A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

that acts as a combined

reuptake inhibitor Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracel ...

of the

monoamine Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All monoamines are ...

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

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, ...

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 ...

, 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 chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. Monoamine structures (including neurotransmitters) contain a singular amino group (mono) linked to an aromatic ring by a chain of two carbons. SNDRIs prevent reuptake of these monoamine neurotransmitters through the simultaneous inhibition of the

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...

(SERT),

norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium ...

(NET), and

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT), respectively, increasing their

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

concentration In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', '' molar concentration'', '' number concentration'', ...

s and, therefore, resulting in an increase in serotonergic,

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 ...

, and

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron ...

. SNDRIs were developed as potential

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

s and treatments for other disorders, such as

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

cocaine addiction Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use of ...

attention-deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD), and

chronic pain Chronic pain is pain that persists or recurs for longer than 3 months.https://icd.who.int/browse/2025-01/mms/en#1581976053 It is also known as gradual burning pain, electrical pain, throbbing pain, and nauseating pain. This type of pain is in cont ...

. The increase in neurotransmitters through triple reuptake inhibition (including the addition of dopaminergic action) has the potential to heighten therapeutic effects in comparison to

selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

s (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), reducing symptoms of depression and anxiety in people struggling with mental illness, as well as potentially combating other ailments such as those listed above. However, increased

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 and

abuse potential Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

are concerns when using these agents relative to their SSRI and SNRI counterparts. Additionally, SNDRIs include the naturally-occurring and drug

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

, a widely used recreational and often illegal drug for the

euphoric Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...

effects it produces.

Ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

and

phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hall ...

are also SNDRIs and are similarly encountered as drugs of abuse. To a lesser extent,

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

also acts as a SNDRI.

Indications

Depression

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 ...

(MDD) is the foremost reason supporting the need for development of an SNDRI. According to the

World Health Organization The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...

, depression is the leading cause of

disability Disability is the experience of any condition that makes it more difficult for a person to do certain activities or have equitable access within a given society. Disabilities may be Cognitive disability, cognitive, Developmental disability, d ...

and the 4th leading contributor to the

global burden of disease Disease burden is the impact of a health problem as measured by financial cost, mortality, morbidity, or other indicators. It is often quantified in terms of quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs). Bot ...

in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of

DALYs A disability-adjusted life year (DALY) is a measure of overall disease burden, representing a year lost due to ill-health, disability, or early death. It was developed in the 1990s as a way of comparing the overall health and life expectancy of d ...

. About 5% of the population is estimated to be affected by depression, and in 2019, another 0.53% was affected by bipolar disorder. The ability to work, familial relationships, social integration, and self-care can all be severely disrupted by MDD. The presence of the common symptoms of these disorders are collectively called 'depressive syndrome' and include a long-lasting depressed mood, feelings of guilt, anxiety, poor concentration, a disturbance of sleep rhythms (

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 ...

hypersomnia Hypersomnia is a neurological disorder of excessive time spent sleeping or excessive sleepiness. It can have many possible causes (such as seasonal affective disorder) and can cause distress and problems with functioning. In the fifth edition ...

), severe fatigue, and recurrent thoughts of death and suicide. Over 700,000 people commit suicide each year worldwide, and people from age 15-29 are the demographic at the highest risk. Individual patients present differing subsets of symptoms, which may change over the course of the disease highlighting its multifaceted and heterogeneous nature. Depression is often highly

comorbid In medicine, comorbidity refers to the simultaneous presence of two or more medical conditions in a patient; often co-occurring (that is, concomitant or concurrent) with a primary condition. It originates from the Latin term (meaning "sicknes ...

with other diseases, e.g.

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

(

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

, and

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. Depressed subjects are prone to smoking, substance abuse,

eating disorders An eating disorder is a mental disorder defined by abnormal eating behaviors that adversely affect a person's health, physical or mental health, mental health. These behaviors may include eating too much food or too little food. Types of eatin ...

, obesity, high blood pressure, pathological gambling and internet addiction, and on average have a 15 to 30 year shorter lifetime compared with the general population. Major depression can strike at virtually any time of life as a function of genetic and developmental predisposition in interaction with adverse life-events. The genetic contribution has been estimated as 40-50%. However, combinations of multiple genetic factors may be involved considering a defect in a single gene usually fails to induce the multifaceted symptoms of depression. Although common in the elderly, over the course of the last century, the average age for a first episode has fallen to around 18–24 years. However, depressive states (with subtly different characteristics) are now frequently identified in adolescents and even children. The differential diagnosis and management of depression in young populations requires considerable care and experience; treatment can include therapy or institutionalization along with medication; SNDRIs could potentially become one of the drugs available to combat depression.

Pharmacotherapy

There remains a need for more efficacious antidepressant agents. Although two-thirds of patients will ultimately respond to antidepressant treatment, one-third of patients respond to placebo, and remission is frequently sub-maximal (''residual'' symptoms). In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy (''

tachyphylaxis Tachyphylaxis (Greek ταχύς, ''tachys'', "rapid", and φύλαξις, ''phylaxis'', "protection") is a medical term describing an acute, sudden decrease in response to a drug after its administration (i.e., a rapid and short-term onset of drug ...

''). Also, currently available antidepressants all elicit undesirable side-effects, and new agents should be divested of the distressing side-effects of both first and second-generation antidepressants. Another serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, in general one must reckon with a delay of 3–6 weeks before full efficacy is attained. In general, this delay to onset of action is attributed to a spectrum of long-term adaptive changes. These include receptor desensitization, alterations in intracellular transduction cascades and

gene expression Gene expression is the process (including its Regulation of gene expression, regulation) by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, proteins or non-coding RNA, ...

, the induction of

neurogenesis Neurogenesis is the process by which nervous system cells, the neurons, are produced by neural stem cells (NSCs). This occurs in all species of animals except the porifera (sponges) and placozoans. Types of NSCs include neuroepithelial cells ( ...

, and modifications in synaptic architecture and signaling. Depression has been associated with impaired

of serotonergic (5-HT),

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

(NE), and

(DA) pathways, although most pharmacologic treatment strategies directly enhance only 5-HT and NE neurotransmission. In some patients with depression, DA-related disturbances improve upon treatment with antidepressants, it is presumed by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not ''directly'' enhance DA neurotransmission, which may contribute to residual symptoms, including impaired

motivation Motivation is an mental state, internal state that propels individuals to engage in goal-directed behavior. It is often understood as a force that explains why people or animals initiate, continue, or terminate a certain behavior at a particul ...

, and

pleasure Pleasure is experience that feels good, that involves the enjoyment of something. It contrasts with pain or suffering, which are forms of feeling bad. It is closely related to value, desire and action: humans and other conscious animals find ...

Preclinical In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...

and

clinical research Clinical research is a branch of medical research that involves people and aims to determine the effectiveness (efficacy) and safety of medications, devices, diagnostic products, and treatment regimens intended for improving human health. The ...

indicates that drugs inhibiting the reuptake of all three of these

s can produce a more rapid onset of action and greater efficacy than traditional antidepressants. DA may promote

neurotrophic Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trop ...

processes in the adult

hippocampus The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...

