Serotonin–norepinephrine–dopamine reuptake inhibitor

{{Short description|Class of drugs}} {{Multiple issues| {{More footnotes needed|date=January 2014}} {{Technical|article is full of jargon abbreviations that make it difficult to read and understand|date=August 2018}} }}

A '''serotonin–norepinephrine–dopamine reuptake inhibitor''' ('''SNDRI'''), also known as a '''triple reuptake inhibitor''' ('''TRI''' or '''TUI'''), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. Monoamine structures (including neurotransmitters) contain a singular amino group (mono) linked to an aromatic ring by a chain of two carbons.<ref>{{Cite journal |last1=Jiang |first1=Yao |last2=Zou |first2=Di |last3=Li |first3=Yumeng |last4=Gu |first4=Simeng |last5=Dong |first5=Jie |last6=Ma |first6=Xianjun |last7=Xu |first7=Shijun |last8=Wang |first8=Fushun |last9=Huang |first9=Jason H. |date=2022-09-28 |title=Monoamine Neurotransmitters Control Basic Emotions and Affect Major Depressive Disorders |journal=Pharmaceuticals |language=en |volume=15 |issue=10 |page=1203 |doi=10.3390/ph15101203 |doi-access=free |pmid=36297314 |pmc=9611768 |issn=1424-8247 }}</ref><ref>{{Cite journal |last1=Rosenberg |first1=Marisa B. |last2=Carroll |first2=F. Ivy |last3=Negus |first3=S. Stevens |date=March 2013 |title=Effects of Monoamine Reuptake Inhibitors in Assays of Acute Pain-Stimulated and Pain-Depressed Behavior in Rats |journal=The Journal of Pain |language=en |volume=14 |issue=3 |pages=246–259 |doi=10.1016/j.jpain.2012.11.006 |pmid=23332494 |pmc=3743421 |issn=1526-5900 }}</ref> SNDRIs prevent reuptake of these monoamine neurotransmitters through the simultaneous inhibition of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively, increasing their extracellular concentrations and, therefore, resulting in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention-deficit hyperactivity disorder (ADHD), and chronic pain.<ref name="Sharma 2385–2406">{{Cite journal |last1=Sharma |first1=Horrick |last2=Santra |first2=Soumava |last3=Dutta |first3=Aloke |date=November 2015 |title=Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope? |journal=Future Medicinal Chemistry |language=en |volume=7 |issue=17 |pages=2385–2406 |doi=10.4155/fmc.15.134 |pmid=26619226 |pmc=4976848 |issn=1756-8919 }}</ref> 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 inhibitors (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.<ref name="Sharma 2385–2406"/>

