Venlafaxine

From Wikipedia the free encyclopedia

Adverse effects

See also: List of adverse effects of venlafaxine

Venlafaxine can increase eye pressure so those with glaucoma may require more frequent eye checks.


Suicide

The US Food and Drug Administration body (FDA) requires all antidepressants including venlafaxine to carry a black box warning with a generic warning about a possible suicide risk.

A 2014 meta analysis of 21 clinical trials of venlafaxine for the treatment of depression in adults found that compared to placebo venlafaxine reduced the risk of suicidal thoughts and behavior.

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.

In another study the data on more than 200 000 cases were obtained from the UK general practice research database. At baseline patients prescribed venlafaxine had a greater number of risk factors for suicide (such as prior suicide attempts) than patients treated with other anti-depressants. The patients taking venlafaxine had significantly higher risk of completed suicide than the ones on fluoxetine or citalopram (Celexa). After adjusting for known risk factors venlafaxine was associated with an increased risk of suicide relative to fluoxetine and dothiepin that was not statistically significant. A statistically significant greater risk for attempted suicide remained after adjustment but the authors concluded that it could be due to residual confounding.

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.

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 behaviour in persons younger than 25. In another analysis venlafaxine was no better than placebo among children (7–11 years old) but improved depression in adolescents (12–17 years old). However in both groups hostility and suicidal behaviour increased in comparison to those receiving a placebo. 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.


Discontinuation syndrome

Main article: Antidepressant discontinuation syndrome

People stopping venlafaxine commonly experience discontinuation symptoms such as dysphoria headaches nausea irritability emotional lability sensation of electric shocks and sleep disturbance. Venlafaxine has a higher rate of moderate to severe discontinuation symptoms relative to other antidepressants (similar to the SSRI paroxetine).

The higher risk and increased severity of discontinuation syndrome symptoms relative to other antidepressants may be related to the short half-life of venlafaxine and its active metabolite. After discontinuing venlafaxine the levels of both serotonin and norepinephrine decrease leading to the hypothesis that the discontinuation symptoms could result from an overly rapid reduction of neurotransmitter levels.


Serotonin syndrome

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 SSRIs and SNRIs many hallucinogens such as tryptamines and phenethylamines (e.g. LSD/LSA DMT MDMA mescaline) dextromethorphan (DXM) tramadol tapentadol pethidine (meperidine) and triptans and with drugs that impair metabolism of serotonin (including MAOIs)[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. 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.


Pregnancy

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. A large case-control study done as part of the National Birth Defects Prevention Study and published in 2012 found a significant association of venlafaxine use during pregnancy and several birth defects including anencephaly cleft palate septal heart defects and coarctation of the aorta. 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 (SRIs) these effects are generally short-lived lasting only 3 to 5 days and rarely resulting in severe complications.


Drug interactions

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.


Bipolar disorder

Venlafaxine is neither recommended nor approved for the treatment of major depressive episodes in bipolar disorder as it can induce mania or mixed episodes. Venlafaxine appears to be more likely than the SSRIs and bupropion to induce mania and mixed episodes in bipolar patients.


Other

There have been false positives reported for phencyclidine (PCP) cocaine and amphetamine with routine urine-based drug tests. Although rare these instances typically occur with higher doses of venlafaxine more than 150 mg per day when used for extended periods of time.[citation needed]

In rare cases drug-induced akathisia can occur after use in some people.

Venlafaxine should be used with caution in hypertensive patients. Venlafaxine must be discontinued if significant hypertension persists. It can also have undesirable cardiovascular effects.

Overdose

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. 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. 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.

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.

Chemistry

The IUPAC 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 two enantiomers present in equal quantities (termed a racemic mixture) both of which have the empirical formula of C17H27NO2. It is usually sold as a mixture of the respective hydrochloride salts (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 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 nausea as a side effect resulting in better compliance.

