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Systematic (IUPAC) name
CAS number 93413-69-5
ATC code N06AX16
PubChem 5656
DrugBank APRD00125
ChemSpider 56641
Chemical data
Formula C17H27NO2 
Mol. mass 277.402 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 45%
Protein binding 27%
Metabolism Hepatic
Half life 5 ± 2 hours (parent compound); 11 ± 2 hours (active metabolite)
Excretion Renal
Therapeutic considerations
Pregnancy cat.


Legal status

Rx-only, not a controlled drug

Routes Oral

Venlafaxine (brand name Effexor, Efexor) is an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class first introduced by Wyeth in 1993. It is prescribed for the treatment of major depression and anxiety disorders, among other uses. Venlafaxine was the sixth most widely-used brand-name drug and most widely-used brand-name antidepressant based on the retail sales ($2.25bn) in 2006.[1]


[edit] Indications

[edit] Approved

Venlafaxine is used primarily for the treatment of major depression, generalized anxiety disorder, social anxiety disorder, and panic disorder in adults.[2]

[edit] Depression

Venlafaxine was shown to be effective for depression in multiple double blind studies. Venlafaxine is similar in efficacy to the tricyclic antidepressants amitriptyline (Elavil) and imipramine and it was better tolerated than amitriptyline. Venlafaxine appears to have efficacy similar or somewhat better than sertraline (Zoloft) and fluoxetine (Prozac) depending on the criteria and rating scales used. In particular, higher doses of venlafaxine are more effective, and more patients achieved remission or were "very much improved". At the same time 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 indicated superiority of venlafaxine.[3] Based on the same set of criteria, venlafaxine was similar in efficacy to an atypical antidepressant bupropion (Wellbutrin); however, the remission rate was significantly lower for venlafaxine.[4] Venlafaxine was also marginally inferior in efficacy to a newer SSRI escitalopram (Lexapro) and had twice higher frequency of the side effects, in particular, nausea, ejaculation disorder, somnolence and sweating.[5] 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.[6]

A popular magazine Consumer Reports, which in 2004 had rated venlafaxine as the most effective among six commonly prescribed antidepressants,[7] no longer recommends it. Fluoxetine, citalopram and bupropion have been chosen as Consumer Reports Best Buy drugs in the updated version of their guide, based upon effectiveness, safety, side effects, and cost.[8]

[edit] Off-label / investigational uses

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.[11][12]

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.[2] Venlafaxine hydrochloride is in the phenethylamine class of modern chemicals, which includes amphetamine, methylendioxymethamphetamine (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.[2]

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.[13]

Venlafaxine was found in one study to be equal to Anafranil in the treatment of OCD with fewer side effects.[14]

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.[15]

[edit] Contraindications

Venlafaxine is not recommended in patients hypersensitive to venlafaxine. It should not 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 in conjunction with a monoamine oxidase inhibitor (MAOI), due to the potential to develop a potentially deadly condition known as serotonin syndrome. At least 14 days time lag are required between the intake of venlafaxine and MAO inhibitors. Caution should also be used in those with a seizure disorder. Venlafaxine is not approved for use in children or adolescents.[2] However, Wyeth does provide information on precautions if venlafaxine is prescribed to this age group for the treatment of non-approved conditions. Studies in these age groups have not established its efficacy or safety.[16]

[edit] Glaucoma

Venlafaxine can increase eye pressure, so those with glaucoma may require more frequent eye checks.[2]

[edit] Pregnancy, labor, and delivery

There are no adequate and well controlled studies with venlafaxine in pregnant women. Therefore, venlafaxine should only be used during pregnancy if clearly needed.[2] Prospective studies have not shown any statistically significant congenital malformations.[17] There have, however, been some reports of self-limiting effects on newborn infants.[18] As with other Serotonin Reuptake Inhibitors, these effects are generally short, lasting only 3 to 5 days[19] and rarely resulting in severe complications.[20] Use of Venlafaxine in pregnancy (like other Serotonin Reuptake Inhibitors) should be considered on a case-by-case basis.

[edit] Heart disease and hypertension

The FDA has asked the sponsors of all SNRIs to include the potential risk for persistent pulmonary hypertension (PPHN) in prescribing data as of July 19, 2006. Medications containing Venlafaxine caused a mean heart rate increase of 4 b.p.m. in clinical trials, along with a sustained increase in blood pressure in some.

