5±2 h (parent compound for immediate release preparations), 15±6 h (parent compound for extended-release preparations), 11±2 h (active metabolite)[2][5]
Venlafaxine was approved for medical use in the United States in 1993.[9] It is available as ageneric medication.[9] In 2023, it was the 51st most commonly prescribed medication in the United States, with more than 13million prescriptions.[13][14]
Concerns that noradrenergic reuptake might precipitate anxiety have not been borne out in randomized trials: a 2016 systematic review of 52 double-blind, placebo-controlled studies (mostly with venlafaxine or duloxetine) found clinically significant improvements in anxiety symptoms and no signal for treatment-emergent anxiety attributable to SNRIs.[16]
Open-label evidence also suggests potential benefit in treatment-resistant cases: in a multicenter Canadian study of adults with inadequate response to prior antidepressants (n=159), 58% achieved response and 28% remission after 8 weeks of venlafaxine (mean 260 mg/day); tolerability was generally acceptable.[28]
Venlafaxine was similar in efficacy to the atypical antidepressantbupropion; however, the remission rate was lower for venlafaxine.[29] In a double-blind study, patients who did not respond to an SSRI were switched to either venlafaxine or another SSRI (citalopram); similar improvement was observed in both groups.[30]
Studies have not established its efficacy for use in pediatric populations.[31] In children and adolescents with depression, venlafaxine increases the risk of suicidal thoughts or attempts.[32][33][34][35][36][37]
Higher doses (e.g., 225 mg and 375 mg per day) of venlafaxine are more effective than lower doses (e.g., 75 mg per day) but also cause more side effects.[38]
Studies have shown that the extended-release is superior to the immediate-release form of venlafaxine.[39]
A 2017 meta-analysis has shown that the efficacy of venlafaxine is not correlated with baseline severity of depression.[39] In other words, regardless of how severe a person's depression is at treatment initiation, the efficacy of venlafaxine remains consistent and is not influenced by the severity of depression at the start of treatment.
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.[42]
A study conducted in Finland followed more than 15,000 patients for 3.4 years. Venlafaxine increased suicide risk by 60% (statistically significant), as compared to no treatment. At the same time,fluoxetine (Prozac) halved the suicide risk.[43]
In a study sponsored byWyeth, which produces and markets venlafaxine, 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 a significantly higher risk of suicide than the ones onfluoxetine orcitalopram (Celexa). After adjusting for known risk factors, venlafaxine was associated with an increased risk of suicide relative to fluoxetine anddothiepin which 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.[44]
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 orplacebo.[45]
Venlafaxine is contraindicated in children, adolescents, and young adults. In children and adolescents with depression, venlafaxine increases the risk of suicidal thoughts or attempts.[32][33][34][35][36][37]
The development of a potentially life-threateningserotonin syndrome (also classified as "serotonin toxicity")[46] may occur with venlafaxine treatment, particularly with concomitant use of serotonergic drugs, including but not limited toSSRIs andSNRIs, many hallucinogens such astryptamines andphenethylamines (e.g.,LSD/LSA,DMT,MDMA,mescaline),dextromethorphan (DXM),tramadol,tapentadol,pethidine (meperidine) andtriptans and with drugs that impair metabolism of serotonin (includingMAOIs).[citation needed] Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination), or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhea). Venlafaxine-induced serotonin syndrome has also been reported when venlafaxine has been taken in isolation in overdose.[47] 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).[48] A case of a patient with serotonin syndrome induced by low-dose venlafaxine (37.5 mg per day) has also been reported.[49]
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 ofmiscarriage.[50][51] Consequently, venlafaxine should only be used during pregnancy if clearly needed.[5] A large case-control study done as part of the National Birth Defects Prevention Study and published in 2012 found a significant association between venlafaxine use during pregnancy and several birth defects including anencephaly, cleft palate, septal heart defects and coarctation of the aorta.[52] Prospective studies have not shown any statistically significantcongenital malformations.[53] There have, however, been some reports of self-limiting effects on newborn infants.[54] As with otherserotonin reuptake inhibitors (SRIs), these effects are generally short-lived, lasting only 3 to 5 days,[55] and rarely resulting in severe complications.[56][needs update]
According to theISBD Task Force report on antidepressant use in bipolar disorder,[57] during the course of treatment for depression with those suffering from bipolar I and II, venlafaxine "appears to carry a particularly high risk of inducing pathologically elevated states of mood and behavior." Because venlafaxine appears to be more likely thanSSRIs andbupropion to induce mania and mixed episodes in these patients, provider discretion is advised through "carefully evaluating individual clinical cases and circumstances."
