Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an

atypical antidepressant An atypical antidepressant is any antidepressant medication that acts in a manner that is different from that of most other antidepressants. Atypical antidepressants include agomelatine, bupropion, iprindole, mianserin, mirtazapine, nefazodone, ...

which was first marketed by Bristol-Myers Squibb (BMS) in 1994 but has since largely been discontinued. BMS withdrew it from the market by 2004 due to decreasing sales due to the rare incidence of severe liver damage and the onset of

generic Generic or generics may refer to: In business * Generic term, a common name used for a range or class of similar things not protected by trademark * Generic brand, a brand for a product that does not have an associated brand or trademark, other ...

competition. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years. Generic versions were introduced in 2003. Nefazodone is a

phenylpiperazine 1-Phenylpiperazine is a simple chemical compound featuring a phenyl group bound to a piperazine ring. The suffix ‘-piprazole’ is sometimes used in the names of drugs to indicate they belong to this class. List phenylpiperazine derivativesAlpe ...

compound and is related to trazodone. It has been described as a

serotonin antagonist and reuptake inhibitor Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of seroto ...

(SARI) due to its combined actions as a potent

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

5-HT_2A receptor and 5-HT_2C receptor

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

and weak serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI).

Medical uses

Nefazodone is used to treat

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introdu ...

aggressive behavior Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...

, anxiety, and panic disorder.

Available forms

Nefazodone is available as 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg

tablet Tablet may refer to: Medicine * Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill" Computing * Tablet computer, a mobile computer that is primarily operated by touching the s ...

s for

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or oral ...

ingestion.

Contraindications

Side effects

Nefazodone can cause severe liver damage, leading to a need for liver transplant, and death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years. By the time that it started to be withdrawn in 2003, nefazodone had been associated with at least 53 cases of liver injury, with 11 deaths, in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...

, and 51 cases of liver toxicity, with 2 cases of liver transplantation, in

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...

. In a Canadian study which found 32 cases in 2002, it was noted that databases like that used in the study tended to include only a small proportion of suspected drug reactions. Protocols are that nefazodone should not be used in patients who have a pre-existing liver condition. Prior to treatment liver enzymes should be tested to make sure there is not an underlying liver condition. If serum AST or serum ALT levels are more than 3 times the upper limit of normal (ULN) should be permanently withdrawn from the drug. Regular enzyme labs should be done every 6 months. Due to liver issues Nefazodone should not be a first line treatment. Common and mild side effects of nefazodone reported in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s more often than

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

include dry mouth (25%), sleepiness (25%), nausea (22%), dizziness (17%), blurred vision (16%),

weakness Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...

(11%), lightheadedness (10%), confusion (7%), and

orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...

(5%). Rare and serious adverse reactions may include allergic reactions, fainting, painful/prolonged erection, and

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

. Nefazodone is not especially associated with increased appetite and weight gain. It is also known for having low levels of sexual side effects in comparisons to SSRI's.

Interactions

Nefazodone is a potent

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

, and may interact adversely with many commonly used medications that are metabolized by CYP3A4. Retrieved on November 29, 2008.

Pharmacology

Pharmacodynamics

Nefazodone acts primarily as a potent

of the

5-HT_2A receptor and to a lesser extent of the serotonin 5-HT_2C receptor. It also has high affinity for the α₁-adrenergic receptor and serotonin 5-HT_1A receptor, and relatively lower affinity for the α₂-adrenergic receptor and

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

D₂ receptor. Nefazodone has low but significant affinity for the

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

, and dopamine transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It has low but potentially significant affinity for the

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in ...

H₁ receptor, where it is an antagonist, and hence may have some

antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides re ...

activity. Nefazodone has negligible activity at

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rece ...

s, and accordingly, has no anticholinergic effects.

