|Systematic (IUPAC) name|
|Legal status||Prescription Only (S4) (AU) POM (UK) ℞-only (US)|
|Half-life||4.9 ± 2.4 h (parent compound); 10.3 ± 4.3 h (active metabolite)|
|Mol. mass||277.402 g/mol|
| (what is this?)
Venlafaxine (brand name: Effexor or Efexor) is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. 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.
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.
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. 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.
Substantial weight loss in patients with major depression, generalized anxiety disorder, and social phobia has been noted, but the manufacturer does not recommend use as an anorectic either alone or in combination with phentermine or other amphetamine-like drugs. 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 approved for the treatment of depressive phases of bipolar disorder; 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.
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.
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.
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. 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. 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.
Studies of venlafaxine in pediatric age groups have not established its efficacy. 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 never be used with a monoamine oxidase inhibitor (MAOI), as it can cause potentially fatal serotonin syndrome. Caution should also be used in those with a seizure disorder.
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. Consequently, venlafaxine should only be used during pregnancy if clearly needed. Prospective studies have not shown any statistically significant congenital malformations. There have, however, been some reports of self-limiting effects on newborn infants. As with other serotonin reuptake inhibitors, these effects are generally short-lived, lasting only 3 to 5 days, and rarely resulting in severe complications.
Cardiopulmonary Effects and Hypertension
The FDA asked the manufacturers of all SNRIs to include the risk of primary pulmonary hypertension (PPH) in prescribing data as of July 19, 2006. Medications containing venlafaxine caused a mean heart rate increase of 4 bpm in clinical trials, along with a sustained increase in blood pressure in some.
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. In addition, the most recent research indicated that patients taking venlafaxine are at increased risk of suicide.
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.
In another study, the data on more than 200,000 cases were obtained from the UK general practice research database. The patients taking venlafaxine had significantly higher risk of completed suicide than the ones on fluoxetine (Prozac) (2.8 times) or citalopram (Celexa) (2.4 times). Even after taking into consideration the fact that venlafaxine was generally prescribed for more severe depression, venlafaxine was associated with 1.6-1.7 times more suicides than fluoxetine or citalopram. This difference was no longer statistically significant due to the rarity of completed suicides. However, for the attempted suicides (more frequent event) the 1.2-1.3 times higher risk for venlafaxine still stayed statistically significant after the adjustment.
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. A possible explanation for this discrepancy is that suicidal patients are generally excluded from clinical trials, and so clinical trials do not represent the real population of patients.
Venlafaxine is contraindicated in children, adolescents and young adults. According to the FDA analysis of clinical trials venlafaxine caused a statistically significant 5-fold increase in suicidal ideation and behavior 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 behavior increased in comparison to those receiving a placebo. 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.
Common side effects
Sexual dysfunction is often a side effect of drugs that inhibit serotonin reuptake. Specifically, common side effects include difficulty becoming aroused, lack of interest in sex, and anorgasmia (trouble achieving orgasm). Genital anesthesia, loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, there are some who report sexual side effects persisting after the drug has been withdrawn. This is known as post-SSRI sexual dysfunction.
NOTE: The percentage of occurrences for each side effect listed comes from clinical trial data provided by Wyeth Pharmaceuticals Inc. The percentage of people experiencing the side effect using Effexor should be compared to those using a placebo, given in parentheses. The following list includes those side effects with a difference of 3% or more.
- Nausea - 37% (placebo 11%)
- Somnolence - 23% (9%)
- Dry mouth - 22% (11%)
- Dizziness - 19% (7%)
- Insomnia - 18% (10%)
- Constipation - 15% (7%)
- Nervousness - 13% (6%)
- Abnormal ejaculation/orgasm - 12% (0%)
- Sweating - 12% (3%)
- Asthenia - 12% (6%)
- Anorexia - 11% (2%)
- Impotence - 6% (0%)
- Anxiety - 6% (3%)
- Vomiting - 6% (2%)
- Blurred vision - 6% (2%)
- Tremor - 5% (1%)
- Chills - 3% (0%)
- Yawn - 3% (0%)
- Personality changes
Difference of 1-2%: abnormal dreams, abnormal thinking, chest pain, confusion, decreased libido, depersonalization, diarrhea, flatulence, headache, hypertonia, increased blood pressure/hypertension, infection, itching, depression, mydriasis, hair loss, paresthesia, postural hypotension, agitation, rash, tachycardia, taste perversion, tinnitus (ringing in the ears), trauma, twitching, upset stomach or indigestion (dyspepsia), urinary retention, vasodilation, weight loss,
Other possible side effects can be found on pp. 26–27 of the report used for the above data. Note that these are from a combination of studies, not all of which were controlled, and so it is possible the individuals reporting the effects may have experienced them even if they had not taken Effexor.
