Haddad in the journal Drug Safety, "another strategy to consider is switching to fluoxetine, which may suppress the discontinuation symptoms, but which has little tendency to cause such symptoms itself," and then discontinuing that.[34]

Norepinephrine may also have a significant role in discontinuation symptoms.[36] During withdrawal from venlafaxine, the levels of both serotonin and norepinephrine decrease, rather than increase, and this would appear to rule out toxic (too high) levels of these neurotransmitters as a likely cause of the withdrawal symptoms. The withdrawal symptoms can be hypothesized to result from an overly rapid deprivation of neurotransmitter levels.

Serotonin syndrome[edit]

The development of a potentially life-threatening serotonin syndrome (also more recently classified as "serotonin toxicity")[37] 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)/dextrorphan (DXO), 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) and/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.[38] 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)[39] A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5 mg per day) has also been reported.[40]


Studies of venlafaxine in paediatric age groups have not established its efficacy.[41] 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.[1][2][27]


Venlafaxine can increase eye pressure, so those with glaucoma may require more frequent eye checks.[13]

Pregnant women[edit]

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.[42][43] Consequently, venlafaxine should only be used during pregnancy if clearly needed.[13] 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]

Drug interactions[edit]

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]


There have been false positive phencyclidine (PCP) results caused by larger doses of venlafaxine, with certain on-site routine urine-based drug tests.[50][51]


Most patients overdosing with venlafaxine develop only mild symptoms. However, severe toxicity is reported, with the most common symptoms being CNS depression, serotonin toxicity, seizure, or cardiac conduction abnormalities.[52] Venlafaxine seems to be more dangerous in overdose than the SSRIs, except perhaps citalopram which is more dangerous than the other SSRIs in overdose. Despite this it appears less dangerous than bupropion, the tricyclic antidepressants and the irreversible monoamine oxidase inhibitors.[27][53] Deaths have been reported following very large doses.[54][55] 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]

On May 31, 2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) UK concluded its review of the latest safety evidence relating to venlafaxine, and particularly looked at the risks associated with overdose. The advice was: the need for specialist supervision in those severely depressed or hospitalized patients who need doses 300 mg or more; cardiac contraindications are more targeted towards high risk groups; patients with uncontrolled hypertension should not take venlafaxine, and blood pressure monitoring is recommended for all patients; and updated advice on possible drug interactions.[57]

On 17 October 2006, Wyeth and the FDA notified healthcare professionals of revisions to the Overdosage/Human Experience section of the prescribing information for Effexor (venlafaxine) indicated for treatment of major depressive disorder. In post-marketing experience, there have been reports of overdose with venlafaxine, occurring predominantly in combination with alcohol and/or other drugs. 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.[58]

A report in the British Medical Journal in 2002 by Nicholas Buckley and colleagues at the Department of Clinical Pharmacology and Toxicology, Canberra Hospital, Australia, studying fatal toxicity index (deaths per million prescriptions), found that venlafaxine's fatal toxicity is higher than that of other serotoninergic antidepressants, but it is similar to that of some of the less toxic tricyclic antidepressants. Overall, they found serious toxicity could occur following venlafaxine overdose with reports of deaths, arrythmias, and seizures. They did, however, state that this type of data is open to criticism, pointing out that mortality data may be influenced by previous literature and that "less toxic" drugs may be preferentially prescribed to patients at higher risk of poisoning and suicide, but they are also less likely to be listed as the sole cause of death from overdose. It also assumed that drugs are taken in overdose with similar frequency and in similar amounts. They suggested "clinicians need to consider whether factors in their patients reduce or compensate for this risk before prescribing venlafaxine."[59]

The 27 February 2007 Vancouver Sun reported that the BC Drug and Poison Information Centre had alerted doctors that the drug poses a significant risk of death from overdose, saying that venlafaxine "appears more toxic than it was originally hoped".[60] A doctor from the Department of Pharmacy Services College of Pharmacy, at the Medical University of South Carolina, reported on the death of a 39-year-old patient with a 30 g overdose.[54] To put this into perspective, a patient would have to take over 66 of the infrequently prescribed 450 mg high dosage pills, or 400 of the commonly prescribed 75 mg pills.

Management of overdose[edit]

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.[61]

Mechanism of action[edit]

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).[62][63] 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,[64] 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.[65][66] Venlafaxine interacts with 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 narcotics become increasingly used as a measure of last resort for refractory cases.[67]


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.[68] 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.[13] 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.[69]

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.[70] A 2007 study[71] 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.


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.[72]

Available forms[edit]

Effexor XR 75 mg and 150 mg capsules
Generic 75mg (top) and 150mg (bottom) venlafaxine capsules by Krka

Extended release[edit]

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 patients suffering from nausea as a side effect, resulting in a lower number of patients stopping their treatment due to nausea.[73] In Australia, New Zealand, Turkey[74] and Switzerland, Wyeth sells their venlafaxine XR tablets under the name "Efexor-XR" (note the spelling with one 'f', rather than "Effexor-XR"). In Brazil, Medley sells a venlafaxine XR capsule under the brand name Alenthus XR. In September 2008, Osmotica Pharmaceuticals began marketing venlafaxine extended release tablets in the United States to compete with Wyeth's capsule-form, Effexor-XR. Sales of branded Efexor XR have remained strong, at US$2.7bn.[75] Per settlement agreements, Teva and Impax began offering generic Effexor XR in the US (with royalties paid to Wyeth); Teva began on July 1, 2010,[76] and Impax on July 1, 2011.[77]


Generic venlafaxine is available in the United States as of August 2006 and in Canada as of December 2006 due to patent expiry. Generic forms of the extended-release version have been available in Canada as of January 2007 and currently include Co Venlafaxine XR (Cobalt Pharmaceuticals Inc.), Gen-Venlafaxine XR (Genpharm), Riva-Venlafaxine XR (Laboratoire Riva Inc.), Novo Venlafaxine XR (Novopharm Limited), PMS-Venlafaxine XR (Pharmascience Inc.), Ratio-Venlafaxine XR (ratiopharm), Viepax (in Israel) and Sandoz Venlafaxine XR (Sandoz Canada Inc.). Generic versions of both drug forms are available now in India and Australia. Generic products on the South African market include Venlor SR Capsules (Cipla Medpro) and Illovex SR Tablets (Pharmadynamics, both are available in 150 mg and 75 mg strengths. Generic versions are also available in the UK such as Vaxalin manufactured by RatioPharm GmbH.[78] On May 7, 2010 the Canadian pharmaceutical company IntelliPharmaCeutics Inc. announced that the FDA had accepted its filing for a generic version of Venlafaxine XR utilizing its own proprietary technologies.[79]


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