Society and culture

Venlafaxine was originally marketed as Effexor in most of the world; generic venlafaxine has been available since around 2008 and extended release venlaxafine has been available since around 2010.

As of January 2020 venlafaxine was marketed under many brand names worldwide many with alternative extended release forms (not shown): Adefaxin Alenthus Altven Alventa Amfax Anapresin Ansifix Arafaxina Argofan Arrow Venlafaxine Axone Axyven Benolaxe Blossom Calmdown Dalium Defaxine Depefex Depretaxer Deprevix Deprexor Deprixol Depurol Desinax Dislaven Dobupal Duofaxin Easyfor Ectien Eduxon Efastad Efaxin Efaxine Efectin Efegen Efevelon Efevelone Efexiva Efexor Effegad Effexine Effexor Elafax Elaxine Elify Enpress Enlafax Envelaf Falven Faxigen Faxine Faxiprol Faxiven Faxolet Flavix Flaxen Fobiless Ganavax Idixor Idoxen Intefred Illovex Lafactin Lafaxin Lanvexin Laroxin Levest Limbic Linexel Maxibral Mazda Melocin Memomax Mezine Neoxacina Neoxacina Nervix Norafexine Norezor Norpilen Noviser Nulev Odiven Olwexya Oriven Paxifar Politid Pracet Prefaxine Psiseven Quilarex Rafax Senexon Sentidol Sentosa Serosmine Seroxine Sesaren Subelan Sulinex Sunveniz Sunvex Symfaxin Tedema Tifaxin Tonpular Trevilor Tudor Vafexin Valosine Vandral Velaf Velafax Velahibin Velaxin Velept Velpine Venax Venaxin Venaxx Vencarm Vencontrol Vendep Venegis Venex Venexor Venfalex Venfax Ven-Fax Venfaxine Venforin Venforspine Veniba Veniz Venjoy Venla Venlabax Venlablue Venlabrain Venladep Venladex Venladoz Venlaf Venlafab Venlafaxin Venlafaxina Venlafaxine Venlagamma Venlalic Venlamax Venlamylan Venlaneo Venlapine Venla-Q Venlasand Venlatrin Venlavitae Venlax Venlaxin Venlaxine Venlaxor Venlazid Venlectine Venlifax Venlift Venlix Venlobax Venlofex Venlor Venorion Venozap Vensate Ventab Venxin Venxor Venzip Vexamode Vfax Viepax ViePax Voxafen Zacalen Zanfexa Zaredrop Zarelis Zarelix and Zenexor.

Mechanism of action

Pharmacology

Transporter	Ki [nM]	IC50 [nM]
SERT	82	27
NET	2480	535
DAT	7647	ND

Receptor	Ki [nM]	Species
5-HT2A	2230	Human
5-HT2C	2004	Human
5-HT6	2792	Human
α1A	>1000	Human

Venlafaxine is usually categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI) but it has also 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 since dopamine is inactivated by norepinephrine reuptake in the frontal cortex. The frontal cortex largely lacks dopamine transporters; therefore venlafaxine can increase dopamine neurotransmission in this part of the brain.

Venlafaxine indirectly affects opioid receptors as well as the alpha2-adrenergic receptor and was shown to increase pain threshold in mice. These benefits with respect to pain were reversed with naloxone an opioid antagonist thus supporting an opioid mechanism.


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 desvenlafaxine (O-desmethylvenlafaxine now marketed as a separate medication named Pristiq ) which is just as potent an SNRI as the parent compound meaning that the differences in metabolism between extensive and poor metabolisers are not clinically important in terms of efficacy. Side effects however are reported to be more severe in CYP2D6 poor metabolisers. 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. The gene encoding P-gp ABCB1 has the SNP rs2032583 with alleles C and T. The majority of people (about 70% of Europeans and 90% of East Asians) have the TT variant. 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.[citation needed]

Contraindications

Venlafaxine is not recommended in patients hypersensitive to it nor should it be taken by anyone who is allergic to the inactive ingredients which include gelatin cellulose ethylcellulose iron oxide titanium dioxide and hypromellose. It should not be used in conjunction with a monoamine oxidase inhibitor (MAOI) as it can cause potentially fatal serotonin syndrome.