, as 5-HT and NA do. It is thus possible that the stimulation of multiple

signalling pathway In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukaryo ...

s resulting from the elevation of all three

monoamines Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromaticity, aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All m ...

may account, in part, for an accelerated and/or greater antidepressant response. Dense connections exist between monoaminergic neurons. Dopaminergic neurotransmission regulates the activity of 5-HT and NE in the

dorsal raphe nucleus The dorsal raphe nucleus is one of the raphe nuclei. It is situated in the brainstem at the midline. It has rostral and caudal subdivisions: * The rostral aspect of the ''dorsal'' raphe is further divided into interfascicular, ventral, ventrolater ...

(DR) and

locus coeruleus The locus coeruleus () (LC), also spelled locus caeruleus or locus ceruleus, is a nucleus in the pons of the brainstem involved with physiological responses to stress and panic. It is a part of the reticular activating system in the reticular ...

(LC), respectively. In turn, the

ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...

(VTA) is sensitive to 5-HT and NE release. In the case of SSRIs, the promiscuity among transporters means that there may be more than a single type of neurotransmitter to consider (e.g. 5-HT, DA, NE, etc.) as mediating the therapeutic actions of a given medication. MATs are able to transport monoamines other than their "native" neurotransmitter. It was advised to consider the role of the

organic cation transporter An organic cation transport protein mediates the transport of organic cations across the cell membrane. These proteins are members of the solute carrier family, subfamily 22. This family of proteins can also transport zwitterions and anions, thoug ...

s (OCT) and the

plasma membrane monoamine transporter The plasma membrane monoamine transporter (PMAT) is a low-affinity monoamine transporter protein which in humans is encoded by the ''SLC29A4'' gene. It is known alternatively as the human equilibrative nucleoside transporter-4 (hENT4). It was disc ...

(PMAT). To examine the role of

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 in models of depression DAT, NET, and SERT

knockout A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, ...

(KO) mice and

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...

littermates were studied in the

forced swim test ''Forced'' is a single-player and co-op action role-playing game developed by BetaDwarf, released in October 2013 for Windows, OS X and Linux through the Steam platform as well as Wii U. It is about gladiators fighting for their freedom in a fant ...

(FST), the

tail suspension test The tail suspension test (TST) is an experimental method used in scientific research to measure stress in rodents. It is based on the observation that if a mouse is subjected to short term inescapable stress then the mouse will become immobi ...

, and for sucrose consumption. The effects of DAT KO in

animal models of depression Animal models of depression are research tools used to investigate Major depressive disorder, depression and action of antidepressant, antidepressants. They are used as a simulation to investigate the symptomatology and pathophysiology of depress ...

are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade. The

SSRIs Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

were intended to be highly selective at binding to their molecular targets. However it may be an oversimplification, or at least controversial in thinking that complex

psychiatric Psychiatry is the medical specialty devoted to the diagnosis, treatment, and prevention of deleterious mental conditions. These include matters related to cognition, perceptions, mood, emotion, and behavior. Initial psychiatric assessment of ...

(and

neurological Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the s ...

) diseases are easily solved by such a monotherapy. While it may be inferred that dysfunction of 5-HT circuits is likely to be a part of the problem, it is only one of many such neurotransmitters whose signaling can be affected by suitably designed medicines attempting to alter the course of the

disease A disease is a particular abnormal condition that adversely affects the structure or function (biology), function of all or part of an organism and is not immediately due to any external injury. Diseases are often known to be medical condi ...

state. Most common CNS disorders are highly

polygenic A polygene is a member of a group of non- epistatic genes that interact additively to influence a phenotypic trait, thus contributing to multiple-gene inheritance (polygenic inheritance, multigenic inheritance, quantitative inheritance), a type ...

in nature; that is, they are controlled by complex interactions between numerous gene products. As such, these conditions do not exhibit the single gene defect basis that is so attractive for the development of highly-specific drugs largely free of major undesirable side-effects ("the magic bullet"). Second, the exact nature of the interactions that occur between the numerous gene products typically involved in CNS disorders remain elusive, and the biological mechanisms underlying mental illnesses are poorly understood.

Clozapine Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered. It is used primarily to treat people with schizophrenia and schizoaffective disorder who have ...

is an example of a drug used in the treatment of certain CNS disorders, such as schizophrenia, that has superior efficacy precisely because of its broad-spectrum

mode of action In pharmacology and biochemistry, mode of action (MoA) describes a functional or anatomical change, resulting from the exposure of a living organism to a substance. In comparison, a mechanism of action (MOA) describes such changes at the molecul ...

. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious. In addition, the nonselective MAOIs and the TCA SNRIs are widely believed to have an efficacy that is superior to the SSRIs normally picked as the first-line choice of agents for/in the treatment of MDD and related disorders. The reason for this is based on the fact that SSRIs are safer than nonselective MAOIs and TCAs. This is both in terms of there being less mortality in the event of overdose, but also less risk in terms of dietary restrictions (in the case of the nonselective MAOIs), hepatotoxicity (MAOIs) or cardiotoxicity (TCAs).

Applications other than depression

Alcoholism Alcoholism is the continued drinking of alcohol despite it causing problems. Some definitions require evidence of dependence and withdrawal. Problematic use of alcohol has been mentioned in the earliest historical records. The World He ...

(cf. DOV 102,677) *

Cocaine addiction Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use of ...

(e.g.,

indatraline Indatraline hydrochloride (Lu 19-005) is an antidepressive agent and non-selective monoamine transporter inhibitor that blocks the reuptake of dopamine, norepinephrine, and serotonin with similar efficacy to cocaine. This compound may be used t ...

) *

Obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

(e.g.,

amitifadine Amitifadine (developmental code names DOV-21,947, EB-1010) is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by Euthymics Bioscience. It was under ...

tesofensine Tesofensine (NS2330) is a serotonin-noradrenaline-dopamine reuptake inhibitor, serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was ...

) *

Attention-deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple con ...

(ADHD) (cf.

NS-2359 NS-2359 (GSK-372475) is a serotonin-norepinephrine-dopamine reuptake inhibitor. It was under development by GlaxoSmithKline (GSK) as an antidepressant, but was discontinued in 2009 when phase II clinical trials showed the drug was not effective ...

, EB-1020) *

Chronic pain Chronic pain is pain that persists or recurs for longer than 3 months.https://icd.who.int/browse/2025-01/mms/en#1581976053 It is also known as gradual burning pain, electrical pain, throbbing pain, and nauseating pain. This type of pain is in cont ...

(cf. bicifadine) *

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

List of SNDRIs

Approved pharmaceuticals

Mazindol Mazindol, sold under the brand names Mazanor and Sanorex, is a central nervous system (CNS) stimulant which is used as an appetite suppressant. It was developed by Sandoz Laboratories, Sandoz-Wander in the 1960s. The US Food and Drug Administrat ...

(Mazanor, Sanorex) —

anorectic An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...

; k_i is 50 nM for SERT, 18 nM for NET, 45 nM for DAT *

Nefazodone Nefazodone, sold formerly under the brand names Serzone, Dutonin, and Nefadar among others, is an atypical antidepressant medication which is used in the treatment of depression and for other uses. Nefazodone was withdrawn in most countries by ...

(Serzone, Nefadar, Dutonin) —

; non-selective; k_i is 200 nM at SERT, 360 nM at NET, 360 nM at DAT *

Nefopam Nefopam, sold under the brand name Acupan among others, is a centrally acting, non-opioid painkilling medication, with central stimulant and sympathomimetic properties that is primarily used to treat moderate to severe pain. History Nefopam i ...