A rare but serious side effect of venlafaxine is liver injury. It appears to affect both male and female patients with a median age of 44. Cessation of venlafaxine is one of the appropriate measures of management. While the mechanism of venlafaxine-related liver injury remains unclear, findings suggest that it may be related to a CYP2D6 polymorphism.[58]
Most patients overdosing with venlafaxine develop only mild symptoms. Plasma venlafaxine concentrations in overdose survivors have ranged from 6 to 24 mg/L, while postmortem blood levels in fatalities are often in the 10–90 mg/L range.[59] 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.[60] It is usually reserved as a second-line treatment for depression due to a combination of its superior efficacy to the first-line treatments like fluoxetine, paroxetine and citalopram and greater frequency of side effects like nausea, headache, insomnia, drowsiness, dry mouth, constipation, sexual dysfunction, sweating and nervousness.[26][61]
There is no specificantidote for venlafaxine, and management is generally supportive, providing treatment for the immediate symptoms. Administration ofactivated charcoal can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed withbenzodiazepines or other anticonvulsants.Forced diuresis,hemodialysis,exchange transfusion, orhemoperfusion are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug's highvolume of distribution.[62]
The higher risk and increased severity of withdrawal symptoms relative to other antidepressants may be related to the shorthalf-life of venlafaxine and its active metabolite.[67] After stopping venlafaxine, the levels of both serotonin andnorepinephrine decrease, leading to the hypothesis that the withdrawal symptoms could result from an overly rapid reduction of neurotransmitter levels.[68]
In rare cases, drug-inducedakathisia can occur after use in some people.[69]
Venlafaxine should be used with caution inhypertensive patients. Venlafaxine must be discontinued if significanthypertension persists.[70][71][72] It can also have undesirable cardiovascular effects.[73]
Venlafaxine indirectly affectsopioid receptors as well as theα2-adrenergic receptor, and was shown to increase pain threshold in mice. These benefits with respect to pain were reversed withnaloxone, an opioid antagonist, thus supporting an opioid mechanism.[86][19]
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 theCYP2D6isoenzyme todesvenlafaxine (O-desmethylvenlafaxine, now marketed as a separate medication named Pristiq[87]), which is just as potent an SNRI as the parent compound, meaning that the differences in metabolism between extensive andpoor metabolisers are not clinically important in terms of efficacy. Side effects, however, are reported to be more severe inCYP2D6 poor metabolisers.[88][89] Steady-state concentrations of venlafaxine and itsmetabolite are attained in theblood 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 thekidneys.[5] Thehalf-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.[90]
Venlafaxine is a substrate ofP-glycoprotein (P-gp), which pumps it out of the brain. The gene encoding P-gp, ABCB1, has theSNP rs2032583, withalleles C and T. The majority of people (about 70% of Europeans and 90% of East Asians) have the TT variant.[91][unreliable source?] A 2007 study[92] found that carriers of at least one C allele (variant CC or CT) are 7.72 times more likely than non-carriers to achieveremission after 4 weeks of treatment withamitriptyline,citalopram,paroxetine or venlafaxine (all P-gp substrates). The study included patients withmood disorders other thanmajor depression, such asbipolar II; the ratio is 9.4 if these other disorders are excluded. At the 6-week mark, 75% of C-carriers had remitted, compared to only 38% of non-carriers.[citation needed]
TheIUPAC name of venlafaxine is 1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]cyclohexanol, though it is sometimes referred to as (±)-1-[a-[a-(dimethylamino)methyl]-p-methoxybenzyl]cyclohexanol. It consists of twoenantiomers present in equal quantities (termed aracemic mixture), both of which have theempirical formula of C17H27NO2. It is usually sold as a mixture of the respectivehydrochloridesalts, (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl]cyclohexanol hydrochloride, C17H28ClNO2, which is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the atypical opioidanalgesictramadol, and more distantly to the newly released opioidtapentadol, but not to any of the conventional antidepressant drugs, includingtricyclic antidepressants,SSRIs, MAOIs, orRIMAs.[93]
Venlafaxine extended-release is chemically the same as normal venlafaxine. The extended-release (controlled release) version distributes the release of the drug into thegastrointestinal 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 ofnausea as a side effect, resulting in better compliance.[94]
Venlafaxine should be taken with caution when usingSt John's wort.[95] Venlafaxine may lower the seizure threshold, and coadministration with other drugs that lower the seizure threshold such asbupropion andtramadol should be done with caution and at low doses.[96]
Effexor XR 75 mg and 150 mg capsulesGeneric 75mg (top) and 150mg (bottom) venlafaxine capsules by Krka
Venlafaxine was originally marketed as Effexor in most of the world; generic venlafaxine has been available since around 2008 and extended-release venlafaxine has been available since around 2010.[98]
Venlafaxine is sold under many brand names worldwide.[1] In some countries, Effexor is marketed byViatris after Upjohn was spun off from Pfizer.[99][100]
Venlafaxine is highly toxic toBacillariophyta andChlorophyta phytoplankton.[102] Cats are drawn to the smell of venlafaxine and tend to ingest the pills, which are highly toxic to them.[103]
^Dean L (2015). Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kane MS, Kattman BL, Malheiro AJ (eds.).Venlafaxine Therapy and CYP2D6 Genotype. National Center for Biotechnology Information (US).PMID28520361.Archived from the original on 29 November 2017. Retrieved28 December 2018.