Dose dependency of adverse events
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, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation.
In vitro studies revealed venlafaxine has virtually no affinity for opiate, benzodiazepine, or N-methyl-D-aspartic acid (NMDA) receptors. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.
Patients stopping venlafaxine commonly experience SSRI discontinuation syndrome, i.e. withdrawal symptoms. Such symptoms may occur when abruptly ceasing the medication, decreasing one's dose too quickly, or even after missing a regular dose. Withdrawal symptoms may include agitation, anorexia, anxiety, confusion, impaired coordination, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness, nightmares, sensory disturbances described as "brain zaps" (shock-like electrical sensations), somnolence, sweating, tremor, vertigo, and vomiting.
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. 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.
Noradrenaline may also have a significant role in discontinuation symptoms. During withdrawal from venlafaxine, the levels of both serotonin and noradrenaline, the neurotransmitters, 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 a too rapid deprivation of neurotransmitter levels.
Withdrawal symptoms can occur when discontinuing both high and low doses of venlafaxine and tapering, the gradual reduction of the dose, may need to carried out over an extended period of time; some cases have been reported as needing a tapering period of 3 months  and may persist or reoccur beyond that period.
Although many other drugs can cause withdrawal symptoms which are not associated with addiction or dependence, for example, anticonvulsants, beta-blockers, nitrates, diuretics, centrally acting antihypertensives, sympathomimetics, heparin, tamoxifen, dopaminergic agents, antipsychotics, and lithium, addiction or dependence is a more common effect described for drugs that (are thought to, or may) improve mental well-being.
The development of a potentially life-threatening serotonin syndrome (also more recently classified as "serotonin toxicity") may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited to SSRI and SNRIs, many hallucinogens such as tryptamines and phenethylamines (LSD/LSA, DMT, MDMA, MDPV, mescaline for example), dextromethorphan (DXM)/dextrorphan (DXO), tramadol, tapentadol, meperidine/pethidine 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. 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) A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5 mg per day) has also been reported.
Serotonin toxicity and discontinuation syndrome
Venlafaxine may be particularly hazardous to those individuals who are susceptible to both venlafaxine-induced serotonin toxicity (also known as serotonin syndrome) and SSRI discontinuation syndrome. In such cases, individuals who have developed the potentially fatal serotonin toxicity and/or may be at risk of doing so, may find cessation or dose reduction unachievable, placing them at continuing risk. As it is not possible to determine which patients are likely to develop the most severe symptoms of the discontinuation syndrome before cessation or dose reduction is attempted, this dual risk requires that all patients be closely monitored during any increase in dosage (when the patient is most at risk of developing serotonin toxicity) and that such increases be carried out in the smallest incremental steps possible. Additionally, patients who recommence venlafaxine or revert to a higher dosage following a failed attempt to discontinue the drug or reduce dosage are another group with an increased risk of developing serotonin toxicity.
Venlafaxine should be taken with caution when using St John's wort. 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.
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. Venlafaxine's toxicity appears to be higher than other SSRIs, with a fatal toxic dose closer to that of the tricyclic antidepressants than the SSRIs. Doses of 900 mg or more are likely to cause moderate toxicity. Deaths have been reported following very large doses. 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.
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.
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.
A report in the British Medical Journal in 2002 by Dr. 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."
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". A doctor from the Department of Pharmacy Services College of Pharmacy, Medical University of South Carolina, Charleston, South Carolina, reported on the death of a 39-year-old patient with a 30 g overdose. 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.