— analgesic, K_i SER/NE/DA = 29/33/531 nM) * Toludesvenlafaxine (Ansofaxine, LY03005/LPM570065). Completed Phase 2 & 3 trials. FDA accepted NDA application. Approved in China.

Sibutramine Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. It works as a serotonin–norepinephrine reuptake inhibitor (SNRI) similar to certain antidepressant ...

(Meridia) is a withdrawn anorectic that is an SNDRI ''in vitro'' with k_i values of 298 nM at SERT, 5451 at NET, 943 nM at DAT. However, it appears to act as a

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

''in vivo'' to

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 that are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and in accordance, sibutramine behaves contrarily as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake (16%).

Venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...

(Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced with k_i values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93. It may weakly inhibit the reuptake of dopamine at high doses.

Coincidental

Esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...

(Ketanest S) —

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into t ...

; ''S''-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

of ketamine; weak SNDRI action likely contributes to effects and

(Ketalar) — anesthetic and

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens that distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

drug of abuse Substance misuse, also known as drug misuse or, in older vernacular, substance abuse, is the use of a drug in amounts or by methods that are harmful to the individual or others. It is a form of substance-related disorder, differing definitions ...

; weak SNDRI action likely contributes to effects and

Phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hall ...

(Sernyl) — discontinued anesthetic and dissociative

psychostimulant 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 ...

drug of abuse; SNDRI action likely contributes to effects and abuse potential *

Tripelennamine Tripelennamine, sold under the brand name Pyribenzamine by Novartis, is a drug that is used as an antipruritic and first-generation antihistamine. It can be used in the treatment of asthma, hay fever, rhinitis, and urticaria, but is now less ...

(Pyribenzamine) —

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 ...

; weak SNDRI; sometimes abused for this reason *

Lamotrigine Lamotrigine ( ), sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastau ...

(Lamictal) —

Anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

; weak SNDRI; IC₅₀ is 240μM (human platelets) / 474 μM (rat brain synaptosomes) for SERT, 239 μM for NET, 322 μM for DAT *

Mepiprazole Mepiprazole (INN, BAN) (brand name Psigodal) is an anxiolytic drug of the phenylpiperazine group with additional antidepressant properties that is marketed in Spain. It acts as a 5-HT2A and α1-adrenergic receptor antagonist and inhibits the ...

Undergoing clinical trials

Cendifensine Cendifensine () is a monoamine reuptake inhibitor (MRI) related to the amphetamines and cathinones which has not been marketed at this time. It was first described by 2013 and its was proposed in 2024. The drug has been patented by Noema Pharma, ...

(NOE-115)Lucas, M. C., Weikert, R. J., Carter, D. S., Cai, H.-Y., Greenhouse, R., Iyer, P. S., Lin, C. J., Lee, E. K., Madera, A. M., Moore, A., Ozboya, K., Schoenfeld, R. C., Steiner, S., Zhai, Y., Lynch, S. M. (September 2010). "Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain". Bioorganic & Medicinal Chemistry Letters. 20 (18): 5559–5566. doi:10.1016/j.bmcl.2010.07.020. * Centanafadine (EB-1020) �
see here for details
1 to 6 to 14 ratio for NDS. Completed Phase 3 trials for ADHD. * OPC-64005 — In phase 2 trials (2022) * Lu AA37096 �
see here
(SNDRI and 5-HT₆ modulator) * NS-2360 — principle metabolite of tesofensine *

Tesofensine Tesofensine (NS2330) is a serotonin-noradrenaline-dopamine reuptake inhibitor, serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity. Tesofensine was ...

(NS-2330) (2001) In trials for obesity.

Failed clinical trials

* Bicifadine (DOV-220,075) (1981) *

Brasofensine Brasofensine (NS-2214, BMS-204756) is a phenyltropane dopamine reuptake inhibitor that had been under development by Bristol-Myers Squibb and defunct company NeuroSearch for the treatment of Parkinson's and Alzheimer's diseases. History In 1996, ...

(NS-2214, BMS-204,756) (1995) * Diclofensine (Ro 8–4650) (1982) * DOV-216,303 (2004) * EXP-561 (1965) SAR analogy with U-32,802A suggests that incorporation of a butyrophenone sidechain might be consistent with antipsychotic properties. The para-bromo derivative of EXP-561 was "a potent and relatively selective inhibitor of uptake into serotonin neurones". *

Liafensine Liafensine (BMS-820836) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) which was under development by Bristol-Myers Squibb for the treatment of major depressive disorder. Though it demonstrated comparable effectiveness to esci ...

(BMS-820,836) *

(GSK-372,475) * SEP-227,162 * SEP-228,425 *

Amitifadine Amitifadine (developmental code names DOV-21,947, EB-1010) is a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) or so-called triple reuptake inhibitor (TRI) which is or was being developed by Euthymics Bioscience. It was under ...

(DOV-21,947, EB-1010) (2003) *

Dasotraline Dasotraline (INN; former developmental code name SEP-225,289) is a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI) that was under development by Sunovion for the treatment of attention-deficit hyperactivity disorder (ADHD) and bin ...

(SEP-225,289) *

Lu AA34893 Lu, Lü, or LU may refer to: Arts and entertainment * Lu (duo), a Mexican band ** ''Lu'' (album) * Character from Mike, Lu & Og * Lupe Fiasco or Lu (born 1982), American musician * Lu Watters (1911-1989), American musician * Lu Gambino (1923 ...

�
see here
(SNDRI and 5-HT_2A, α₁, and 5-HT₆ modulator) * Tedatioxetine (Lu AA24530) — SNDRI and 5-HT_2C, 5-HT₃, 5-HT_2A, and α₁ modulator

Designer drugs A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...

3-Methyl-PCPy 3-Methyl-PCPy (3-Me-PCPy) is an arylcyclohexylamine derivative with an unusual spectrum of pharmacological effects, acting as both a potent NMDA antagonist and also a triple reuptake inhibitor which inhibits reuptake of all three monoamine neurot ...

Naphyrone Naphyrone, also known as O-2482 and naphthylpyrovalerone, is a stimulant drug of the cathinone and naphthylaminopropane families. It was derived from pyrovalerone and acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI). ...

(O-2482, naphthylpyrovalerone, NRG-1) (2006) *

5-APB 5-APB (abbreviation of "5-(2-aminopropyl)benzofuran") is an empathogenic psychoactive compound of the phenethylamine, amphetamine, and benzofuran families. The drug and other compounds have sometimes been informally called "Benzofury". 5-APB ha ...

Research compounds (no record of having been taken by humans)

*First invented at Hoechst Marion Roussel, MDL 47,832 2423-89-9has a SAR that is similar to RG-7166 &

. Further details of the SAR study can be seen under Osanetant. *

3,3-Diphenylcyclobutanamine 3,3,-Diphenylcyclobutanamine is a psychostimulant drug which was originally prepared as an antidepressant in the late 1970s. It appears to inhibit the reuptake of serotonin, norepinephrine, and dopamine, and may also induce their release Rele ...

(1978) *AK Dutta: D-161 (2008) D-473 632000-05-5& D-578. ''Informative review'': * DOV-102,677 (2006–2011) ''Informative reviews'': * Fezolamine (Win-41,528-2) *

GlaxoSmithKline GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...