However, increased side effects and abuse potential are concerns when using these agents relative to their SSRI and SNRI counterparts. Additionally, SNDRIs include the naturally occurring drug cocaine, a widely used recreational and often illegal drug for the euphoric effects it produces.<ref name="pmc.ncbi.nlm.nih.gov">{{Cite journal |title= Short- and Long-Term Effects of Cocaine on Enteric Neuronal Functions| date=2023 | pmc=9954635 | last1=Elfers | first1=K. | last2=Menne | first2=L. | last3=Colnaghi | first3=L. | last4=Hoppe | first4=S. | last5=Mazzuoli-Weber | first5=G. | journal=Cells | volume=12 | issue=4 | page=577 | doi=10.3390/cells12040577 | doi-access=free | pmid=36831246 }}</ref> Ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse.<ref>{{Cite journal |title= Phencyclidine Intoxication and Adverse Effects: A Clinical and Pharmacological Review of an Illicit Drug| date=2007 | pmc=2859735 | last1=Bey | first1=T. | last2=Patel | first2=A. | journal=The California Journal of Emergency Medicine | volume=8 | issue=1 | pages=9–14 | pmid=20440387 }}</ref> To a lesser extent, MDMA also acts as a SNDRI.<ref name="DunlapAndrewsOlson2018">{{cite journal | vauthors = Dunlap LE, Andrews AM, Olson DE | title = Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine | journal = ACS Chem Neurosci | volume = 9 | issue = 10 | pages = 2408–2427 | date = October 2018 | pmid = 30001118 | pmc = 6197894 | doi = 10.1021/acschemneuro.8b00155 | url = https://shaunlacob.com/wp-content/uploads/2020/12/DC-MDMA.pdf}}</ref><ref name="DochertyAlsufyani2021">{{cite journal | vauthors = Docherty JR, Alsufyani HA | title = Pharmacology of Drugs Used as Stimulants | journal = J Clin Pharmacol | volume = 61 | issue = Suppl 2 | pages = S53–S69 | date = August 2021 | pmid = 34396557 | doi = 10.1002/jcph.1918 | url = | quote = Receptor-mediated actions of amphetamine and other amphetamine derivatives [...] may involve trace amine-associated receptors (TAARs) at which amphetamine and MDMA also have significant potency.85–87 Many stimulants have potency at the rat TAAR1 in the micromolar range but tend to be about 5 to 10 times less potent at the human TAAR1, [...] Activation of the TAAR1 receptor causes inhibition of dopaminergic transmission in the mesocorticolimbic system, and TAAR1 agonists attenuated psychostimulant abuse-related behaviors.89 It is likely that TAARs contribute to the actions of specific stimulants to modulate dopaminergic, serotonergic, and glutamate signaling,90 and drugs acting on the TAAR1 may have therapeutic potential.91 In the periphery, stimulants such as MDMA and cathinone produce vasoconstriction, part of which may involve TAARs, although only relatively high concentrations produced vascular contractions resistant to a cocktail of monoamine antagonist drugs.86 | doi-access = free }}</ref><ref name="RothmanBaumann2003">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Monoamine transporters and psychostimulant drugs | journal = European Journal of Pharmacology | volume = 479 | issue = 1–3 | pages = 23–40 | date = October 2003 | pmid = 14612135 | doi = 10.1016/j.ejphar.2003.08.054 }}</ref><ref name="RothmanBaumann2006">{{cite journal | vauthors = Rothman RB, Baumann MH | title = Therapeutic potential of monoamine transporter substrates | journal = Current Topics in Medicinal Chemistry | volume = 6 | issue = 17 | pages = 1845–1859 | date = 2006 | pmid = 17017961 | doi = 10.2174/156802606778249766 }}</ref><ref name="SetolaHufeisenGrande-Allen2003">{{cite journal | vauthors = Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL | title = 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro | journal = Molecular Pharmacology | volume = 63 | issue = 6 | pages = 1223–1229 | date = June 2003 | pmid = 12761331 | doi = 10.1124/mol.63.6.1223 | s2cid = 839426 }}</ref>

==Indications==

===Depression=== Major depressive disorder (MDD) is the foremost reason supporting the need for development of an SNDRI.<ref name=Millan2>{{Cite journal|pmid=19110199|pmc=5084256|year=2009|last1=Millan|first1=MJ|title=Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: Novel concepts, new drugs|volume=6|issue=1|pages=53–77|doi=10.1016/j.nurt.2008.10.039|journal=Neurotherapeutics}}</ref><ref name=Kulkarni>{{Cite journal|pmid=19426122|year=2009|last1=Kulkarni|first1=SK|last2=Dhir|first2=A|title=Current investigational drugs for major depression|volume=18|issue=6|pages=767–88|doi=10.1517/13543780902880850|journal=Expert Opinion on Investigational Drugs|s2cid=71382550}}</ref><ref name=Guiard>{{Cite journal|pmid=19702555|year=2009|last1=Guiard|first1=BP|last2=El Mansari|first2=M|last3=Blier|first3=P|title=Prospect of a dopamine contribution in the next generation of antidepressant drugs: The triple reuptake inhibitors|volume=10|issue=11|pages=1069–84|journal=Current Drug Targets|doi=10.2174/138945009789735156}}</ref><ref name=Marks>{{Cite journal|pmid=19587855|year=2008|last1=Marks|first1=DM|last2=Pae|first2=CU|last3=Patkar|first3=AA|title=Triple reuptake inhibitors: The next generation of antidepressants|volume=6|issue=4|pages=338–43|doi=10.2174/157015908787386078|pmc=2701280|journal=Current Neuropharmacology}}</ref><ref name=Chen>{{Cite journal|pmid=17714023|year=2007|last1=Chen|first1=Z|last2=Skolnick|first2=P|title=Triple uptake inhibitors: Therapeutic potential in depression and beyond|volume=16|issue=9|pages=1365–77|doi=10.1517/13543784.16.9.1365|journal=Expert Opinion on Investigational Drugs|s2cid=20271918}}</ref><ref name=Millan1>{{Cite journal|pmid=16522330|year=2006|last1=Millan|first1=MJ|title=Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application|volume=110|issue=2|pages=135–370|doi=10.1016/j.pharmthera.2005.11.006|journal=Pharmacology & Therapeutics}}</ref><ref name=Perona>{{Cite journal| pmid=18690111|year=2008|last1=Perona|first1=MT|last2=Waters|first2=S|last3=Hall|first3=FS|last4=Sora|first4=I|last5=Lesch|first5=KP|last6=Murphy|first6=DL|last7=Caron|first7=M|last8=Uhl|first8=GR|title=Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: Prominent effects of dopamine transporter deletions|volume=19|issue=5–6|pages=566–74|doi=10.1097/FBP.0b013e32830cd80f|pmc=2644662|journal=Behavioural Pharmacology}}</ref><ref name=Chen2>{{Cite journal|pmid=18311656|year=2008|last1=Chen|first1=Z|last2=Yang|first2=J|last3=Tobak|first3=A|title=Designing new treatments for depression and anxiety|volume=11|issue=3|pages=189–97|journal=IDrugs: The Investigational Drugs Journal}}</ref><ref name=Perovic>{{Cite journal|pmid=20856599|year=2010|last1=Perović|first1=B|last2=Jovanović|first2=M|last3=Miljković|first3=B|last4=Vezmar|first4=S|title=Getting the balance right: Established and emerging therapies for major depressive disorders|volume=6|pages=343–64|pmc=2938284|journal=Neuropsychiatric Disease and Treatment|doi=10.2147/ndt.s10485 |doi-access=free }}</ref><ref name="Emerging">{{Cite journal|pmid=19501541|year=2009|last1=Rakofsky|first1=JJ|last2=Holtzheimer|first2=PE|last3=Nemeroff|first3=CB|title=Emerging targets for antidepressant therapies|volume=13|issue=3|pages=291–302|doi=10.1016/j.cbpa.2009.04.617|journal=Current Opinion in Chemical Biology|pmc=4410714}}</ref> According to the World Health Organization, depression is the leading cause of disability and the 4th leading contributor to the global burden of disease in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of DALYs.<ref>{{cite web|url=https://www.who.int/mental_health/management/depression/definition/en/|title=Depression|website=World Health Organization|publisher=WHO|archive-url=https://web.archive.org/web/20100717040203/http://www.who.int/mental_health/management/depression/definition/en/|archive-date=2010-07-17}}</ref>