Two cases are known of patients who deliberately overdosed on a huge quantity of venlafaxine, resulting in their stomach or intestines respectively being blocked by a mass of tablets (pharmaco-bezoar). The first patient died; the second recovered after the blocked part of her colon was surgically removed. The second patient's physicians speculate that the vasoconstrictive effects of venlafaxine contributed to tissue ischaemia (lack of blood supply) in the affected part of the intestine.
Management of overdose
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
Venlafaxine is a bicyclic antidepressant, and is usually categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI), but it has been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). 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, 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, which largely lacks dopamine transporters: therefore, venlafaxine can increase dopamine neurotransmission in this part of the brain. Venlafaxine interacts with opioid receptors (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) as well as alpha2-adrenergic receptor, and was shown to increase pain threshold in mice. When mice were tested with a hotplate analgesia meter, 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.
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 serotonin-norepinephrine reuptake inhibitor as the parent compound, meaning that the differences in metabolism between extensive and poor metabolizers are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe in CYP2D6 poor metabolizers. 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. 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.
Venlafaxine is a substrate of P-glycoprotein (P-gp), which pumps it out of the brain. ABCB1, the gene encoding P-gp, 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. A 2007 study 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.
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. In Australia, New Zealand, Turkey 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. Teva may begin to offer generic Effexor XR in the US on July 1, 2010, per a settlement agreement with Wyeth, but will have to pay Wyeth a portion of the sale price, driving up the cost. Impax may begin to offer generic Effexor XR in the US on July 1, 2011, per a settlement agreement with Wyeth, but, like Teva, will have to pay Wyeth a portion of the sale price.
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 150mg and 75mg strengths. Generic versions are also available in the UK such as Vaxalin manufactured by RatioPharm GmbH. 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.
- Laurence L Brunton, ed. (2006). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-142280-3.
- Muth EA, Haskins JT, Moyer JA, Husbands GE, Nielsen ST, Sigg EB (December 1986). "Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative". Biochemical Pharmacology 35 (24): 4493–7. doi:10.1016/0006-2952(86)90769-0. PMID 3790168.
- Yardley JP, Husbands GE, Stack G, et al. (October 1990). "2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: synthesis and antidepressant activity". Journal of Medicinal Chemistry 33 (10): 2899–905. doi:10.1021/jm00172a035. PMID 1976813.
- Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, et al. (December 2001). "Comparative affinity of duloxetine and venlafaxine for serotonin and norepinephrine transporters in vitro and in vivo, human serotonin receptor subtypes, and other neuronal receptors". Neuropsychopharmacology 25 (6): 871–80. doi:10.1016/S0893-133X(01)00298-6. PMID 11750180.
- The number of prescriptions was calculated as the total of prescriptions for the corresponding generic and brand-name drugs using data from the charts for generic and brand-name drugs. "Top 200 generic drugs by units in 2007.". Drug Topics, Feb 18, 2008. Retrieved 2008-10-23. "Top 200 brand drugs by units in 2007.". Drug Topics, Feb 18, 2008. Retrieved 2008-10-23.
- "venlafaxine-hydrochloride". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
- Redrobe, JP; Bourin M, Colombel MC, Baker GB (July 1998). "Dose-dependent noradrenergic and serotonergic properties of venlafaxine in animal models indicative of antidepressant activity". Psychopharmacology 138 (1): 1–8. doi:10.1007/s002130050638. PMID 9694520.
- Rowbotham M, Goli V, Kunz N, Lei D (2004). "Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study". Pain 110 (3): 697–706. doi:10.1016/j.pain.2004.05.010. PMID 15288411.
- Ozyalcin S, Talu G, Kiziltan E, Yucel B, Ertas M, Disci R (2005). "The efficacy and safety of venlafaxine in the prophylaxis of migraine". Headache 45 (2): 144–52. doi:10.1111/j.1526-4610.2005.05029.x. PMID 15705120.
- Mayo Clinic staff (2005). "Beyond hormone therapy: Other medicines may help". Hot flashes: Ease the discomfort of menopause. Mayo Clinic. Retrieved 19 August 2005.
- Schober C, Ansani N (2003). "Venlafaxine hydrochloride for the treatment of hot flashes". Ann Pharmacother 37 (11): 1703–7. doi:10.1345/aph.1C483. PMID 14565812.
- "Effexor Medicines Data Sheet". Wyeth Pharmaceuticals Inc. 2006. Retrieved 17 September 2006.