(Italia):

GSK1360707F GSK1360707F is a potent and selective SNDRI, triple reuptake inhibitor. It is chemically related to amitifadine and NS-2359 (GSK-372,475). Until recently, it was under development for the treatment of major depressive disorder; its development ...

(2010)
CID:46866510
* HP-505 * Lundbeck group:

Indatraline Indatraline hydrochloride (Lu 19-005) is an antidepressive agent and non-selective monoamine transporter inhibitor that blocks the reuptake of dopamine, norepinephrine, and serotonin with similar efficacy to cocaine. This compound may be used t ...

(1985)
Lu-AA42202

CID:11515108
74296-10-3 *

JNJ-7925476 JNJ-7925476 is a triple reuptake inhibitor antidepressant discovered by Johnson & Johnson, but never marketed. These molecules were first prepared by Bruce E. Maryanoff and coworkers during the late 1970s–1980s. The structure is a pyrroloisoq ...

(2008; first appeared in 1987),

McN 5707 MCN may refer to: Media * ''MCN'' (journal), a peer-reviewed journal of obstetrical and neonatal nursing * Multi-channel network, a type of organization working with video platforms to assist their owners * Metro Chinese Network, a Rockville, Mar ...

6795-88-9& Mcn-5292 05234-89-7 * Kozikowski group:

DMNPC ''N'',''O''-Dimethyl-4β-(2-naphthyl)piperidine-3β-carboxylate (DMNPC) is a piperidine based stimulant drug which is synthesised from arecoline. It is similar to nocaine in chemical structure, and has two and a half times more activity than coca ...

(2000),

JZ-IV-10 JZ-IV-10 is a piperidine derivative related to cocaine which acts as a highly potent serotonin–norepinephrine–dopamine reuptake inhibitor (also called SNDRI, or triple reuptake inhibitor). The eugeroic modafinil was used as a lead to fuel th ...

(2005) & JZAD-IV-22 (2010) * Lilly group:

LR-5182 LR-5182 is a stimulant drug which acts as a norepinephrine–dopamine reuptake inhibitor, structurally related to the better known drug fencamfamine. It was developed by the pharmaceutical company Eli Lilly and Company, Eli Lilly in the 1970s, an ...

(maybe only NDRI) (1978
CID:9903806

CID:11335177CID:9867350CID:11234430
*HM Deutsch group:

Methylnaphthidate HDMP-28 or methylnaphthidate is a stimulant drug of the piperidine and naphthylaminopropane groups, closely related to methylphenidate (Ritalin), but with the benzene ring replaced by naphthalene. It is a potent dopamine reuptake inhibitor, wit ...

(HDMP-28) (2001) * MI-4 MI-4 is the same compound as Ro-25-6981 69274-78-6 This is

NMDA antagonist NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the ''N''-Methyl-D-aspartate receptor ( NMDAR). They are commonly used as anesthetics for humans and animals; the state of anesthesia they ind ...

. *

Benzazepine Benzazepines are heterocyclic chemical compounds consisting of a benzene ring fused to an azepine ring. Examples include: File:Benazepril structure.svg, Benazepril File:Fenoldopam.svg, Fenoldopam File:GSK-189,254.svg, GSK-189,254 File:Ivabrad ...

derivatives: SKF-83,959 (2013) & ''Nor''-

Trepipam Trepipam (; developmental code name SCH-12679) is a dopamine receptor agonist of the benzazepine group that was never marketed. It acts specifically as an agonist of the dopamine D1 receptor. It is closed related structurally to fenoldopam, a ...

0569-49-7 * Various

phenyltropane Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. This research has spanned beyond the last couple decade ...

s, such as WF-23,

dichloropane Dichloropane ((−)-2β-Carbomethoxy-3β-(3,4-dichlorophenyl)tropane, RTI-111, O-401) is a stimulant of the phenyltropane class that acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) with IC50 values of 3.13, 18, and ...

, and

RTI-55 RTI(-''4229'')-55, also called RTI-55 or iometopane, is a phenyltropane-based stimulant, psychostimulant used in scientific research and in some medical applications. This drug was first cited in 1991. RTI-55 is a non-selective dopamine reuptake ...

NeuroSearch NeuroSearch A/S is a Danish biotechnology company specializing in pharmaceuticals for treating diseases and disorders affecting the central nervous system (CNS). History NeuroSearch was founded in Denmark in April 1989 as one of the first comp ...

group
NS9775
NS18283
& 4-Benzhydryl-1,2,3,6-tetrahydropyridine 186529-81-6
CID:54673194
(k_i S/N/D = 0.26/6.0/4.8 nM) *
CID:9921901
87869-25-2br>3-(3,4-Dichlorophenyl)-tropan-2-ene
(S/N/D = 4.7/26/79 nM) *Liming Shao (Sepracor/Sunovion). 3’,4’-Dichlorotramadol
CID:53321058
(S/N/D = 19/04/01 nM). **A patent review was also disclosed:
CID:66809062CID:46870521CID:10151573CID:46701015
*

Takeda is a Japanese name, Japanese family name.1990 Census Name Files *Although not specifically a SNDRI, ''

Rosmarinus officinalis ''Salvia rosmarinus'' (), commonly known as rosemary, is a shrub with fragrant, evergreen, needle-like leaves and white, pink, purple, or blue flowers. It is a member of the sage family, Lamiaceae. The species is native to the Mediterranean r ...

'' is one of the trimonoamine modulator (TMM) that affect SER/CAs. * Hederagenin: * Yuanzhi-1 ('' Polygala tenuifolia'').

Toxicological

Toxicological Toxicology is a scientific discipline (academia), discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnos ...

screening is important to ensure safety of the drug molecules. In this regard, the p m-di

chloro Chlorine is a chemical element; it has symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine is a ...

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula , and is often represented by the symbol Ph (archaically φ) or Ø. The phenyl group is closely related to benzene and can be viewed as a benzene ...

analog Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...

was dropped from further

development Development or developing may refer to: Arts *Development (music), the process by which thematic material is reshaped * Photographic development *Filmmaking, development phase, including finance and budgeting * Development hell, when a proje ...

after its potential

mutagenicity In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer in ...

was called into question. The mutagenicity of this

compound Compound may refer to: Architecture and built environments * Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall ** Compound (fortification), a version of the above fortified with defensive struc ...

is still doubtful though. It was dropped for other reasons likely related to speed at which it could be released onto the market relative to the more developed compound venlafaxine. More recently, the

carcinogenicity A carcinogen () is any agent that promotes the development of cancer. Carcinogens can include synthetic chemicals, naturally occurring substances, physical agents such as ionizing and non-ionizing radiation, and Biological agent, biologic agent ...

PRC200-SS PRC200-SS is an experimental drug of the triple reuptake inhibitor class that was investigated by the Mayo Clinic. Preclinical toxicology studies of PRC200-SS in cynomolgus monkeys showed dose proportional kidney toxicity, precluding any furt ...

was likewise reported. (+)-CPCA ("

nocaine (+)-CPCA (nocaine, 3α-carbomethoxy-4β-(4-chlorophenyl)-''N''-methylpiperidine aka CTDP 31,446) is a stimulant drug similar in structure to pethidine (an opioid that possesses NDRI actions) and to RTI-31, but nocaine lacks the two-carbon brid ...