About 5% of the population is estimated to be affected by depression,<ref>{{Cite web |title=Depressive disorder (depression) |url=https://www.who.int/news-room/fact-sheets/detail/depression |access-date=2025-03-08 |website=www.who.int |language=en}}</ref> and in 2019, another 0.53% was affected by bipolar disorder.<ref>{{Cite web |title=Bipolar disorder |url=https://www.who.int/news-room/fact-sheets/detail/bipolar-disorder |access-date=2025-03-08 |website=www.who.int |language=en}}</ref> 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 or hypersomnia), 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.<ref>{{Cite web |title=Suicide worldwide in 2019 |url=https://www.who.int/publications/i/item/9789240026643 |access-date=2025-03-03 |website=www.who.int |language=en}}</ref> Individual patients present differing subsets of symptoms, which may change over the course of the disease highlighting its multifaceted and heterogeneous nature.<ref name="Millan1" /> Depression is often highly comorbid with other diseases, e.g. cardiovascular disease (myocardial infarction,<ref>{{Cite journal |last1=Larsen |first1=KK |last2=Vestergaard |first2=M |last3=Søndergaard |first3=J |last4=Christensen |first4=B |year=2012 |title=Screening for depression in patients with myocardial infarction by general practitioners |journal=European Journal of Preventive Cardiology |volume=20 |issue=5 |pages=800–6 |doi=10.1177/2047487312444994 |pmid=22496274 |s2cid=24986156 |doi-access=free}}</ref> stroke),<ref name="Saravane">{{Cite journal |last1=Saravane |first1=D |last2=Feve |first2=B |last3=Frances |first3=Y |last4=Corruble |first4=E |last5=Lancon |first5=C |last6=Chanson |first6=P |last7=Maison |first7=P |last8=Terra |first8=JL |last9=Azorin |first9=JM |author10=avec le soutien institutionnel du laboratoire Lilly |display-authors=8 |year=2009 |title=Drawing up guidelines for the attendance of physical health of patients with severe mental illness |journal=L'Encéphale |volume=35 |issue=4 |pages=330–9 |doi=10.1016/j.encep.2008.10.014 |pmid=19748369}}</ref> diabetes,<ref>{{Cite journal |last1=Rustad |first1=JK |last2=Musselman |first2=DL |last3=Nemeroff |first3=CB |year=2011 |title=The relationship of depression and diabetes: Pathophysiological and treatment implications |journal=Psychoneuroendocrinology |volume=36 |issue=9 |pages=1276–86 |doi=10.1016/j.psyneuen.2011.03.005 |pmid=21474250 |s2cid=32439196}}</ref> and cancer.<ref>{{Cite journal |last1=Li |first1=M |last2=Fitzgerald |first2=P |last3=Rodin |first3=G |year=2012 |title=Evidence-based treatment of depression in patients with cancer |journal=Journal of Clinical Oncology |volume=30 |issue=11 |pages=1187–96 |doi=10.1200/JCO.2011.39.7372 |pmid=22412144}}</ref> Depressed subjects are prone to smoking,<ref>{{Cite journal |last1=Tsuang |first1=MT |last2=Francis |first2=T |last3=Minor |first3=K |last4=Thomas |first4=A |last5=Stone |first5=WS |year=2012 |title=Genetics of smoking and depression |journal=Human Genetics |volume=131 |issue=6 |pages=905–15 |doi=10.1007/s00439-012-1170-6 |pmid=22526528 |s2cid=11532256}}</ref> substance abuse,<ref>{{Cite journal |last1=Davis |first1=LL |last2=Wisniewski |first2=SR |last3=Howland |first3=RH |last4=Trivedi |first4=MH |last5=Husain |first5=MM |last6=Fava |first6=M |last7=McGrath |first7=PJ |last8=Balasubramani |first8=GK |last9=Warden |first9=D |last10=Rush |first10=A. John |display-authors=8 |year=2010 |title=Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR*D level one treatment outcomes |journal=Drug and Alcohol Dependence |volume=107 |issue=2–3 |pages=161–70 |doi=10.1016/j.drugalcdep.2009.10.003 |pmid=19945804 |url=http://scholarbank.nus.edu.sg/handle/10635/110527 }}</ref> eating disorders, obesity, high blood pressure, pathological gambling and internet addiction,<ref>{{Cite journal |last1=Barrault |first1=S |last2=Varescon |first2=I |year=2012 |title=Psychopathology in online pathological gamblers: A preliminary study |journal=L'Encéphale |volume=38 |issue=2 |pages=156–63 |doi=10.1016/j.encep.2011.01.009 |pmid=22516274}}</ref> and on average have a 15 to 30 year shorter lifetime compared with the general population.<ref name="Saravane" />