- "Medications". Stanford University School of Medicine, Center for Narcolepsy. Revised 02/07/2003. Retrieved 2007-09-03.
- Albert U, Aguglia E, Maina G, Bogetto F (November 2002). "Venlafaxine versus clomipramine in the treatment of obsessive-compulsive disorder: a preliminary single-blind, 12-week, controlled study" (PDF). J Clin Psychiatry 63 (11): 1004–9. PMID 12444814.
- Hain T (Revised 12/30/2007). "Orthostatic Hypotension". www.dizziness-and-balance.com. Retrieved 2008-03-29.
- Golden RN, Nicholas L (2000). "Antidepressant efficacy of venlafaxine". Depression and Anxiety. 12 Suppl 1: 45–9. doi:10.1002/1520-6394(2000)12:1+<45::AID-DA5>3.0.CO;2-5. PMID 11098413.
- Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA (2006). "A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability". Journal of Clinical Psychopharmacology 26 (5): 482–8. doi:10.1097/01.jcp.0000239790.83707.ab. PMID 16974189.
- Lenox-Smith AJ, Jiang Q (2008). "Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor". Int Clin Psychopharmacol 23 (3): 113–9. doi:10.1097/YIC.0b013e3282f424c2. PMID 18408525.
- Courtney D (2004). "Selective serotonin reuptake inhibitor and venlafaxine use in children and adolescents with major depressive disorder: a systematic review of published randomized controlled trials". Can J Psychiatry 49 (8): 557–63. PMID 15453105.
- Broy, P.; Bérard, A. (2010). "Gestational exposure to antidepressants and the risk of spontaneous abortion: a review". Current drug delivery 7 (1): 76–92. doi:10.2174/156720110790396508. PMID 19863482.
- Nakhai-Pour, H. R.; Broy, P.; Berard, A. (2010). "Use of antidepressants during pregnancy and the risk of spontaneous abortion". Canadian Medical Association Journal 182 (10): 1031–1037. doi:10.1503/cmaj.091208. PMC 2900326. PMID 20513781. Lay summary.
- Gentile S (2005). "The safety of newer antidepressants in pregnancy and breastfeeding". Drug Saf 28 (2): 137–52. doi:10.2165/00002018-200528020-00005. PMID 15691224.
- de Moor R, Mourad L, ter Haar J, Egberts A (2003). "[Withdrawal symptoms in a neonate following exposure to venlafaxine during pregnancy]". Ned Tijdschr Geneeskd 147 (28): 1370–2. PMID 12892015.
- Ferreira E, Carceller AM, Agogué C, Martin BZ, St-André M, Francoeur D, Bérard A (2007). "[Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates]". Pediatrics 119 (1): 52–9. doi:10.1542/peds.2006-2133. PMID 17200271.
- Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, Wisner KL (2005). "[Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: Literature review and implications for clinical applications]". JAMA 293 (19): 2372–83. doi:10.1001/jama.293.19.2372. PMID 15900008.
- Tiihonen J, Lönnqvist J, Wahlbeck K, Klaukka T, Tanskanen A, Haukka J (2006). "Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort". Arch. Gen. Psychiatry 63 (12): 1358–67. doi:10.1001/archpsyc.63.12.1358. PMID 17146010.
- Rubino A, Roskell N, Tennis P, Mines D, Weich S, Andrews E (2007). "Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study". BMJ 334 (7587): 242. doi:10.1136/bmj.39041.445104.BE. PMC 1790752. PMID 17164297.
- "Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee" (PDF). November 16, 2006. Retrieved 2007-06-20.
- Emslie GJ, Findling RL, Yeung PP, Kunz NR, Li Y (2007). "Venlafaxine ER for the treatment of pediatric subjects with depression: results of two placebo-controlled trials". Journal of the American Academy of Child and Adolescent Psychiatry 46 (4): 479–88. doi:10.1097/chi.0b013e31802f5f03. PMID 17420682.
- Brent DA, Emslie GJ, Clarke GN, et al. (April 2009). "Predictors of spontaneous and systematically assessed suicidal adverse events in the treatment of SSRI-resistant depression in adolescents (TORDIA) study". Am J Psychiatry 166 (4): 418–26. doi:10.1176/appi.ajp.2008.08070976. PMID 19223438.