^Schober CE, Ansani NT (November 2003). "Venlafaxine hydrochloride for the treatment of hot flashes".The Annals of Pharmacotherapy.37 (11):1703–1707.doi:10.1345/aph.1C483.PMID14565812.S2CID45334784.
^"Medications". Stanford University School of Medicine, Center for Narcolepsy. 7 February 2003. Archived fromthe original on 21 August 2007. Retrieved3 September 2007.
^Ghanizadeh A, Freeman RD, Berk M (March 2013). "Efficacy and adverse effects of venlafaxine in children and adolescents with ADHD: a systematic review of non-controlled and controlled trials".Reviews on Recent Clinical Trials.8 (1):2–8.doi:10.2174/1574887111308010002.PMID23157376.
^Pae CU, Lim HK, Ajwani N, Lee C, Patkar AA (June 2007). "Extended-release formulation of venlafaxine in the treatment of post-traumatic stress disorder".Expert Review of Neurotherapeutics.7 (6):603–615.doi:10.1586/14737175.7.6.603.PMID17563244.S2CID25215502.
^Phelps NJ, Cates ME (January 2005). "The role of venlafaxine in the treatment of obsessive-compulsive disorder".The Annals of Pharmacotherapy.39 (1):136–140.doi:10.1345/aph.1E362.PMID15585743.S2CID30973410.
^abCipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, et al. (February 2009). "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis".Lancet.373 (9665):746–758.doi:10.1016/S0140-6736(09)60046-5.PMID19185342.S2CID35858125.
^de Montigny C, Silverstone PH, Debonnel G, Blier P, Bakish D (1999). "Venlafaxine in treatment-resistant major depression: a Canadian multicenter, open-label trial".Journal of Clinical Psychopharmacology.19 (5):401–406.doi:10.1097/00004714-199910000-00003.PMID10505581.
^Thase ME, Clayton AH, Haight BR, Thompson AH, Modell JG, Johnston JA (October 2006). "A double-blind comparison between bupropion XL and venlafaxine XR: sexual functioning, antidepressant efficacy, and tolerability".Journal of Clinical Psychopharmacology.26 (5):482–488.doi:10.1097/01.jcp.0000239790.83707.ab.PMID16974189.S2CID276619.
^Lenox-Smith AJ, Jiang Q (May 2008). "Venlafaxine extended release versus citalopram in patients with depression unresponsive to a selective serotonin reuptake inhibitor".International Clinical Psychopharmacology.23 (3):113–119.doi:10.1097/YIC.0b013e3282f424c2.PMID18408525.S2CID34986490.
^Rudolph RL, Fabre LF, Feighner JP, Rickels K, Entsuah R, Derivan AT (March 1998). "A randomized, placebo-controlled, dose-response trial of venlafaxine hydrochloride in the treatment of major depression".The Journal of Clinical Psychiatry.59 (3):116–122.doi:10.4088/jcp.v59n0305.PMID9541154.
^abcThase M, Asami Y, Wajsbrot D, Dorries K, Boucher M, Pappadopulos E (February 2017). "A meta-analysis of the efficacy of venlafaxine extended release 75-225 mg/day for the treatment of major depressive disorder".Current Medical Research and Opinion.33 (2). Informa UK Limited:317–326.doi:10.1080/03007995.2016.1255185.PMID27794623.S2CID4394404.
