Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

(TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a lesser extent as a norepinephrine reuptake inhibitor. Amineptine was developed by the French Society of Medical research in the 1960s. Introduced in France in 1978 by the

pharmaceutical Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

company

Servier Servier Laboratories (French: Laboratoires Servier, often abbreviated to Servier) is an international Pharmaceutical industry, pharmaceutical company governed by a non-profit foundation, with its headquarters in France (Suresnes). The consolida ...

, amineptine soon gained a reputation for abuse due to its short-lived, but pleasant,

stimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...

effect experienced by some patients. After widespread adoption of this drug, cases of

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

emerged, some serious. This, along with the potential for abuse, led to the suspension of the French marketing authorization for Survector in 1999. Amineptine is illegal in both Germany and the United States.

Medical uses

Amineptine was approved in France for severe

clinical depression 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. Intro ...

of endogenous origin in 1978.

Contraindications

Chorea Chorea, or (rarely) choreia, () is an abnormal involuntary movement disorder, characterized by quick movements of the hands or feet. It is one of a group of neurological disorders called dyskinesias. The term ''chorea'' is derived , as the move ...

Hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

: Known hypersensitivity to amineptine, in particular antecedents of hepatitis after dosage of the product. *

MAO inhibitor Monoamine oxidase inhibitors (MAOIs) are a 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 antidepressants, espec ...

Precautions for use

Warnings and precautions before taking amineptine: *

Breast feeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a pump and then fed to the infant. The World Health Organization (WH ...

* Children less than 15-year of age *

General anaesthesia General anaesthesia (UK) or general anesthesia (US) is medically induced loss of consciousness that renders a patient unarousable even by painful stimuli. It is achieved through medications, which can be injected or inhaled, often with an analges ...

: Discontinue the drug 24 to 48 hours before anaesthesia. * Official sports/

Olympic Games The modern Olympic Games (Olympics; ) are the world's preeminent international Olympic sports, sporting events. They feature summer and winter sports competitions in which thousands of athletes from around the world participate in a Multi-s ...

: Prohibited substance. ** 7 March Official Journal 2000. *

Pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

(first trimester)

Effects on the fetus

* Lacking information in humans * Non-

teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by ...

in rodents

Side effects

Dermatological

Severe

acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...

due to amineptine was first reported in 1988 by various authors—Grupper, Thioly-Bensoussan, Vexiau, Fiet, Puissant, Gourmel, Teillac, Levigne, to name a few—simultaneously in the same issue of ''Annales de Dermatologie et de Vénéréologie'' and in the 12 March 1988 issue of ''The Lancet.'' A year later, Dr Martin-Ortega and colleagues in Barcelona, Spain reported a case of "acneiform eruption" in a 54-year-old woman whose intake of amineptine was described as "excessive." One year after that, Vexiau and colleagues reported six women, one of whom never admitted to using amineptine, getting severe acne concentrated in the face, back and

thorax The thorax (: thoraces or thoraxes) or chest is a part of the anatomy of mammals and other tetrapod animals located between the neck and the abdomen. In insects, crustaceans, and the extinct trilobites, the thorax is one of the three main di ...

, the severity of which varied with the dosage. Most of them were treated unsuccessfully with

isotretinoin Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication used to treat skin diseases like harlequin-type ichthyosis, and lamellar ichthyosis, and severe cystic acne or moderat ...

(Accutane) for about 18 months; two of the three that discontinued amineptine experienced a reduction in cutaneous symptoms, with the least affected patient going into remission.

Psychiatric

Psychomotor excitation can very rarely occur with this drug. *

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 ...

Irritability Irritability is the excitatory ability that living organisms have to respond to changes in their environment. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimul ...

Nervousness Anxiety is an emotion characterised by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different from fear in that fear is defined as the emotional response to a present threat, where ...

Suicidal Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or acad ...

ideation. Seen early in the treatment, by lifting of psychomotor inhibition.

Abuse and dependence

The risk of

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

is low, but exists nonetheless. Between 1978 and 1988, there were 186 cases of amineptine addiction reported to the French Regional Centres of Pharmacovigilance; an analysis of 155 of those cases found that they were predominantly female, and that two-thirds of cases had known risk factors for addiction. However, a 1981 study of known

opiate An opiate is an alkaloid substance derived from opium (or poppy straw). It differs from the similar term ''opioid'' in that the latter is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain ( ...

addicts and

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

patients found no drug addiction in any of the subjects. In a 1990 study of eight amineptine dependence cases, the gradual withdrawal of amineptine could be achieved without problems in six people; in two others,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

, psychomotor agitation, and/or

bulimia Bulimia nervosa, also known simply as bulimia, is an eating disorder characterized by binge eating (eating large quantities of food in a short period of time, often feeling out of control) followed by compensatory behaviors, such as self-induc ...

appeared.

Withdrawal

Pharmacodependence is very common with amineptine compared to other antidepressants. A variety of psychological symptoms can occur during withdrawal from amineptine, such as

and agitation.

Cardiovascular

Very rarely: *

Arterial An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

Palpitation Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...

s * Vasomotor episode

Hepatic

Amineptine can rarely cause

hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...

, of the

cytolytic Cytolysis, or osmotic lysis, occurs when a cell bursts due to an osmotic imbalance that has caused excess water to diffuse into the cell. Water can enter the cell by diffusion through the cell membrane or through selective membrane channels ...