") is the 3''R'',4''S''

piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor de ...

stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...

of (

based)

RTI-31 RTI-31 ((–)-2β-carbomethoxy-3β-(4'-chlorophenyl)tropane) is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article, RTI ...

. It is non addictive, although this might be due to it being a NDRI, not a SNDRI. The β-naphthyl analog of "Nocaine" is a SNDRI though in the case of both the ''SS'' and ''RR'' enantiomers. Consider the piperidine analogs of

brasofensine Brasofensine (NS-2214, BMS-204756) is a phenyltropane dopamine reuptake inhibitor that had been under development by Bristol-Myers Squibb and defunct company NeuroSearch for the treatment of Parkinson's and Alzheimer's diseases. History In 1996, ...

and

. These were prepared by

(In

Denmark Denmark is a Nordic countries, Nordic country in Northern Europe. It is the metropole and most populous constituent of the Kingdom of Denmark,, . also known as the Danish Realm, a constitutionally unitary state that includes the Autonomous a ...

) by the

chemists A chemist (from Greek ''chēm(ía)'' alchemy; replacing ''chymist'' from Medieval Latin ''alchemist'') is a graduated scientist trained in the study of chemistry, or an officially enrolled student in the field. Chemists study the composition of ...

Peter Moldt (2002), and

Frank Wätjen Frank, FRANK, or Franks may refer to: People * Frank (given name) * Frank (surname) * Franks (surname) * Franks, a Germanic people in late Roman times * Franks, a term in the Muslim world for all western Europeans, particularly during the Crusa ...

(2004–2009). There are four separate isomers to consider (''SS'', ''RR'', ''S/R'' and ''R/S''). This is because there are two chiral carbon sites of

asymmetry Asymmetry is the absence of, or a violation of, symmetry (the property of an object being invariant to a transformation, such as reflection). Symmetry is an important property of both physical and abstract systems and it may be displayed in pre ...

(means 2 to the power of n isomers to consider where n is the number of chiral carbons). They are therefore a diastereo(iso)meric pair of racemers. With a

racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

pair of diastereomers, there is still the question of syn ( cis) or anti (

trans Trans- is a Latin prefix meaning "across", "beyond", or "on the other side of". Used alone, trans may refer to: Sociology * Trans, a sociological term which may refer to: ** Transgender, people who identify themselves with a gender that di ...

). In the case of the phenyltropanes, although there are four chiral carbons, there are only eight possible isomers to consider. This is based on the fact that the compound is bicyclic and therefore does not adhere to the equation given above. It is complicated to explain which

isomer In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element (chemistry), element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the exi ...

s are desired. For example, although

Alan P. Kozikowski Alan P. Kozikowski is an American medicinal chemist, drug designer, and pharmaceutical entrepreneur, best known for his research on 5-HT receptors, and GSK-3 inhibitors. He is an author of a book ''Drug Design for Neuroscience''. He has over 10 ...

showed that ''R/S'' nocaine is less addictive than ''SS'' Nocaine, studies on variously substituted phenyltropanes by

F. Ivy Carroll F is the sixth letter of the Latin alphabet. F may also refer to: Science and technology Mathematics * F or f, the number 15 in hexadecimal and higher positional systems * ''p'F'q'', the hypergeometric function * F-distribution, a conti ...

''et at.'' revealed that the ββ isomers were less likely to cause

convulsions A convulsion is a medical condition where the body muscles contract and relax rapidly and repeatedly, resulting in uncontrolled shaking. Because epileptic seizures typically include convulsions, the term ''convulsion'' is often used as a synony ...

tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

and

death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...

than the corresponding ''trans'' isomers (more specifically, what is meant is the 1''R'',2''R'',3''S'' isomers). While it does still have to be conceded that

caused death at a dosage of 100 mg/kg, its

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

of safety is still much better than the corresponding ''trans'' isomers because it is a more potent compound. In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...

(and hence

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

), increased locomotor activity (LMA) etc. In the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose. People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. On removal of the 2C tropane bridge and on going from RTI-31 to the simpler ''SS'' and ''RS'' Nocaine it was seen that these compounds still possessed activity as NDRIs but were not powerful psychostimulants. Hence, this might be viewed as a strategy for increasing the safety of the compounds and would also be preferable to use in patients who are not looking to achieve weight loss. In light of the above paragraph, another way of reducing the psychomotor stimulant and addictive qualities of phenyltropane stimulants is in picking one that is relatively serotonergic. This strategy was employed with success for

RTI-112 RTI(-''4229'')-112 (2β-carbomethoxy-3β-(3-methyl-4-chlorophenyl)tropane) is a synthetic stimulant drug from the phenyltropane family. In contrast to RTI-113, which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor. ''In ...

. Another thing that is important and should be mentioned is the risk for

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 ...

when incorporating the element of 5-HT transporter inhibition into a compound that is already fully active as a NDRI (or vice versa). The reasons for

are complicated and not fully understood.

Addiction

Drug addiction may be regarded as a disease of the brain's reward system. This system, closely related to the system of emotional arousal, is located predominantly in the

limbic The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''P ...

structures of the brain. There are several groups of substances that activate the reward system and they may result in addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behavior. Drug abuse affects the prefrontal cortex, a brain region also involved in the reward system, diminishing or impairing the use of self control or judgment in addicts. Dopamine is the primary neurotransmitter involved in the reward mechanism of the limbic system.

Relation to Cocaine

Cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors. Cocaine is a relatively "balanced" inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. Cocaine users may experience symptoms of extreme fatigue, decreased mood, and a "crash" following the original euphoria of the drug; subsequent to the crash, users begin to crave for more. In addition, cocaine has some serious limitations in terms of its

cardiotoxicity Cardiotoxicity is the occurrence of heart dysfunction as electric or muscle damage, resulting in heart toxicity. This can cause heart failure, arrhythmia, myocarditis, and cardiomyopathy in patients. Some effects are reversible, while in others, p ...

due to its

local anesthetic A local anesthetic (LA) is a medication that causes absence of all sensation (including pain) in a specific body part without loss of consciousness, providing local anesthesia, as opposed to a general anesthetic, which eliminates all sensati ...

activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health. Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

. There has been speculation over whether the new SNDRIs will have an

like cocaine does. However, for pharmacotherapeutics, treatment of cocaine addiction is advantageous if a substitute medication is at least weakly reinforcing because it can serve to retain addicts in treatment programs.

Legality

is a controlled drug (Class A in the UK; Schedule II in the USA); it has not been entirely outlawed in most countries, as despite having some "abuse potential" it is recognized as useful for surgery considering it is a local anesthetic that can be applied to areas such as the nose, mouth, or throat for numbing purposes.

, a dopamine inhibitor developed to treat Parkinson's disease, was made "class A" in the UK under the MDA (misuse of drugs act). The semi-synthetic procedure for making brasofensine uses cocaine as the starting material.

