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Venlafaxine chemical structure
Venlafaxine

1-[2-dimethylamino-1- (4-methoxyphenyl)- ethyl]cyclohexan-1-ol
IUPAC name
CAS number
93413-69-5
ATC code

N06AX16

PubChem
5656
DrugBank
APRD00125
Chemical formula {{{chemical_formula}}}
Molecular weight 277.402 g/mol
Bioavailability 45%
Metabolism Hepatic
Elimination half-life 5 ± 2 hours (parent compound); 11 ± 2 hours (active metabolite)
Excretion Renal
Pregnancy category C
Legal status Rx-only, not a controlled drug
Routes of administration Oral

Venlafaxine hydrochloride is a prescription antidepressant used in the treatment of clinical depression, anxiety disorders, and (controversially) bipolar disorder. It was first introduced by Wyeth in 1993. It belongs to a class of antidepressants called Serotonin-norepinephrine reuptake inhibitors (SNRI).

Trade names[]

Venlafaxine is marketed under the brand names:

  • Depurol® (CL)
  • Dobupal® (ES)
  • Efectin® (AT, CZ, HR, HU, PL, RO, SI, YU)
  • Efexor Depot® (FI, SE, DK)
  • Efexor XR® (AU, NZ, ZA)
  • Efexor® (AR, AU, BE, BR, CH, CL, CO, CR, CY, DK, DO, EC, EG, FI, GB, GT, HN, ID, IE, IL, IT, JO, KW, LB, LU, MT, MX, NL, NO, NZ, PA, PT, SE, SG, SV, TH, TR)
  • Effexor Paranova® (DK)
  • Effexor® (FR, IE, US)
  • Effexor® XR (CA, US)
  • Elafax® (AR)
  • Faxine® (IT)
  • Flavix® (IN)
  • Norpilen® (CL)
  • Trevilor® (DE)
  • Vandral® (DK, ES)
  • Velafax® (HR)
  • Venlafaxina Combino Pharm® (ES)
  • Venlafaxina Dosa® (AR)
  • Venlafaxina Masterfarm® (ES)
  • Venlafaxina Ratiopharm® (ES)
  • Venlafaxine-Apex® (NL)
  • Venlax® (CL)
  • Venlor® (IN)
  • Viepax (IL)

Description of compound[]

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).[1]

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.[2][3] 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,[4] 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).

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. 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.[5] 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.[6]

Indications[]

Approved[]

Venlafaxine is used primarily for the treatment of depression, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, and panic disorder usually in adults only. It is also used for other general depressive disorders.[5]

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.[7][8] It has also been found to reduce the severity of 'hot-flashes' in menopausal women.[9][10]

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.[5] Venlafaxine hydrochloride is in the phenylthylamine class of modern chemicals, which indludes 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.[5] Venlafaxine is perhaps one of the most likely of all modern antidepressants to trigger manic and hypomanic states.

Contraindications[]

Venlafaxine is not recommended in patients hypersensitive to venlafaxine. 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. Caution should also be used in those with a seizure disorder. Venlafaxine is not approved for use in children or adolescents.[5] 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.[11]

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.[5] Prospective studies have not shown any statistically significant congenital malformations.[12] There have, however, been some reports of effects on newborn infants.[13] In view of the possibility of severe discontinuation syndrome and the difficulties this presents, use of venlafaxine for pregnant women is not generally indicated.

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 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.

Dose range[]

Prescribed dosages are typically in the range of 75 to 225 mg per day, but higher dosages up to 450 mg are sometimes used for the treatment of severe or treatment-resistant depression. Venlafaxine is sometimes prescribed in 37.5 mg per day dosages in patients with anxiety. Low doses only work on the serotonin reuptake mechanism (presumed defective in those with anxiety) therefore avoiding the anxiety inducing effects of norepinephrine reuptake experienced at higher doses. Because of its relatively short half-life of 5 hours, venlafaxine should be administered in divided dosages throughout the day. The extended release version (largely manufactured on spheronization equipment) eliminates this problem and has largely replaced the original in use.

EffexorXR 75and150mg

Effexor XR® 75 mg and 150 mg capsules

Available forms[]

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).

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 of time 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.[14]

Generic[]

Generic venlafaxine is available in the United States as of August 2006 and in Canada as of December 2006. A generic form of the extended-release version is available in Canada as of January 2007 and will become available in the United States in 2010.[15]

Effectiveness[]

Venlafaxine is a very effective anti-depressant for many persons; however, it seems to be especially effective for those with treatment-resistant depression. Some of these persons have taken two or more antidepressants prior to venlafaxine with no relief. Patients suffering with severe long-term depression typically respond better to venlafaxine than other drugs. However, venlafaxine has been reported to be more difficult to discontinue than other anti-depressants. In addition, a September 2004 Consumer Reports study ranked venlafaxine as the most effective among six commonly prescribed antidepressants. Like most psychiatric medications, however, the results of such studies alone should not be relied upon by potential patients, as responses to psychiatric medications can vary significantly from individual to individual.

Adverse effects[]

As with most antidepressants, lack of sexual desire is a common side effect. Venlafaxine can raise blood pressure at high doses, so it is usually not the drug of choice for persons with hypertension.

It has a higher rate of treatment emergent mania than many modern antidepressants, and many people find it to be a more activating medication (one that increases energy or wakefulness) than other antidepressants.[How to reference and link to summary or text] Paradoxically, some users find it highly sedating and find that it must be taken in the evening.

Suicide Ideation/Risk[]

A Black box warning has been issued with Effexor and with other SSRI and SNRI anti-depressants advising of risk of suicide. Thoughts of suicide (suicide ideation) as potential risk of suicide as shown in studies by Wyeth and reported on their datasheet for Effexor were twice that of placebo (4% compared to 2%, however, no suicides occurred in these trials).[5] The black box warnings advise physicians to carefully monitor patients for suicide risk at start of usage and whenever the dosage is changed. There is an additional risk if a physician misinterprets patient expression of adverse effects such as panic or akathisia as symptoms of worsening depression rather than effects of the medication and increases dose. Assessment of patient history and comorbid risk factors such as drug abuse are recommended when evaluating the safety of venlafaxine for individual patients. These cautions are emphasized in Wyeth's information sheet with special precautions if prescribed to children. The extent of this effect and the actual risk are not known as studies may exclude individuals with higher risk.

In the UK, one study evaluated whether risk factors for suicide were more prevalent among patients prescribed venlafaxine than patients prescribed other antidepressants. Results showed patients prescribed venlafaxine were more likely to have attempted suicide in the previous year, although it was concluded that venlafaxine had been selectively prescribed to a patient population with a higher burden of suicide risk factors to begin with, and that this might have led to a higher future risk of suicide independent of any drug effect. Studies with baseline data are required to determine the actual risk with venlafaxine.[16]

Serotonin Syndrome[]

Another risk is Serotonin syndrome. This is a rare, however serious side effect that can be caused by interactions with other Central Nervous System depressant drugs and is potentially fatal.[17] This risk necessitates clear information to patients and proper medical history. For example, the drug abuse by at risk patients of certain non-prescription drugs can cause this serious effect and emphasizes the importance of good medical history sharing between General Practitioners and Psychiatrists as both may prescribe Venlafaxine. Involvement of family in awareness of risk factors is highlighted in Wyeth information sheets on Effexor.

Common side effects[]

Less common to rare side-effects[]

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.[5]

Physical and Psychological Dependency[]

Main article: SSRI discontinuation syndrome#Discontinuation of Venlafaxine

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.[5]

Notwithstanding these in-vitro and non-human research findings, some patients using venlafaxine may become dependent on this drug. 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. This may result in experiencing withdrawal symptoms described as severe discontinuation syndrome. The high risk of withdrawal symptoms may reflect venlafaxine's short half-life.[18] Missing even a single dose can induce discontinuation effects in some patients.[6] Discontinuation is similar in nature to those of SSRIs such as Paroxetine (Paxil or Seroxat). Sudden discontinuation of venlafaxine has a high risk of causing potentially severe withdrawal symptoms.[19]

As the drug has direct impact on mood (i.e., anti-depressant), many users who have suffered the effects of attempted withdrawal from this drug define their dependency on the drug also as being addicted.[18] 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,[18] addiction or dependence is a more common effect described for drugs that (are thought to, or may) improve mental well-being.[20]

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.[21] Venlafaxines 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.[1] Deaths have been reported following large doses.[22][23]

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.[24]

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.[25]

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 venlafaxines 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."[26]

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".[27] 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.[22]

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.[28]

Footnotes[]