^Taylor D, Paton C, Kapur S, eds. (2012).The Maudsley Prescribing Guidelines in Psychiatry (illustrated ed.). John Wiley & Sons.ISBN978-0-470-97948-8.
^Ripple MG, Pestaner JP, Levine BS, Smialek JE (December 2000). "Lethal combination of tramadol and multiple drugs affecting serotonin".The American Journal of Forensic Medicine and Pathology.21 (4):370–374.doi:10.1097/00000433-200012000-00015.PMID11111800.
^de Moor RA, Mourad L, ter Haar J, Egberts AC (July 2003). "[Withdrawal symptoms in a neonate following exposure to venlafaxine during pregnancy]".Nederlands Tijdschrift voor Geneeskunde.147 (28):1370–1372.PMID12892015.
^Ferreira E, Carceller AM, Agogué C, Martin BZ, St-André M, Francoeur D, et al. (January 2007). "Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates".Pediatrics.119 (1):52–59.doi:10.1542/peds.2006-2133.PMID17200271.S2CID27443298.
^Moses-Kolko EL, Bogen D, Perel J, Bregar A, Uhl K, Levin B, et al. (May 2005). "Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications".JAMA.293 (19):2372–2383.doi:10.1001/jama.293.19.2372.PMID15900008.S2CID30284439.
^Stadlmann S, Portmann S, Tschopp S, Terracciano LM (November 2012). "Venlafaxine-induced cholestatic hepatitis: case report and review of literature".The American Journal of Surgical Pathology.36 (11). Ovid Technologies (Wolters Kluwer Health):1724–1728.doi:10.1097/pas.0b013e31826af296.PMID23073329.
^Baselt R (2008).Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 1634–1637.ISBN978-0-9626523-7-0.
^Papp A, Onton JA (December 2018). "Brain Zaps: An Underappreciated Symptom of Antidepressant Discontinuation".The Primary Care Companion for CNS Disorders.20 (6) 18m02311.doi:10.4088/PCC.18m02311.PMID30605268.S2CID58577252.
^Rizkalla M, Kowalkowski B, Prozialeck WC (February 2020). "Antidepressant Discontinuation Syndrome: A Common but Underappreciated Clinical Problem".The Journal of the American Osteopathic Association.120 (3):174–178.doi:10.7556/jaoa.2020.030.PMID32077900.
^Khurana RN, Baudendistel TE (December 2003). "Hypertensive crisis associated with venlafaxine".The American Journal of Medicine.115 (8):676–677.doi:10.1016/S0002-9343(03)00472-8.PMID14656626.
^Thase ME (October 1998). "Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients".The Journal of Clinical Psychiatry.59 (10):502–508.doi:10.4088/JCP.v59n1002.PMID9818630.
^Johnson EM, Whyte E, Mulsant BH, Pollock BG, Weber E, Begley AE, et al. (September 2006). "Cardiovascular changes associated with venlafaxine in the treatment of late-life depression".The American Journal of Geriatric Psychiatry.14 (9):796–802.doi:10.1097/01.JGP.0000204328.50105.b3.PMID16943176.
^Delgado PL, Moreno FA (2000). "Role of norepinephrine in depression".The Journal of Clinical Psychiatry.61 (Suppl 1):5–12.PMID10703757.[full citation needed]
^Parker G, Blennerhassett J (April 1998). "Withdrawal reactions associated with venlafaxine".The Australian and New Zealand Journal of Psychiatry.32 (2):291–294.doi:10.3109/00048679809062742.PMID9588310.S2CID34824025.
^DeVane CL (2003). "Immediate-release versus controlled-release formulations: pharmacokinetics of newer antidepressants in relation to nausea".The Journal of Clinical Psychiatry.64 (Suppl 18):14–19.PMID14700450.
^Iliou T, Casta P, Lequeux J, Pochard L, Frauger E, Spadari M, et al. (2019). "Venlafaxine Abuse in a Patient With a History of Methylphenidate Abuse: A Case Report".Journal of Clinical Psychopharmacology.39 (2):172–174.doi:10.1097/JCP.0000000000001011.PMID30811375.S2CID73496502.
-_and_(S)-venlafaxine_ball-and-stick_model_from_xtal_2008.png)