Medical uses

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

Venlafaxine has been used off label for the treatment of diabetic neuropathy and migraine prevention (in some people however venlafaxine can exacerbate or cause migraines). It may work on pain via effects on the opioid receptor. 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.

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. Some open-label and three double-blind studies have suggested the efficacy of venlafaxine in the treatment of attention deficit-hyperactivity disorder (ADHD). Clinical trials have found possible efficacy in those with post-traumatic stress disorder (PTSD). Case reports open trials and blinded comparisons with established medications have suggested the efficacy of venlafaxine in the treatment of obsessive–compulsive disorder.


Depression

A comparative meta-analysis of 21 major antidepressants found that venlafaxine agomelatine amitriptyline escitalopram mirtazapine paroxetine and vortioxetine were more effective than other antidepressants although the quality of many comparisons was assessed as low or very low.

Venlafaxine was similar in efficacy to the atypical antidepressant bupropion; however the remission rate was lower for venlafaxine. 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.

Studies of venlafaxine in children have not established its efficacy.

simple explanation

Venlafaxine

Clinical data
Pronunciation	/ˌvɛnləˈfæksiːn/
Trade names	Effexor Efexor others
AHFS/Drugs.com	Monograph
License data	US DailyMed: Venlafaxine
Pregnancy category	AU: B2
Routes of administration	By mouth
ATC code	N06AX16 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	42±15%
Protein binding	27±2% (parent compound) 30±12% (active metabolite desvenlafaxine)
Metabolism	Extensively metabolised by the liver
Elimination half-life	5±2 h (parent compound for immediate release preparations) 15±6 h (parent compound for extended release preparations) 11±2 h (active metabolite)
Excretion	Kidney (87%; 5% as unchanged drug; 29% as desvenlafaxine and 53% as other metabolites)
Identifiers
IUPAC name (RS)-1-[2-dimethylamino-1-(4-methoxyphenyl)-ethyl]cyclohexanol
CAS Number	93413-69-5 Y
PubChem CID	5656
DrugBank	DB00285 Y
ChemSpider	5454 Y
UNII	GRZ5RCB1QG
KEGG	D08670 Y
ChEBI	CHEBI:9943 Y
ChEMBL	ChEMBL637 Y
CompTox Dashboard (EPA)	DTXSID6023737
ECHA InfoCard	100.122.418
Chemical and physical data
Formula	C17H27NO2
Molar mass	277.408 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES OC2(C(c1ccc(OC)cc1)CN(C)C)CCCCC2
InChI InChI=1S/C17H27NO2/c1-18(2)13-16(17(19)11-5-4-6-12-17)14-7-9-15(20-3)10-8-14/h7-10 16 19H 4-6 11-13H2 1-3H3 Y Key:PNVNVHUZROJLTJ-UHFFFAOYSA-N Y
(verify)

Venlafaxine sold under the brand name Effexor among others is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder (MDD) generalized anxiety disorder (GAD) panic disorder and social phobia. It may also be used for chronic pain. It is taken by mouth.

Common side effects include loss of appetite constipation dry mouth dizziness sweating and sexual problems. Severe side effects include an increased risk of suicide mania and serotonin syndrome. Antidepressant withdrawal syndrome may occur if stopped. There are concerns that use during the later part of pregnancy can harm the baby. How it works is not entirely clear but it seems to be related to the potentiation of the activity of some neurotransmitters in the brain.

Venlafaxine was approved for medical use in the United States in 1993. It is available as a generic medication. In 2018 it was the 50th most commonly prescribed medication in the United States with more than 16 million prescriptions.