, cholestatic varieties. Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an immunoallergic reaction. It resolves upon discontinuation of the offending drug. The risk of getting this may or may not be genetically determined. Additionally, amineptine is known to rarely elevate

transaminase Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins. Function and mechanism An amino acid con ...

alkaline phosphatase The enzyme alkaline phosphatase (ALP, alkaline phenyl phosphatase, also abbreviated PhoA) is a phosphatase with the physiological role of dephosphorylating compounds. The enzyme is found across a multitude of organisms, prokaryotes and eukaryo ...

, and

bilirubin Bilirubin (BR) (adopted from German, originally bili—bile—plus ruber—red—from Latin) is a red-orange compound that occurs in the normcomponent of the straw-yellow color in urine. Another breakdown product, stercobilin, causes the brown ...

. Mixed hepatitis, which is very rare, generally occurs between the 15th and 30th day of treatment of amineptine. Often preceded by sometimes intense abdominal pains, nausea, vomiting or a rash, the jaundice is variable. Hepatitis is either of mixed type or with cholestatic prevalence. The evolution was, in all the cases, favorable to the discontinuation of the drug. The mechanism is discussed (immunoallergic and/or toxic). In circa 1994 Spain, there was a case associating acute pancreatitis and mixed hepatitis, after three weeks of treatment. Lazaros and colleagues at the Western Attica General Hospital in

Athens Athens ( ) is the Capital city, capital and List of cities and towns in Greece, largest city of Greece. A significant coastal urban area in the Mediterranean, Athens is also the capital of the Attica (region), Attica region and is the southe ...

, Greece reported two cases of drug induced hepatitis 18 and 15 days of treatment. One case of cytolytic hepatitis occurred after ingestion of only one tablet.

Gastrointestinal

* Acute pancreatitis (very rare) A case associating acute

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

and mixed hepatitis after three weeks of treatment.

Immunological

A case of

anaphylactic shock Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typically ...

in a woman who had been taking amineptine has been reported.

Pharmacology

Pharmacodynamics

Amineptine

inhibit 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 ...

s the

reuptake Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal (i.e., the pre-synaptic neuron at a synapse) or glial cell after it has performed its function of transmi ...

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

and, to a much lesser extent, of

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

. In addition, it has been found to induce the release of dopamine. However, amineptine is much less efficacious as a

dopamine releasing agent A dopamine releasing agent (DRA) is a type of drug which induces the release of dopamine in the Body (biology), body and/or brain. No binding selectivity, selective DRAs are currently known. However, non-selective DRAs, including norepinephrin ...

relative to D-amphetamine, and the drug appears to act predominantly as a dopamine reuptake inhibitor. In contrast to the case for dopamine, amineptine does not induce the release of norepinephrine, and hence acts purely as a norepinephrine reuptake inhibitor. Unlike other TCAs, amineptine interacts very weakly or not at all with 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, ...

adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

, and

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

s. The major

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 amineptine have similar activity to that of the parent compound, albeit with lower

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

. No human data appear to be available for binding or inhibition of the

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

s by amineptine.

Pharmacokinetics

Peak plasma levels of amineptine following a single 100 mg oral dose have been found to range between 277 and 2,215 ng/mL (818–6,544 nM), with a mean of 772 ng/mL (2,281 nM), whereas maximal plasma concentrations of its major

ranged between 144 and 1,068 ng/mL (465–3,452 nM), with a mean of 471 ng/mL (1,522 nM). After a single 200 mg oral dose of amineptine, mean peak plasma levels of amineptine were around 750 to 940 ng/mL (2,216–2,777 nM), while those of its major metabolite were about 750 to 970 ng/mL (2,216–3,135 nM). The time to peak concentrations is about 1 hour for amineptine and 1.5 hours for its major metabolite. The

elimination half-life Biological half-life (elimination half-life, pharmacological 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 blood plasma. ...

of amineptine is about 0.80 to 1.0 hours and that of its major metabolite is about 1.5 to 2.5 hours. Due to their very short elimination half-lives, amineptine and its major metabolite do not accumulate significantly with repeated administration.

Society and culture

Brand names

Amineptine has been sold under a variety of brand names including Survector, Maneon, Directim, Neolior, Provector, and Viaspera.

Legal status

It had been proposed that Amineptine become a Schedule I

controlled substance A controlled substance is generally a drug or chemical whose manufacture, possession and use is regulated by a government, such as illicitly used drugs or prescription medications that are designated by law. Some treaties, notably the Sing ...

in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

in July 2021. This announcement was followed by the placement of Amineptine into Schedule I.

Research

Wakefulness

Amineptine shows

wakefulness-promoting A wakefulness-promoting agent (WPA), or wake-promoting agent, is a drug that increases wakefulness and arousal. They are similar to but distinct from psychostimulants, which not only promote wakefulness but also produce other more overt central n ...

effects in animals and might be useful in the treatment of

narcolepsy Narcolepsy is a chronic neurological disorder that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-r ...

References

{{Tricyclics Secondary amines Carboxylic acids Dibenzocycloheptenes Dopamine releasing agents Hepatotoxins Laboratoires Servier Norepinephrine–dopamine reuptake inhibitors Stimulants Tricyclic antidepressants Wakefulness-promoting agents Withdrawn drugs