, a drug that inhibits monoamine transporters, first appeared in 2006 as one of quite a large number of analogs of

pyrovalerone (Centroton, 4-Methyl-β-keto-prolintane, Thymergix, O-2371) is a central nervous system (CNS) stimulant that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It was developed in the 1980s and had briefly been approved in Spain an ...

designer drug A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...

mephedrone Mephedrone, also known as , , and , is a synthetic stimulant drug belonging to the amphetamine and cathinone classes. It is commonly referred to by slang names such as drone, , white magic, meow meow, and bubble. Chemically, it is similar to ...

and

methylone Methylone, also known as 3,4-methylenedioxy-''N''-methylcathinone (MDMC), is an entactogen and stimulant drug of the amphetamine, cathinone, and benzodioxole families related to 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"). It is th ...

became banned in the United Kingdom, vendors of these chemicals needed to find a suitable replacement. Mephedrone and methylone affect the same chemicals in the brain as a SNDRI, although they are thought to act as monoamine ''releasers'' and not act through the reuptake inhibitor mechanism of activity. A short time later, mephedrone and methylone were banned (which had become quite popular by the time they were illegalized), naphyrone appeared under the trade name NRG-1. NRG-1 was promptly illegalized, although it is not known if its use resulted in any hospitalizations or deaths.

Self-Administration of Drugs

According to various studies, the relative likelihood of rodents and non-human primates self-administering various psychostimulants that modulate monoaminergic neurotransmission is lessened as the dopaminergic compounds become more serotonergic. This finding has been found for amphetamine and some of its variously substituted analogs including

PAL-287 Naphthylaminopropane (NAP; code name PAL-287), also known as naphthylisopropylamine (NIPA), is an experimental drug of the amphetamine and naphthylaminopropane families that was under investigation for the treatment of alcohol and stimulant ad ...

etc.

is another good example of the compound becoming less likely to be self-administered by the test subject in the case of a dopaminergic compound that also has a marked affinity for the serotonin transporter. Further evidence that 5-HT (serotonin) dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with SSRIs, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only. However, not all SNDRIs are reliably self-administered by animals. Examples include: * PRC200-SS was not reliably self-administered. *

was not self-administered because at low doses the compound preferentially occupies the SERT and not the DAT. *

was also not reliably self-administered by

human Humans (''Homo sapiens'') or modern humans are the most common and widespread species of primate, and the last surviving species of the genus ''Homo''. They are Hominidae, great apes characterized by their Prehistory of nakedness and clothing ...

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, ...

addicts. * The

analog JZAD-IV-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction.

Role of monoamine neurotransmitters

Monoamine hypothesis

The original

monoamine hypothesis The biology of depression is the attempt to identify a biochemical origin of Depression (mood), depression, as opposed to theories that emphasize psychological or situational causes. Scientific studies have found that different brain areas show al ...

postulates that depression is caused by a deficiency or imbalances in the monoamine neurotransmitters (5-HT, NE, and DA). This has been the central topic of depression research for approximately the last 50 years; it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways. When

reserpine Reserpine is a drug that is used for the treatment of hypertension, high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diur ...

(an

alkaloid Alkaloids are a broad class of natural product, naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids. Alkaloids are produced by a large varie ...

with uses in the treatment of

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

and

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

) was first introduced to

the West West is a cardinal direction or compass point. West or The West may also refer to: Geography and locations Global context * The Western world * Western culture and Western civilization in general * The Western Bloc, countries allied with NAT ...

from

India India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...

in 1953, the drug was unexpectedly shown to produce depression-like symptoms. Further testing was able to reveal that reserpine causes a depletion of monoamine concentrations in the brain. Reserpine's effect on monoamine concentrations results from blockade of the

vesicular monoamine transporter The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrin ...

, leading to their increased catabolism by monoamine oxidase. However, not everyone has been convinced by claims that reserpine is depressogenic, some authors ( David Healy in particular) have even claimed that it is antidepressant.

Tetrabenazine Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the US Food and Drug Administration (FDA) approved the use of tet ...

, a similar agent to reserpine, which also depletes catecholamine stores, and to a lesser degree 5-HT, was shown to induce depression in many patients.

Iproniazid Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non-selective, irreversible inhibition, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine (antidepressant), hydrazine class. It is a xenobiotic that was origi ...

, an inhibitor of MAO, was noted to elevate mood in depressed patients in the early 1950s, and soon thereafter was shown to lead to an increase in NA and 5-HT. Hertting et al. demonstrated that the first TCA, imipramine, inhibited cellular uptake of NA in peripheral tissues. Moreover, both antidepressant agents were demonstrated to prevent reserpine-induced sedation. Likewise, administration of DOPA to laboratory animals was shown to reverse reserpine induced sedation; a finding reproduced in humans. Amphetamine, which releases NA from vesicles and prevents re-uptake was also used in the treatment of depression at the time with varying success. In 1965 Schildkraut formulated the

catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...

theory of depression. This was subsequently the most widely cited article in the

American Journal of Psychiatry ''The American Journal of Psychiatry'' is a monthly peer-reviewed medical journal covering all aspects of psychiatry, and is the official journal of the American Psychiatric Association. The first volume was issued in 1844, at which time it was k ...

. The theory stated that "some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, in particular noradrenaline (NA), at functionally important adrenergic receptor sites in the brain. However, elation may be associated with an excess of such amines." Shortly after Schildkraut's catecholamine hypothesis was published, Coppen proposed that 5-HT, rather than NA, was the more important neurotransmitter in depression. This was based on similar evidence to that which produced the NA theory as reserpine, imipramine, and iproniazid affect the 5-HT system, in addition to the noradrenergic system. It was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-HT neurotransmission remained unaltered there was no sedation in animals. Alongside this, the main observation promoting the 5-HT theory was that administration of a MAOI in conjunction with tryptophan (precursor of 5-HT) elevated mood in control patients and potentiated the antidepressant effect of MAOI. Set against this, combination of an MAOI with DOPA did not produce a therapeutic benefit. Inserting a chlorine atom into imipramine leads to

clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyper ...

, a drug that is much more SERT selective than the parent compound.

Clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyper ...

was a predecessor to the development of the more recent SSRIs. There was, in fact, a time prior to the SSRIs when selective NRIs were being considered (cf. talopram and

melitracen Melitracen (brand names Melixeran, Trausabun) is a tricyclic antidepressant (TCA), for the treatment of depression and anxiety. In addition to single drug preparations, it is also available as Deanxit, marketed by Lundbeck, a combination produc ...

). In fact, it is also believed that the selective NRI

nisoxetine Nisoxetine (developmental code name LY-94939), originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently ...

was discovered prior to the invention of

fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

. However, the selective NRIs did not get promoted in the same way as did the SSRIs, possibly due to an increased risk of suicide. This was accounted for on the basis of the energizing effect that these agents have. Moreover, NRIs have the additional adverse safety risk of

that is not seen for SSRIs. Nevertheless, NRIs have still found uses. Further support for the monoamine hypothesis came from monoamine depletion studies: * Alpha-methyl-''p''-tyrosine ( AMPT) is a

tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...

enzyme inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its Enzyme activity, activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which Substrate (biochemistry), substrate molecules are converted ...

that serves to inhibit catecholamine synthesis. AMPT led to a resurgence of depressive symptoms in patients improved by the NE reuptake inhibitor (NRI) desipramine, but not by the SSRI fluoxetine. The mood changes induced by AMPT may be mediated by decreases in norepinephrine, while changes in selective attention and motivation may be mediated by dopamine. * Dietary depletion of the DA precursors phenylalanine and tyrosine does not result in the relapse of formerly depressed patients off their medication. * Administration of

fenclonine Fenclonine, also known as ''para''-chlorophenylalanine (PCPA), acts as a selective and irreversible inhibitor of tryptophan hydroxylase, which is a rate-limiting enzyme in the biosynthesis of serotonin. It has been used experimentally to treat c ...