[edit] Adverse effects

[edit] Suicide ideation/risk

The US Food and Drug Administration body (FDA) requires all antidepressants, including venlafaxine, to carry a black box 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.[21]

In another study, the data on more than 200,000 cases was 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.[22]

An analysis of clinical trials by the FDA statisticians showed the incidence of suicidal behavior among the adults on venlafaxine to be not significantly different from fluoxetine or placebo.[23] A possible explanation for this discrepancy is that suicidal patients are generally excluded from clinical trials, and so clinical trials are not quite representative of the real population of patients.[citation needed]

Venlafaxine is contraindicated to children, adolescents and young adults. According to the FDA analysis of clinical trials[23] venlafaxine caused a 5-fold increase (statistically significant) of suicidal ideation and behavior in subjects younger than 25. In another analysis, venlafaxine was no better than placebo among children (7–11 years old) and improved the depression in adolescents (12–17 years old). However, in both groups hostility and suicidal behavior were increased in comparison to the placebo treatment.[24]

[edit] Common side effects

NOTE: The percentage of occurrences for each side effect listed comes from clinical trial data provided by Wyeth Pharmaceuticals Inc. The percentages indicate the percentage of people that experienced the side effect in clinical trials.[2]

[edit] Less common to rare side-effects

Note 'Rare' adverse effects occur in fewer than 1 in 1000 patients. 'Infrequent' adverse effects occur in 1 in 100 to 1 in 1000 patients.[2]

[edit] 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.[2]

[edit] Memory Loss

In a study comparing the tolerability of venlafaxine at standard doses, ranging from 75 to 300 mg, against relatively high doses (rarely prescribed), ranging from 375 to 600 mg per day, for treating DSM-IV major depressive disorder "failing memory" was reported in 44% of cases. The severity of venlafaxine-induced memory loss was also noted to increase with dose and length of treatment.[25]

[edit] Discontinuation Syndrome

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), 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.[2]

Notwithstanding these findings, some patients stopping venlafaxine use experience SSRI discontinuation syndrome . This is especially noted if a patient misses a dose, but can also occur when reduction of dosage is done with a doctor's care. The high risk of discontinuation syndrome symptoms may reflect venlafaxine's short half-life.[26] Missing even a single dose can induce discontinuation effects in some patients.[27] Discontinuation is similar in nature to those of SSRIs such as Paroxetine (Paxil or Seroxat). Sudden discontinuation of venlafaxine seems to cause particularly severe discontinuation symptoms.[28] 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.[26]

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,[26] addiction or dependence is a more common effect described for drugs that (are thought to, or may) improve mental well-being.[29]

[edit] Serotonin syndrome

The development of a potentially life-threatening serotonin syndrome (also more recently classified as "serotonin toxicity")[30] may occur with Venlafaxine treatment, particularly with concomitant use of serotonergic drugs (including SSRIs, SNRIs, 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 venlafxine has been taken in isolation in overdose.[31] 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)[32] A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5 mg per day) has also been reported.[33]

[edit] Combined Serotonin Toxicity and SSRI 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 are closely monitored during any increase in dosage (when the patient is most at risk of developing serotonin toxicity)[34] and that such increases are 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.[29]

[edit] Available forms

Effexor XR 75 mg and 150 mg capsules

Effexor is distributed in pentagon-shaped peach-colored tablets of 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg. There is also an extended-release version distributed in capsules of 37.5 mg (gray/peach), 75 mg (peach), and 150 mg (brownish red).

[edit] Venlafaxine extended release (XR)

Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release version (sometimes referred to as controlled release) controls 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.[35] In Australia, New Zealand 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.

[edit] Generic

Generic venlafaxine is available in the United States as of August 2006 and in Canada as of December 2006. 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), and Sandoz Venlafaxine XR (Sandoz Canada Inc.). Generic extended-release venlafaxine will become available in the United States in 2010.[36] Generic versions of both drug forms are available now in India. Generic versions are also available in the UK such as Vaxalin manufactured by RatioPharm GmbH. [1]

[edit] Overdose

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.[37] 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.[38] Deaths have been reported following very large doses.[39][40]

On May 31 2006, The Medicines and Healthcare products Regulatory Agency (MHRA) UK has concluded its review into all the latest safety evidence relating to venlafaxine particularly looked at the risks associated with overdose. The advice are, the need for specialist supervision in those severely depressed or hospitalized patients who need doses 300 mg or more; cardiac contra-indications 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.[41]

On October 17, 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 postmarketing 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.[42]

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 assumes 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."[43]

The February 27, 2007 Vancouver Sun reported that the BC Drug and Poison Information Centre has alerted doctors that the drug poses a significant risk of death from overdose, saying that venlafaxine "appears more toxic than it was originally hoped".[44] 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.[39] 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.