- Bolton JM, Sareen J, Reiss JP (2006). "Genital anaesthesia persisting six years after sertraline discontinuation". J Sex Marital Ther 32 (4): 327–30. doi:10.1080/00926230600666410. PMID 16709553. Unknown parameter
- Csoka AB, Bahrick AS, Mehtonen O-P (2008). "Persistent Sexual Dysfunction after Discontinuation of Selective Serotonin Reuptake Inhibitors (SSRIs)". J Sex Med. 5 (1): 227–33. doi:10.1111/j.1743-6109.2007.00630.x. PMID 18173768.
- Harrison CL, Ferrier N, Young AH (June 2004). "Tolerability of high-dose venlafaxine in depressed patients". J. Psychopharmacol. (Oxford) 18 (2): 200–4. doi:10.1177/0269881104042621. PMID 15260908.
- Haddad PM (2001). "Antidepressant discontinuation syndromes". Drug Saf 24 (3): 183–97. doi:10.2165/00002018-200124030-00003. PMID 11347722.
- Parker G, Blennerhassett J (1998). "Withdrawal reactions associated with venlafaxine". Aust N Z J Psychiatry 32 (2): 291–4. doi:10.3109/00048679809062742. PMID 9588310.
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1681629/%7CVenlafaxine and Serious Withdrawal Symptoms: Warning to Drivers
- Fava M, Mulroy R, Alpert J, Nierenberg A, Rosenbaum J (1997). "Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine". Am J Psychiatry 154 (12): 1760–2. PMID 9396960.
- http://www.ncbi.nlm.nih.gov/pubmed/10659465%7CSierra Santos L, Raigal Martin Y, Ortega Garcia A, Berriochoa Martinez de Pison C, Aparicio Jabalquinto G. Venlafaxina y sindrome de discontinuación. Atencion Primaria. 1999;24:617–618.
- Selective serotonin re-uptake inhibitors and withdrawal reactions. WHO Drug Information. 1998;12(3):136.
- Double D (1997). "Prescribing antidepressants in general practice. People may become psychologically dependent on antidepressants". BMJ 314 (7083): 829. PMC 2126213. PMID 9081020.
- Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM (September 2003). "The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity". QJM 96 (9): 635–42. doi:10.1093/qjmed/hcg109. PMID 12925718.
- Kolecki P (1997). "Isolated venlafaxine-induced serotonin syndrome". J Emerg Med 15 (4): 491–3. doi:10.1016/S0736-4679(97)00078-4. PMID 9279702.
- Ebert D. et al. "Hallucinations as a side effect of venlafaxine treatment". Psychiatry On-line. Retrieved 2008-06-17.
- Pan JJ, Shen WW (February 2003). "Serotonin syndrome induced by low-dose venlafaxine". Ann Pharmacother 37 (2): 209–11. doi:10.1345/aph.1C021. PMID 12549949.
- Venlafaxine (marketed as Effexor) FDA Alert: SSRIs/SNRI/Triptan and Serotonin Syndrome [issued 7/2006]
- Karch, Amy (2006). 2006 Lippincott's Nursing Drug Guide. Philadelphia, Baltimore, New York, London, Buenos Aires, Hong Kong, Sydney, Tokyo: Lippincott Williams & Wilkins. ISBN 1-58255-436-6.
- Thundiyil JG, Kearney TE, Olson KR (March 2007). "Evolving epidemiology of drug-induced seizures reported to a Poison Control Center System". J Med Toxicol 3 (1): 15–9. doi:10.1007/BF03161033. PMID 18072153.
- Santos PM, López-García P, Navarro JS, Fernández AS, Sádaba B, Vidal JP (February 2007). "False positive phencyclidine results caused by venlafaxine". Am J Psychiatry 164 (2): 349. doi:10.1176/appi.ajp.164.2.349. PMID 17267806.
- Sena SF, Kazimi S, Wu AH (2002). "False-positive phencyclidine immunoassay results caused by venlafaxine and O-desmethylvenlafaxine". Clin. Chem. 48 (4): 676–7. PMID 11901076.