(''para''-chlorophenylalanine) is able to bring about a depletion of 5-HT. The mechanism of action for this is via

tryptophan hydroxylase Tryptophan hydroxylase (TPH) is an enzyme () involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-depen ...

inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients, but it is considered too toxic for use today. * Although depletion of

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

— the rate-limiting factor of serotonin synthesis — does not influence the mood of healthy volunteers and untreated patients with depression, it does produce a rapid relapse of depressive symptoms in about 50% of remitted patients who are being, or have recently been treated with serotonin selective antidepressants.

Dopaminergic

There appears to be a pattern of symptoms that are currently inadequately addressed by serotonergic antidepressants — loss of pleasure (anhedonia), reduced motivation, loss of interest, fatigue and loss of energy, motor retardation, apathy and hypersomnia. Addition of a pro-dopaminergic component into a serotonin based therapy would be expected to address some of these short-comings. Several lines of evidence suggest that an attenuated function of the dopaminergic system may play an important role in depression: * Mood disorders are highly prevalent in pathologies characterized by a deficit in central DA transmission such as Parkinson's disease (PD). The prevalence of depression can reach up to 50% of individuals with PD. * Patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to develop symptoms of depression. * Data from clinical studies have shown that DA agonists, such as

bromocriptine Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malig ...

pramipexole Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease and restless legs syndrome. In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a ...

and

ropinirole Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). It is taken by mouth. Common side effects include sleepiness, vomiting, and dizziness. Seriou ...

, exhibit antidepressant properties. *

Amineptine Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a le ...

, a TCA-derivative that predominantly inhibits DA re-uptake and has minimal noradrenergic and serotonergic activity has also been shown to possess antidepressant activity. A number of studies have suggested that amineptine has similar efficacy to the TCAs, MAOIs and SSRIs. However, amineptine is no longer available as a treatment for depression due to reports of an abuse potential. * The B-subtype selective

MAOI 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 ...

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

(a drug developed for the treatment of PD) has now been approved for the treatment of depression in the form of a

transdermal Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointm ...

patch (

Emsam Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

). For some reason, there have been numerous reports of users taking this drug in conjunction with β-

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

. * Taking psychostimulants for the alleviation of depression is well proven strategy, although in a clinical setting the use of such drugs is usually prohibited because of their strong addiction propensity. * When users withdraw from psychostimulant drugs of abuse (in particular, amphetamine), they experience symptoms of depression. This is likely because the brain enters into a hypodopaminergic state, although there might be a role for noradrenaline also. For these drugs to be reinforcing, they must block more than 50% of the DAT within a relatively short time period (<15 minutes from administration) and clear the brain rapidly to enable fast repeated administration. In addition to mood, they may also improve cognitive performance, although this remains to be demonstrated in humans. The rate of clearance from the body is faster for ritalin than it is for regular amphetamine.

Noradrenergic

The decreased levels of NA proposed by Schildkraut, suggested that there would be a compensatory upregulation of β-adrenoceptors. Despite inconsistent findings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ECT) decrease β-adrenoceptor density in the rat forebrain. This led to the theory that β-adrenoceptor downregulation was required for clinical antidepressant efficacy. However, some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density. Another adrenoceptor implicated in depression is the presynaptic α₂-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of α₂-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of α₂-adrenoceptor activity) although platelet studies proved inconsistent. This supersensitivity of α₂-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression. In addition to enhancing NA release, α₂-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of α₂-adrenoceptors present on 5-HT nerve terminals.

Serotonergic

5-Hydroxytryptamine (5-HT or serotonin) is an important cell-to-cell signaling molecule found in all animal phyla. In mammals, substantial concentrations of 5-HT are present in the central and peripheral nervous systems, gastrointestinal tract and cardiovascular system. 5-HT is capable of exerting a wide variety of biological effects by interacting with specific membrane-bound receptors, and at least 13 distinct 5-HT receptor subtypes have been cloned and characterized. With the exception of the 5-HT₃ receptor subtype, which is a transmitter-gated ion channel, 5-HT receptors are members of the 7-transmembrane G protein-coupled receptor superfamily. In humans, the serotonergic system is implicated in various physiological processes such as sleep-wake cycles, maintenance of mood, control of food intake and regulation of blood pressure. In accordance with this, drugs that affect 5-HT-containing cells or 5-HT receptors are effective treatments for numerous indications, including depression, anxiety, obesity, nausea, and migraine. Because serotonin and the related

hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...

melatonin Melatonin, an indoleamine, is a natural compound produced by various organisms, including bacteria and eukaryotes. Its discovery in 1958 by Aaron B. Lerner and colleagues stemmed from the isolation of a substance from the pineal gland of cow ...

are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. This is accounted for by the lethargic feel that some SSRIs can produce, although TCAs and antipsychotics can also cause lethargy albeit through different mechanisms. Appetite suppression is related to 5-HT_2C receptor activation as for example was reported for PAL-287 recently. Activation of the 5-HT_2C receptor has been described as "panicogen" by users of ligands for this receptor (e.g., mCPP). Antagonism of the 5-HT_2C receptor is known to augment dopaminergic output. Although SSRIs with 5-HT_2C antagonist actions were recommended for the treatment of depression, 5-HT_2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless, the 5-HT_2C is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonized. Azapirone-type drugs (e.g.,

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 ...

), which act as 5-HT_1A receptor agonists and partial agonists have been developed as anxiolytic agents that are not associated with the dependence and side-effect profile of the benzodiazepines. The hippocampal neurogenesis produced by various types of antidepressants, likewise, is thought to be mediated by 5-HT_1A receptors. Systemic administration of a 5-HT_1A agonist also induces

growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...

and

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...

(ACTH) release through actions in the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

Current antidepressants

Most antidepressants on the market today target the monoaminergic system.

SSRIs

The most commonly prescribed class of antidepressants in the USA today are the

s (SSRIs). These drugs inhibit the uptake of the neurotransmitter 5-HT by blocking the SERT, thus increasing its synaptic concentration, and have shown to be efficacious in the treatment of depression, however

sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction ...

and

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

are two very common side-effects that result in discontinuation of treatment. Although many patients benefit from SSRIs, it is estimated that approximately 50% of depressive individuals do not respond adequately to these agents. Even in remitters, a relapse is often observed following drug discontinuation. The major limitation of SSRIs concerns their delay of action. It appears that the clinical efficacy of SSRIs becomes evident only after a few weeks. SSRIs can be combined with a host of other drugs including

bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

, α₂ adrenergic antagonists (e.g., yohimbine) as well as some of the atypical antipsychotics. The augmentation agents are said to behave synergistically with the SSRI although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. It is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. In addition, single compounds are more likely to be approved by the FDA than are drugs that contain greater than one pharmaceutical ingredient (polytherapies). A number of SRIs were under development that had auxiliary interactions with other receptors. Particularly notable were agents behaving as co-joint SSRIs with additional antagonist activity at 5-HT_1A receptors. 5-HT_1A receptors are located presynaptically as well as post-synaptically. It is the presynaptic receptors that are believed to function as

autoreceptors An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the aut ...

(cf. studies done with

pindolol Pindolol, sold under the brand name Visken among others, is a non-selective beta blocker which is used in the treatment of hypertension.Drugs.coInternational brand names for pindolol Page accessed Sept 4, 2015 It is also an antagonist of the se ...

). These agents were shown to elicit a more robust augmentation in the % elevation of extracellular 5-HT relative to baseline than was the case for SSRIs as measured by in vivo microdialysis.

NRIs

Norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...

s (NRIs) such as

reboxetine Reboxetine, sold under the brand name Edronax among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication marketed as an antidepressant by Pfizer for use in the treatment of major depressive disorder, although it has also be ...

prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. In addition,

atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...

has found use in the treatment of

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by symptoms of inattention, hyperactivity, impulsivity, and emotional dysregulation that are excessive and pervasive, impairing in multiple ...

as a non-addictive alternative to

Ritalin Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken by mouth ...

. The chemical structure of atomoxetine is closely related to that of

(an SSRI) and also

duloxetine Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive–compulsive disorder, fibromyalgia, neuropathic pain, central sensitization, and ...

(an SNRI).

NDRIs

Bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

is a commonly prescribed antidepressant that acts as a

norepinephrine–dopamine reuptake inhibitor A norepinephrine–dopamine reuptake inhibitor (NDRI) is a type of drug that inhibits the reuptake of the monoamine neurotransmitters norepinephrine and dopamine and thereby increases extracellular levels of these neurotransmitters and nor ...

(NDRI). It prevents the reuptake of NA and DA (weakly) by blocking the corresponding transporters, leading to increased noradrenergic and dopaminergic neurotransmission. This drug does not cause sexual dysfunction or weight gain like the SSRIs but has a higher incidence of nausea.

Methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...

is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Methylphenidate is used in the treatment of

; its use in treating depression is not known to have been reported, but it is presumed owing to its psychomotor activating effects and it functioning as a

positive reinforcer In Behaviorism, behavioral psychology, reinforcement refers to consequences that increase the likelihood of an organism's future behavior, typically in the presence of a particular ''Antecedent (behavioral psychology), antecedent stimulus''. Fo ...

. There are also reports of methylphenidate being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter.

SNRIs

Serotonin–norepinephrine reuptake inhibitor Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopaus ...

s (SNRIs) such as

(Effexor), its active metabolite desvenlafaxine (Pristiq), and

(Cymbalta) prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the SSRIs.

is the name of an SNRI based appetite suppressant with use in the treatment of

. This was explored in the treatment of depression, but was shown not to be effective. Both

sibutramine Sibutramine, formerly sold under the brand name Meridia among others, is an appetite suppressant which has been discontinued in many countries. It works as a serotonin–norepinephrine reuptake inhibitor (SNRI) similar to certain antidepressant ...

and

are

-based. At high doses, both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA reuptake is unlikely to be relevant at clinically approved doses.

MAOIs

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 ...

s (MAOIs) were the first antidepressants to be introduced. They were discovered entirely by serendipity. Iproniazide (the first MAOI) was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity.

Isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. F ...

also displayed activity as an antidepressant, even though it is not a MAOI. This led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the MAOI activity could be a secondary side-effect. However, with the discovery of tranylcypromine (the first non-hydrazine MAOI), it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents. Etryptamine is another example of a non-hydrazine MAOI that was introduced. The MAOIs work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. The fact that they are more efficacious than the newer generation antidepressants is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters. The problem with MAOIs is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. Although selective MAOIs can reduce, if not eliminate these risks, their efficacy tends to be lower. MAOIs may preferentially treat TCA-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. This may be a function of the ability of MAOIs to increase synaptic levels of DA in addition to 5-HT and NE. The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia (FM) or chronic fatigue syndrome (CFS). Although a substantial number of MAOIs were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. The reason for this is that they were

hepatotoxic 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 ...

and could cause

jaundice Jaundice, also known as icterus, is a yellowish or, less frequently, 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 ...

TCAs

The first

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),

imipramine Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth. Common s ...

(Tofranil), was derived from the

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

drug

chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar d ...

, which was developed as a useful

antihistaminergic 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 r ...

agent with possible use as a hypnotic sedative. Imipramine is an iminodibenzyl (

dibenzazepine Dibenzazepine (iminostilbene) is a chemical compound with two benzene functional group, rings fused to an azepine ring (chemistry), ring. Many pharmaceuticals, such as carbamazepine, oxcarbazepine, and depramine, are based on a dibenzazepine struc ...

). The TCAs such as imipramine and amitriptyline typically prevent the reuptake of serotonin or norepinephine. It is the histaminiergic (H₁), muscarinic acetylcholinergic (M₁), and alpha adrenergic (α₁) blockade that is responsible for the side-effects of TCAs. These include somnolence and lethargy, anticholinergic side-effects, and hypotension. Due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the TCAs could be lethal. TCAs were, for 25 years, the leading cause of death from overdoses in many countries. Patients being treated with antidepressants are prone to attempt suicide and one method they use is to take an overdose of their medications. Another example of a TCA is

amineptine Amineptine, formerly sold under the brand name Survector among others, is an atypical antidepressant of the tricyclic antidepressant (TCA) family. It acts as a selective and mixed dopamine reuptake inhibitor and releasing agent, and to a le ...

which is the only one believed to function as a DRI. It is no longer available.

Failure of SNDRIs for depression

SNDRIs have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in

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. In addition, the augmentation of a

(SSRI) or serotonin-norepinephrine reuptake inhibitor with

lisdexamfetamine Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used as a treatment for attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge ...

, a

norepinephrine–dopamine releasing agent A norepinephrine–dopamine releasing agent (NDRA) is a type of drug which induces the synapse, release of norepinephrine (and epinephrine) and dopamine in the body and/or brain. Many of these are amphetamine type stimulants. Examples Examples ...

, recently failed to separate from

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 phase III clinical trials of individuals with

treatment-resistant depression Treatment-resistant depression (TRD) is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inad ...

, and clinical development was subsequently discontinued. These occurrences have shed doubt on the potential benefit of

augmentation of conventional serotonergic and

antidepressant therapy. As such, skepticism has been cast on the promise of the remaining SNDRIs that are still being trialed, such as

ansofaxine Toludesvenlafaxine, also formerly known as ansofaxine and sold under the brand name Ruoxinlin, is an antidepressant which is approved for the treatment of major depressive disorder in China. It is also under development for use in other countries ...

(currently in phase II trials), in the treatment of depression. Despite being a weak SNDRI, nefazodone has been successful in treating major depressive disorder.

References

External links

* {{DEFAULTSORT:Serotonin-norepinephrine-dopamine reuptake inhibitor

Indications

Depression

Pharmacotherapy

Applications other than depression

List of SNDRIs

Approved pharmaceuticals

Coincidental

Undergoing clinical trials

Failed clinical trials

Designer drugs A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug, while avoiding classification as illegal and/or detection in standard drug tests. ...

Research compounds (no record of having been taken by humans)

Toxicological

Addiction

Relation to Cocaine

Legality

Self-Administration of Drugs

Role of monoamine neurotransmitters

Monoamine hypothesis

Dopaminergic

Noradrenergic

Serotonergic

Current antidepressants

SSRIs

NRIs

NDRIs

SNRIs

MAOIs

TCAs

Failure of SNDRIs for depression

See also

References

External links