[edit] Management of overdosage

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 anti-convulsants. 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.[45]

[edit] 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.[46][47] 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 (5-hydroxytryptamine) and norepinephrine (noradrenaline). Additionally, in high doses it weakly inhibits the reuptake of dopamine,[48] with recent evidence showing that the norepinephrine transporter also transports some dopamine as well, implying that SNRIs may also increase dopamine transmission. This is because SNRIs work by inhibiting reuptake, i.e. preventing the serotonin and norepinephrine transporters from taking their respective neurotransmitters back to their storage vesicles for later use. If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine (particularly in the prefrontal cortex).

[edit] 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 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.[49] 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.[2] The half-life of venlafaxine is relatively short, therefore patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed dose can result in the withdrawal symptoms.[27]

Carriers of the (T;T) allele of rs2032583 [50] SNP in the ABCB1 gene are 7x less likely to respond to Venlafaxine treatment. This genetic variant is present about two thirds of people of European descent and 80% to 90% of East Asians.

[edit] Drug interactions

Venlafaxine should be taken with caution when using St John's wort.[51] Venlafaxine may lower the seizure threshold, and co-administration with other drugs that lower the seizure threshold such as bupropion and tramadol should be done with caution and at low doses.[52] Seizures have also anecdotally been reported with combination of venlafaxine and marijuana.[53][54]

There have been false positive phencyclidine (PCP) results caused by Venlafaxine with certain on-site routine urine-based drug tests.[55][56]

[edit] Physical/chemical properties

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 analgesic tramadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, Selective serotonin reuptake inhibitors (SSRI), Monoamine oxidase inhibitors (MAOI), or reversible inhibitors of monoamine oxidase A (RIMA).[38]

[edit] See also

[edit] Notes

  1. ^ "Top 200 brand-name drugs by units.". Drug Topics, Mar 5, 2007. Retrieved on 2007-04-08. 
  2. ^ a b c d e f g h i j k "Effexor Medicines Data Sheet". Wyeth Pharmaceuticals Inc. 2006. Retrieved on 17 September 2006. 
  3. ^ 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. 
  4. ^ 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/ PMID 16974189. 
  5. ^ Bielski RJ, Ventura D, Chang CC (2004). "A double-blind comparison of escitalopram and venlafaxine extended release in the treatment of major depressive disorder". The Journal of clinical psychiatry 65 (9): 1190–6. PMID 15367045. 
  6. ^ 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 (inactive 2008-06-21). PMID 18408525. 
  7. ^ "Mental health, readers rate antidepressant drugs", Consumer Reports, September 2004 
  8. ^ "Consumer Reports Best Buy Drugs. Antidepressants." (PDF). Consumer Reports. Retrieved on 2007-06-23. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ Mayo Clinic staff (2005). "Beyond hormone therapy: Other medicines may help". Hot flashes: Ease the discomfort of menopause. Mayo Clinic. Retrieved on 19 August 2005. 
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  13. ^ "Medications". Stanford University School of Medicine, Center for Narcolepsy. Revised 02/07/2003. Retrieved on 2007-09-03. 
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  17. ^ 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. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ 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. PMID 17164297. 
  23. ^ a b "Overview for December 13 Meeting of Psychopharmacologic Drugs Advisory Committee" (PDF). November 16, 2006. Retrieved on 2007-06-20. 
  24. ^ 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. 
  25. ^ 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. 
  26. ^ a b c Haddad PM (2001). "Antidepressant discontinuation syndromes". Drug Saf 24 (3): 183–97. doi:10.2165/00002018-200124030-00003. PMID 11347722. 
  27. ^ a b 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. 
  28. ^ 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. 
  29. ^ a b Double D (1997). "Prescribing antidepressants in general practice. People may become psychologically dependent on antidepressants". BMJ 314 (7083): 829. PMID 9081020. 
  30. ^ 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. PMID 12925718. 
  31. ^ Kolecki P (1997). "Isolated venlafaxine-induced serotonin syndrome". J Emerg Med 15 (4): 491–3. PMID 9279702. 
  32. ^ Ebert D. et al.. "Hallucinations as a side effect of venlafaxine treatment". Psychiatry On-line. Retrieved on 2008-06-17. 
  33. ^ Pan JJ, Shen WW (February 2003). "Serotonin syndrome induced by low-dose venlafaxine". Ann Pharmacother 37 (2): 209–11. PMID 12549949. 
  34. ^ Venlafaxine (marketed as Effexor) FDA Alert: SSRIs/SNRI/Triptan and Serotonin Syndrome [issued 7/2006]
  35. ^ 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. 
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