- Blythe D, Hackett L (1999). "Cardiovascular and neurological toxicity of venlafaxine". Hum Exp Toxicol 18 (5): 309–13. doi:10.1191/096032799678840165. PMID 10372752.
- Whyte I, Dawson A, Buckley N (2003). "Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants". QJM 96 (5): 369–74. doi:10.1093/qjmed/hcg062. PMID 12702786.
- Mazur J, Doty J, Krygiel A (2003). "Fatality related to a 30-g venlafaxine overdose". Pharmacotherapy 23 (12): 1668–72. doi:10.1592/phco.23.15.1668.31951. PMID 14695048.
- Banham N (1998). "Fatal venlafaxine overdose". Med J Aust 169 (8): 445, 448. PMID 9830400.
- R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1634–1637.
- MHRA UK (31 May 2006). "Updated product information for venlafaxine". Safeguarding public health 120 (8): 778. doi:10.1016/j.puhe.2006.03.006.
- "Wyeth Letter to Health Care Providers". Wyeth Pharmaceuticals Inc. 2006. Retrieved 2009-08-06.
- Buckley N, McManus P (2002). "Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data". BMJ 325 (7376): 1332–3. doi:10.1136/bmj.325.7376.1332. PMC 137809. PMID 12468481.
- Fayerman, Pamela (February 27, 2007). "Warning issued over drug". Vancouver Sun. Retrieved 2007-06-02.
- Lung, Derrick; Cristina Cuevas, Uwais Zaid and Benedict Ancock (4 March 2011). "Venlafaxine Pharmacobezoar Causing Intestinal Ischemia Requiring Emergent Hemicolectomy". Journal of Medical Toxicology. doi:10.1007/s13181-011-0144-8. Retrieved 14 March 2011.
- Hanekamp B, Zijlstra J, Tulleken J, Ligtenberg J, van der Werf T, Hofstra L (2005). "Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning: a case report". Neth J Med 63 (8): 316–8. PMID 16186642.
- [No Authors listed]. "Acute Effectiveness of Additional Drugs to the Standard Treatment of Depression". ClinicalTrials.gov. Retrieved 23 June 2005.
- Goeringer K, McIntyre I, Drummer O (2001). "Postmortem tissue concentrations of venlafaxine". Forensic Sci Int 121 (1–2): 70–5. doi:10.1016/S0379-0738(01)00455-8. PMID 11516890.
- Wellington K, Perry C (2001). "Venlafaxine extended-release: a review of its use in the management of major depression". CNS Drugs 15 (8): 643–69. doi:10.2165/00023210-200115080-00007. PMID 11524036.
- Delgado, P.L.; Moreno, F.A. (2000). "Role of norepinephrine in depression". Journal of Clinical Psychiatry 61: 5–12. PMID 10703757.
- Shams ME et al. (2006). "CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine". J Clin Pharm Ther 31 (5): 493–502. doi:10.1111/j.1365-2710.2006.00763.x. PMID 16958828.
- "Rs2032583 - SNPedia".
- Uhr, M.; Tontsch, A.; Namendorf, C.; Ripke, S.; Lucae, S.; Ising, M.; Dose, T.; Ebinger, M. et al. (2008). "Polymorphisms in the drug transporter gene ABCB1 predict antidepressant treatment response in depression". Neuron 57 (2): 203–209. doi:10.1016/j.neuron.2007.11.017. PMID 18215618.
- DeVane CL. (2003). "Immediate-release versus controlled-release formulations: pharmacokinetics of newer antidepressants in relation to nausea". J Clin Psychiatry 64 (Suppl 18): 14–9. PMID 14700450.
- Details for Effexor XR
- http://www.wyeth.com/irj/servlet/prt/portal/prtroot/com.sap.km.cm.docs//wyeth_xml/home/news/announcements/1153395074748.pdf (Archived by WebCite at http://www.webcitation.org/5pXQuFykU) p. 3, 4
- U.S. Food and Drug Administration information on Effexor
- Efexor patient information leaflet (UK)
- Effexor XR prescribing information for healthcare professionals (pdf) (USA only)
- Detailed Patient/Parent Information on Effexor
- List of international brand names for Venlafaxine
- U.S. National Library of Medicine: Drug Information Portal - Venlafaxine
- The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity