Nefazodone is an antidepressant

Antidepressant

An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...

 marketed by Bristol-Myers Squibb

Bristol-Myers Squibb

Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...

. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity

Hepatotoxicity

Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...

 (liver damage), which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every 250,000 to 300,000 patient-years. On June 14, 2004, Bristol-Myers Squibb discontinued the sale of Serzone in the United States

United States

The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 and Canada

Canada

Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

. Several generic formulations of nefazodone are still available.

Pharmacology

Nefazodone acts primarily as a potent antagonist

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

 at the 5-HT_2A receptor

5-HT2 receptor

The 5-HT2 receptors are a subfamily of 5-HT receptors that bind the endogenous neurotransmitter serotonin . The 5-HT2 subfamily consists of three G protein-coupled receptors which are coupled to Gq/G11 and mediate excitatory neurotransmission, including 5-HT2A, 5-HT2B, and 5-HT2C...

s (Kd 26 nM). It also has moderate affinity for the α₁-adrenergic receptor (Kd 48 nM) and 5-HT_1A receptor

5-HT1A receptor

The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...

 (Kd 80 nM), and very low affinity for the α₂-adrenergic receptor (Kd 640 nM) and D₂ receptor (Kd 910 nM). It acts as an antagonist at all of these sites. Nefazodone has low affinity for the serotonin

Serotonin transporter

The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...

 (200 nM), norepinephrine

Norepinephrine transporter

The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....

 (360 nM), and dopamine

Dopamine transporter

The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...

 (360 nM) transporters as well, and therefore acts as a weak serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It has negligible affinity for the H₁ receptor

H1 receptor

The H1 receptor is a histamine receptor belonging to the family of Rhodopsin like G-protein-coupled receptors. This receptor, which is activated by the biogenic amine histamine, is expressed throughout the body, to be specific, in smooth muscles, on vascular endothelial cells, in the heart, and in...

 (24,000 nM) or muscarinic acetylcholine receptor

Muscarinic acetylcholine receptor

Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...

s (11,000 nM), and accordingly lacks any antihistamine

Antihistamine

An H1 antagonist is a histamine antagonist of the H1 receptor that serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions...

 or anticholinergic

Anticholinergic

An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....

 side effects.

Dosing

Nefazodone doses for adults typically start at 50 mg twice daily uptitrated by 100 mg/day per week to a maximum of 600 mg (300 mg twice daily), according to Food and Drug Administration

Food and Drug Administration

The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) regulations. Some patients with severe depression were treated with more than 600 mg/day. Most patients were treated with 300 mg–600 mg daily.

Side effects

Common and mild side effect

Side effect

In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...

s of nefazodone reported in clinical trial

Clinical trial

Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s more often than placebo

Placebo

A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

 include dry mouth (25%), sedation

Sedation

Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...

/somnolence

Somnolence

Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...

 (25%), nausea

Nausea

Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

 (22%), dizziness

Dizziness

Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....

 (17%), blurred

Blurred vision

-Causes:There are many causes of blurred vision:* Use of atropine or other anticholinergics* Presbyopia -- Difficulty focusing on objects that are close. The elderly are common victims....

/abnormal vision

Visual impairment

Visual impairment is vision loss to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive...

 (16%), weakness

Weakness

Weakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. 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...

 (11%), lightheadedness

Lightheadedness

Light-headedness is a common and often unpleasant sensation of dizziness and/or feeling that one may be about to faint, which may be transient, recurrent, or occasionally chronic. In some cases, the individual may feel as though his or her head is weightless. The individual may also feel as...

 (10%), confusion

ConFusion

ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...

 (7%), and orthostatic hypotension

Orthostatic hypotension

Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...

 (5%). Rare and serious adverse reactions may include allergic reaction, fainting

Syncope

In phonology, syncope is the loss of one or more sounds from the interior of a word; especially, the loss of an unstressed vowel. It is found bothin Synchronic analysis of languages and Diachronics .-Found synchronically:...

, priapism

Priapism

Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...

 (painful/prolonged erection), and jaundice

Jaundice

Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

.

Unlike most serotonin reuptake inhibitors, nefazodone has a low incidence of negative effects on libido

Libido

Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...

 or sexual function

Sexual function

Sexual function is a model developed at the Karolinska Institute in Stockholm, Sweden, defining different aspects of the assessment of sexual dysfunction comprises the following components....

, and is occasionally used as treatment for to SSRI or SNRI-induced impotence

Erectile dysfunction

Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....

 and anorgasmia

Anorgasmia

Anorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...

 in men. Additionally, unlike mirtazapine

Mirtazapine

Mirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...

, nefazodone is not especially associated with increased appetite

Appetite

The appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...

 and weight gain

Weight gain

Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...

 either.

Interactions

Nefazodone is a potent inhibitor

Enzyme inhibitor

An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

 of CYP3A4

CYP3A4

Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...

, an isozyme

Isozyme

Isozymes are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes usually display different kinetic parameters Isozymes (also known as isoenzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. These enzymes...

 of the cytochrome P450 system, and may therefore interact adversely

Drug interaction

A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...

 with many commonly-used medications that are metabolized by CYP3A4.

Advantages

Nefazodone's claimed advantages over other antidepressants include reduced possibility of disturbed sleep or sexual dysfunction, and ability to treat some patients who did not respond to other antidepressant drugs.

Nefazodone, though an antidepressant, may also be beneficial in the prophylaxis of migraines due to its antagonistic effects on the 5-HT_2A and 5-HT_2C receptors. It has a more favorable side effect profile than amitriptyline, a tricyclic antidepressant commonly used for migraine prophylaxis.

Chemistry

Nefazadone is a piperazine

Piperazine

Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....

 compound

Compound

Compound may refer to:* Chemical compounds, combinations of two or more elements* Compound , a cluster of buildings having a shared purpose, usually inside a fence or wall...

 incorporating a 1,2,4-triazol-3-one ring. Rxn of the starting propionamide with phosgene

Phosgene

Phosgene is the chemical compound with the formula COCl2. This colorless gas gained infamy as a chemical weapon during World War I. It is also a valued industrial reagent and building block in synthesis of pharmaceuticals and other organic compounds. In low concentrations, its odor resembles...

 leads to the corresponding imino chloride. This intermediate is condensed with hydrazine methylurethane to afford the corresponding guanidine from the displacement of chlorine by basic hydrazine nitrogen. Rxn with sodium methoxide

Sodium methoxide

Sodium methoxide is a chemical compound, with formula CH3ONa. This colourless solid, which is formed by the deprotonation of methanol, is a widely used reagent in industry and the laboratory...

 leads first to
the ionization of the amine

Amine

Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

 on the side chain; this then cyclizes to a triazolone by displacing the carbamate

Carbamate

Carbamates are organic compounds derived from carbamic acid . A carbamate group, carbamate ester, and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.-Synthesis:Carbamic acids are derived...

 methoxyl. Alkylation of the anion from rxn of the triazolone with a strong base

Base (chemistry)

For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

with chloride affords nefazodone.