Pharmacokinetics

The bioavailability of nefazodone is low and variable, about 20%. Its

plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse th ...

is approximately 99%, but it is bound loosely. Nefazodone is

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

in the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

, with the main

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

involved thought to be

. The drug has at least four

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

s, which include hydroxynefazodone, ''para''-hydroxynefazodone, triazoledione, and ''meta''-chlorophenylpiperazine. Nefazodone has a short

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of about 2 to 4 hours. Its metabolite hydroxynefazodone similarly has an elimination half-life of about 1.5 to 4 hours, whereas the elimination half-lives of triazoledione and mCPP are longer at around 18 hours and 4 to 8 hours, respectively. Due to its long elimination half-life, triazole is the major metabolite and predominates in the circulation during nefazodone treatment, with plasma levels that are 4 to 10 times higher than those of nefazodone itself. Conversely, hydroxynefazodone levels are about 40% of those of nefazodone at steady state. Plasma levels of mCPP are very low at about 7% of those of nefazodone; hence, mCPP is only a minor metabolite. mCPP is thought to be formed from nefazodone specifically by CYP2D6. The ratios of

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

-to-plasma concentrations of mCPP to nefazodone are 47:1 in mice and 10:1 in rats, suggesting that brain exposure to mCPP may be much higher than plasma exposure. Conversely, hydroxynefazodone levels in the brain are 10% of those in plasma in rats. As such, in spite of its relatively low plasma concentrations, brain exposure to mCPP may be substantial, whereas that of hydroxynefazodone may be minimal.

Chemistry

Nefazodone is a

; it is an alpha-phenoxyl derivative of

etoperidone Etoperidone, associated with several brand names, is an atypical antidepressant which was developed in the 1970s and either is no longer marketed or was never marketed. It is a phenylpiperazine related to trazodone and nefazodone in chemical str ...

which in turn was a derivative of trazodone.

History

Nefazodone was discovered by scientists at Bristol-Myers Squibb (BMS) who were seeking to improve on trazodone by reducing its sedating qualities. BMS obtained marketing approvals worldwide for nefazodone in 1994. It was marketed in the US under the brand name Serzone and in Europe under the brand name Dutonin. In 2002 the FDA obligated BMS to add a black box warning about potential fatal liver toxicity to the drug label. Worldwide sales in 2002 were $409 million. In 2003

Public Citizen Public Citizen is a non-profit, progressive consumer rights advocacy group and think tank based in Washington, D.C., United States, with a branch in Austin, Texas. Lobbying efforts Public Citizen advocates before all three branches of the Unit ...

filed a citizen petition asking the FDA to withdraw the marketing authorization in the US, and in early 2004 the organization sued the FDA to attempt to force withdrawal of the drug. The FDA issued a response to the petition in June 2004 and filed a motion to dismiss, and Public Citizen withdrew the suit. Generic versions were introduced in the US in 2003 and Health Canada withdrew the marketing authorization that year. Sales of nefazodone were about $100 million in 2003. By that time it was also being marketed under the additional brand names Serzonil, Nefadar, and Rulivan. In April 2004, BMS announced that it was going to discontinue the sale of Serzone in the US in June 2004 and said that this was due to declining sales. By that time BMS had already withdrawn the drug from the market in Europe, Australia, New Zealand and Canada. As of 2012 generic nefazodone was available in the US. In August 2020, Teva Pharmaceuticals placed nefazodone in shortage due to a shortage of a raw ingredient. On December 20, 2021, Nefazodone was again made available in all strengths.

Society and culture

Generic names

''Nefazodone'' is the generic name of the drug and its and , while ''néfazodone'' is its and ''nefazodone hydrochloride'' is its and .

Brand names

Nefazodone has been marketed under a number of brand names including ''Dutonin'' (, , , ), Menfazona (), ''Nefadar'' (, , , ), Nefazodone BMS (), Nefazodone Hydrochloride Teva (), Reseril (), Rulivan (), and ''Serzone'' (, , ).

Research

The use of nefazodone to prevent

migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

has been studied, due to its antagonistic effects on the 5-HT_2A and 5-HT_2C receptors.

References

External links

* {{Navboxes , title =

Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemical and physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or combinations of organisms (fo ...

, titlestyle = background:#ccccff , list1 = {{Adrenergic receptor modulators {{Monoamine reuptake inhibitors {{Serotonin receptor modulators {{Xenobiotic-sensing receptor modulators Alpha-1 blockers Alpha-2 blockers Antidepressants Anxiolytics 5-HT1A agonists 5-HT2A antagonists 5-HT2C antagonists CYP3A4 inhibitors H1 receptor antagonists Hepatotoxins Phenol ethers 2-(3-(4-(3-chlorophenyl)piperazin-1-yl)propyl)-1,2,4-triazol-3-ones Serotonin–norepinephrine–dopamine reuptake inhibitors Ureas Withdrawn drugs