Gepirone, sold under the brand name Exxua, is a

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

used for the treatment of

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

. It is taken orally.

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of gepirone include

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

abdominal pain Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Since the abdomen contains most of the body's vital organs, it can be an indicator of a wide variety of diseases. Given th ...

, and

dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

(indigestion). Gepirone acts as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_1A receptor. An active metabolite of gepirone, 1-(2-pyrimidinyl)piperazine, is an α₂-adrenergic receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Gepirone is a member of the

azapirone Azapirones are a class of drugs used as anxiolytics, antidepressants, and antipsychotics. They are commonly used as Augmentation (psychiatry), add-ons to other antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). List of ...

group of compounds. Gepirone was synthesized by

Bristol-Myers Squibb The Bristol-Myers Squibb Company, doing business as Bristol Myers Squibb (BMS), is an American multinational pharmaceutical company. Headquartered in Princeton, New Jersey, BMS is one of the world's largest pharmaceutical companies and consist ...

in 1986 and was developed and marketed by Fabre-Kramer Pharmaceuticals. It was approved for the treatment of major depressive disorder in the United States in September 2023. This came after the drug had been rejected by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) three times over two decades due to insufficient evidence of effectiveness.

Medical uses

Gepirone is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of

(MDD) in adults. Of 15 clinical trials of gepirone for major depressive disorder submitted to the U.S.

(FDA), three were excluded for

methodological In its most common sense, methodology is the study of research methods. However, the term can also refer to the methods themselves or to the philosophical discussion of associated background assumptions. A method is a structured procedure for bri ...

reasons, three were deemed "failed" and "uninformative", seven were deemed negative and did not demonstrate effectiveness, and two were deemed positive and did show effectiveness. Two positive trials are needed for FDA drug approval, with this being the case regardless of the number of negative trials. In the two positive trials of gepirone for depression, the drug significantly outperformed

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

in terms of depressive symptom reduction and showed

effect size In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...

s similar to those of other approved antidepressants. In both trials, gepirone reduced depressive symptoms by about 2.5 points more than placebo on the 52-point Hamilton Depression Rating Scale (17-item version or HAMD-17). The baseline depression scores in the trials ranged from 22.7 to 24.2 in the different patient groups.

Available forms

Gepirone comes in the form of extended-release tablets of the hydrochloride

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

, gepirone hydrochloride, in the strengths 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg.

Specific populations

It is not known if gepirone is safe in women who are breastfeeding. Medications with more data in this setting may be preferred.

Contraindications

Gepirone is

contraindicated In medicine, a contraindication is a condition (a situation or factor) that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a rea ...

in people that have experienced an allergic reaction to gepirone, a corrected

QT interval The QT interval is a measurement made on an Electrocardiography, electrocardiogram used to assess some of the electrical properties of the heart. It is calculated as the time from the start of the QRS complex, Q wave to the end of the T wave, an ...

> 450 msec, a history of congenital

long QT syndrome Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainti ...

, use medications that strongly inhibit CYP3A4 (an enzyme involved in gepirone's metabolism), severe liver problems, or have used a

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

(MAOI) medication within 14 days.

Side effects

Serious

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of gepirone include QT prolongation (increases the risk of a potentially life-threatening cardiac arrhythmia called torsade de pointes),

serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

(especially in the presence of other serotonergic drugs), and activation of

mania Mania, also known as manic syndrome, is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome defined as a state of Abnormality (behavior), abnormally elevated arousal, affect (psychology), affect, and energy level. During a mani ...

hypomania Hypomania (literally "under mania" or "less than mania") is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome characterized essentially by an apparently non-contextual elevation of Mood (psychology), mood (i.e., euphoria) th ...

in people with

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

. Common side effects include

, and

(indigestion).

Interactions

The

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

inhibitor Inhibitor or inhibition may refer to: 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 neurotransmi ...

ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...

and verapamil strongly increase exposure to gepirone, whereas

lithium Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...

paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

, and

warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

have no effect on exposure to gepirone. The CYP3A4 inducer

rifampin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...

profoundly decreases exposure to gepirone.

Pharmacology

Pharmacodynamics

Gepirone acts as a selective

of the 5-HT_1A receptor. Unlike its relative

buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

, however, gepirone has greater

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...

in activating the 5-HT_1A and has negligible

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the D₂ receptor (30- to 50-fold lower in comparison to

). However, similarly to buspirone, gepirone metabolizes into 1-(2-pyrimidinyl)piperazine (1-PP), which is known to act as a potent

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.α₂-adrenergic receptor.

Pharmacokinetics

Absorption

The

absolute bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of gepirone is 14 to 17%. The time to peak concentrations of gepirone with the extended-release formulation is 6hours. When taken with a high-fat meal, the time to peak levels decreases to 3hours. A high-fat meal increases exposure to gepirone, with the effect increasing dependent on the amount of fat in the meal. Peak concentrations were increased by 27% with a low-fat meal, 55% with a medium-fat meal, and 62% with a high-fat meal, while area-under-the-curve levels of gepirone were increased by 14% with a low-fat meal, 22% with a medium-fat meal, and 32 to 37% with a high-fat meal. The effect was similar for the

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s of gepirone, 1-PP and 3'-hydroxygepirone (3'-OH-gepirone).

Distribution

The apparent

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of gepirone is approximately 94.5L. The

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

of gepirone ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' is 72% and is independent of concentration. The plasma protein binding of 3'-OH-gepirone is 59% and of 1-PP is 42%.

Metabolism

Gepirone is metabolized primarily by

. Its major metabolites are 1-PP and 3'-OH-gepirone, both of which are pharmacologically active. These metabolites are present in the circulation at higher concentrations than gepirone.

Elimination

With a single oral dose of

radiolabel A radioactive tracer, radiotracer, or radioactive label is a synthetic derivative of a natural compound in which one or more atoms have been replaced by a radionuclide (a radioactive atom). By virtue of its radioactive decay, it can be used to exp ...

ed gepirone, 81% is recovered in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

and 13% is recovered in

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

s. About 60% of the gepirone is eliminated in urine within 24hours. The terminal half-life of gepirone as the extended-release form is approximately 5hours.

Chemistry

Gepirone is a member of the

group of compounds and is structurally related to

, tandospirone, and other azapirones.

History

Gepirone was developed by Bristol-Myers Squibb in 1986, but was out-licensed to Fabre-Kramer in 1993. The FDA rejected approval for gepirone in 2002 and 2004. It was submitted for the preregistration (NDA) phase again in May 2007 after adding additional information from clinical trials as the FDA required in 2009. However, in 2012 it once again failed to convince the FDA of its qualities for treating anxiety and depression. In December 2015, the FDA once again gave gepirone a negative review for depression due to concerns of efficacy. However, in March 2016, the FDA reversed its decision and gave gepirone ER a positive review. Gepirone ER was finally approved for the treatment of major depressive disorder in the United States in September 2023.

Society and culture

Names

The brand name of gepirone is Exxua. Former tentative brand names which were never used included Ariza, Variza, and Travivo.

Research

Gepirone is under development for the treatment of decreased libido and

generalized anxiety disorder Generalized anxiety disorder (GAD) is an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning. Individuals with GAD are often overly con ...

(GAD). As of October 2023, it is in phase III

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

s for these indications. The pro-sexual effects of gepirone appear to be independent of its antidepressant and anxiolytic effects.

References

{{Authority control 5-HT1A agonists Alpha-2 blockers Aminopyrimidines Antidepressants Anxiolytics Azapirones Glutarimides 1-(2-Pyrimidinyl)piperazines