  1. 1.0 1.1 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. PMID 12702786.
  2. [No Authors listed]. Acute Effectiveness of Additional Drugs to the Standard Treatment of Depression. ClinicalTrials.gov.
  3. Goeringer K, McIntyre I, Drummer O (2001). Postmortem tissue concentrations of venlafaxine. Forensic Sci Int 121 (1-2): 70-5. PMID 11516890.
  4. 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. PMID 11524036.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 (2006). Effexor Medicines Data Sheet. Wyeth Pharmaceuticals Inc.
  6. 6.0 6.1 Parker G, Blennerhassett J (1998). Withdrawal reactions associated with venlafaxine. Aust N Z J Psychiatry 32 (2): 291-4. PMID 9588310.
  7. 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. PMID 15288411.
  8. 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. PMID 15705120.
  9. Mayo Clinic staff (2005). Beyond hormone therapy: Other medicines may help. Hot flashes: Ease the discomfort of menopause. Mayo Clinic.
  10. Schober C, Ansani N (2003). Venlafaxine hydrochloride for the treatment of hot flashes. Ann Pharmacother 37 (11): 1703-7. PMID 14565812.
  11. 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.
  12. Gentile S (2005). The safety of newer antidepressants in pregnancy and breastfeeding. Drug Saf 28 (2): 137-52. PMID 15691224.
  13. 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.
  14. 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.
  15. Wigginton, Catherine (2006-09-19), Wyeth's Battle for Effexor Continues, IP Law & Business, http://www.law.com/jsp/article.jsp?id=1158582919715, retrieved on 2007-04-25 
  16. Mines D, Hill D, Yu H, Novelli L (2005). Prevalence of risk factors for suicide in patients prescribed venlafaxine, fluoxetine, and citalopram. Pharmacoepidemiol Drug Saf 14 (6): 367-72. PMID 15883980.
  17. Adan-Manes J, Novalbos J, López-Rodríguez R, Ayuso-Mateos J, Abad-Santos F (2006). Lithium and venlafaxine interaction: a case of serotonin syndrome. J Clin Pharm Ther 31 (4): 397-400. PMID 16882112.
  18. 18.0 18.1 18.2 Haddad P (2001). Antidepressant discontinuation syndromes. Drug Saf 24 (3): 183-97. PMID 11347722.
  19. 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.
  20. Double D (1997). Prescribing antidepressants in general practice. People may become psychologically dependent on antidepressants. BMJ 314 (7083): 829. PMID 9081020.
  21. Blythe D, Hackett L (1999). Cardiovascular and neurological toxicity of venlafaxine. Hum Exp Toxicol 18 (5): 309-13. PMID 10372752.
  22. 22.0 22.1 Mazur J, Doty J, Krygiel A (2003). Fatality related to a 30-g venlafaxine overdose. Pharmacotherapy 23 (12): 1668-72. PMID 14695048.
  23. Banham N (1998). Fatal venlafaxine overdose. Med J Aust 169 (8): 445, 448. PMID 9830400.
  24. MHRA UK (May 31 2006). Updated product information for venlafaxine. Safeguarding public health.
  25. (2006). Wyeth Letter to Health Care Providers. Wyeth Pharmaceuticals Inc.
  26. Buckley N, McManus P (2002). Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ 325 (7376): 1332-3.
  27. Fayerman, Pamela Warning issued over drug. Vancouver Sun. URL accessed on 2007-06-02.
  28. 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.

External links[]

Drug information[]

Industry pages[]

Patient experiences[]

Chemical data[]



Antidepressants (ATC N06A) edit
Monoamine oxidase inhibitors (MAOI) Harmaline, Iproclozide, Iproniazid, Isocarboxazid, Nialamide, Phenelzine, Selegiline, Toloxatone, Tranylcypromine
Reversible inhibitor of monoamine oxidase A (RIMA) Brofaromine, Moclobemide
Dopamine reuptake inhibitor (DARI) Amineptine, Phenmetrazine, Vanoxerine, Modafinil
Norepinephrine-dopamine reuptake inhibitors Bupropion
Norepinephrine reuptake inhibitor (NRI) or (NARI) Atomoxetine, Maprotiline, Reboxetine, Viloxazine
Serotonin-norepinephrine reuptake inhibitor (SNRI) Duloxetine, Milnacipran, Venlafaxine
Selective serotonin reuptake inhibitor (SSRI) Alaproclate, Etoperidone, Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline, Zimelidine
Selective serotonin reuptake enhancer (SSRE) Tianeptine
Tricyclic antidepressants (TCA) Amitriptyline, Amoxapine, Butriptyline, Clomipramine, Desipramine, Dibenzepin, Dothiepin, Doxepin, Imipramine, Iprindole, Lofepramine, Melitracen, Nortriptyline, Opipramol, Protriptyline, Trimipramine
Tetracyclic antidepressants Maprotiline, Mianserin, Nefazodone, Trazodone
Noradrenergic and specific serotonergic antidepressant (NaSSA) Mirtazapine
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