Amineptine
Encyclopedia
Amineptine was developed by the French Society of Medical research in the 1960s. Under the trade-names (Survector, Maneon, Directim, Neolior, Provector, Viaspera) is used as an atypical tricyclic antidepressant
(TCA) that selectively inhibits the reuptake of dopamine
and to a lesser extent norepinephrine
, thus exerting a powerful and fast-acting antidepressant
effect.
Introduced in France
in 1978 by the pharmaceutical giant Servier and marketed under the trade name
Survector, amineptine soon gained a reputation for abuse due to its short-lived, but pleasant, stimulant
effect experienced by some patients. (This is to be distinguished from its antidepressant effect, which appears in approximately 7 days after commencing treatment.)
After its release into the Europe
an market, cases of hepatotoxicity
emerged, some serious. This, along with the potential for abuse, led to the suspension of the French
marketing authorization for Survector in 1999.
Amineptine was never approved by the U.S. Food and Drug Administration
(FDA) for marketing in the United States
, meaning that it is not legal to market or sell amineptine for any medical uses in the US.
of endogenous origin in 1978.
, amotivational syndromes, ADHD (Attention Deficit/Hyperactivity Disorder)
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 Venereologie and in the 12 March 1988 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 severity of which varied with the dosage. Most of them were treated unsuccessfully with isotretinoin
(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.
This can be seen as a general side effect of central dopamine enhancement, due to the inhibitory effect of dopamine on prolactin
, with the subsequent increase in testosterone output, leading in turn to the same potential for acne as is typical of pubescents.
, of the cytolytic
, cholestatic varieties. Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an allergic 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
s, alkaline phosphatase
, and bilirubin
.
Mixed hepatitis, which is very rare, generally occurs between the 15th and 30th day of treatment. 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, 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.
reported a case of anaphylactic shock in a woman who had been taking amineptine.
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
addicts and schizophrenia
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
, psychomotor agitation, and/or bulimia appeared.
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
(TCA) that selectively inhibits the reuptake of dopamine
Dopamine reuptake inhibitor
A dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
and to a lesser extent norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, thus exerting a powerful and fast-acting 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;...
effect.
Introduced in France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
in 1978 by the pharmaceutical giant Servier and marketed under the trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....
Survector, amineptine soon gained a reputation for abuse due to its short-lived, but pleasant, stimulant
Stimulant
Stimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
effect experienced by some patients. (This is to be distinguished from its antidepressant effect, which appears in approximately 7 days after commencing treatment.)
After its release into the Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
an market, cases 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...
emerged, some serious. This, along with the potential for abuse, led to the suspension of the French
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...
marketing authorization for Survector in 1999.
Amineptine was never approved by the U.S. 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) for marketing in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
, meaning that it is not legal to market or sell amineptine for any medical uses in the US.
Approved
Amineptine was approved in France for severe clinical depressionClinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
of endogenous origin in 1978.
Unapproved/off-label/investigational
Parkinson's DiseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, amotivational syndromes, ADHD (Attention Deficit/Hyperactivity Disorder)
Mechanism of action
- Inhibitor of the reuptake of norepinephrineNorepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
and dopamineDopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
. - Very weak muscarinic and histaminic receptors antagonist.
Dermatological
Severe acneAcne vulgaris
Acne vulgaris is a common human skin disease, characterized by areas of skin with seborrhea , comedones , papules , pustules , Nodules and possibly scarring...
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 Venereologie and in the 12 March 1988 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
Thorax
The thorax is a division of an animal's body that lies between the head and the abdomen.-In tetrapods:...
, the severity of which varied with the dosage. Most of them were treated unsuccessfully with isotretinoin
Isotretinoin
Isotretinoin, INN, is a medication used mostly for cystic acne. It was first developed for brain, pancreatic and other cancers. It is used to treat harlequin-type ichthyosis, a usually lethal skin disease, and lamellar ichthyosis. Its effects are systemic and nonselective...
(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.
This can be seen as a general side effect of central dopamine enhancement, due to the inhibitory effect of dopamine on prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
, with the subsequent increase in testosterone output, leading in turn to the same potential for acne as is typical of pubescents.
Psychiatric
Psychomotor excitation can very rarely occur with this drug.- NervousnessAnxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
- Irritability
- InsomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
- Suicidal ideation. Seen early in the treatment, by lifting of psychomotor inhibition. This is a common occurrence with most, if not all, antidepressants.
Cardiovascular
Very rarely:- Vasomotor episode
- Arterial hypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
- PalpitationPalpitationA palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating, whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself...
s
Hepatic
Amineptine can rarely cause hepatitisHepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, of the cytolytic
Cytolysis
Cytolysis, or osmotic lysis, occurs when a cell bursts due to an osmotic imbalance that has caused excess water to move into the cell. It occurs in a hypotonic environment, where water diffuses into the cell and causes its volume to increase. If the volume of water exceeds the cell membrane's...
, cholestatic varieties. Amineptine-induced hepatitis, which is sometimes preceded by a rash, is believed to be due to an allergic 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
Transaminase
In biochemistry, a transaminase or an aminotransferase is an enzyme that catalyzes a type of reaction between an amino acid and an α-keto acid. To be specific, this reaction involves removing the amino group from the amino acid, leaving behind an α-keto acid, and transferring it to the...
s, alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
, and bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
.
Mixed hepatitis, which is very rare, generally occurs between the 15th and 30th day of treatment. 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, 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 pancreatitisPancreatitisPancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
and mixed hepatitis after three weeks of treatment.
Immunological
In 1989, Sgro and colleagues at the Centre de Pharmacovigilance in DijonDijon
Dijon is a city in eastern France, the capital of the Côte-d'Or département and of the Burgundy region.Dijon is the historical capital of the region of Burgundy. Population : 151,576 within the city limits; 250,516 for the greater Dijon area....
reported a case of anaphylactic shock in a woman who had been taking amineptine.
Abuse and dependence
The risk of addictionSubstance dependence
The section about substance dependence in the Diagnostic and Statistical Manual of Mental Disorders does not use the word addiction at all. It explains:...
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
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
addicts and schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
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
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, psychomotor agitation, and/or bulimia appeared.
Precautions for use
- General anaesthesiaGeneral anaesthesiaGeneral anaesthesia is a state of unconsciousness and loss of protective reflexes resulting from the administration of one or more general anaesthetic agents...
: Discontinue the drug 24 to 48 hours before anaesthesia. - PregnancyPregnancyPregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
(first trimester) - Breast feeding
- Official sports/Olympic GamesOlympic GamesThe Olympic Games is a major international event featuring summer and winter sports, in which thousands of athletes participate in a variety of competitions. The Olympic Games have come to be regarded as the world’s foremost sports competition where more than 200 nations participate...
: Prohibited substance.- 7 March Official Journal 2000.
Contraindications
- ChoreaChorea (disease)Choreia is an abnormal involuntary movement disorder, one of a group of neurological disorders called dyskinesias. The term choreia is derived from the Greek word χορεία , see choreia , as the quick movements of the feet or hands are vaguely comparable to dancing or piano playing.The term...
- MAO inhibitors
- Children less than 1 year of age
- HypersensitivityHypersensitivityHypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
: Known hypersensitivity to amineptine, in particular antecedents of hepatitis after dosage of the product.