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%.<ref>{{Cite web |title=Major Depression and Genetics |url=https://med.stanford.edu/depressiongenetics/mddandgenes.html |access-date=2025-03-09 |website=Genetics of Brain Function |language=en-US}}</ref> 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.<ref>{{Cite journal |last=Lee |first=Benjamin |date=2023 |title=National, State-Level, and County-Level Prevalence Estimates of Adults Aged ≥18 Years Self-Reporting a Lifetime Diagnosis of Depression — United States, 2020 |url=https://www.cdc.gov/mmwr/volumes/72/wr/mm7224a1.htm |journal=MMWR. Morbidity and Mortality Weekly Report |language=en-us |volume=72 |issue=24 |pages=644–650 |doi=10.15585/mmwr.mm7224a1 |pmid=37318995 |pmc=10328468 |issn=0149-2195}}</ref> 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.<ref>{{Cite journal |last1=Korczak |first1=Daphne J. |last2=Westwell-Roper |first2=Clara |last3=Sassi |first3=Roberto |date=2023-05-28 |title=Diagnosis and management of depression in adolescents |journal=Canadian Medical Association Journal |language=en |volume=195 |issue=21 |pages=E739–E746 |doi=10.1503/cmaj.220966 |pmid=37247881 |pmc=10228578 |issn=0820-3946 }}</ref>

===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,<ref name=Belmaker>{{Cite journal|pmid=18704023|year=2008|last1=Belmaker|first1=RH|title=The future of depression psychopharmacology|volume=13|issue=8|pages=682–7|journal=CNS Spectrums|doi=10.1017/S1092852900013766|s2cid=33347610}}</ref> 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''). 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.<ref name=Millan1/>

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, the induction of neurogenesis, and modifications in synaptic architecture and signaling.<ref name=Millan1/>

Depression has been associated with impaired neurotransmission of serotonergic (5-HT), noradrenergic (NE), and dopaminergic (DA) pathways, although most pharmacologic treatment strategies directly enhance only 5-HT and NE neurotransmission.<ref name=Marks/> 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, concentration, and pleasure.<ref>{{Cite journal|pmid=17339521|year=2007|last1=Dunlop|first1=BW|last2=Nemeroff|first2=CB|title=The role of dopamine in the pathophysiology of depression|volume=64|issue=3 |pages=327–37|doi=10.1001/archpsyc.64.3.327|journal=Archives of General Psychiatry|s2cid=26550661 }}</ref>

Preclinical and clinical research indicates that drugs inhibiting the reuptake of all three of these neurotransmitters can produce a more rapid onset of action and greater efficacy than traditional antidepressants.<ref name=Chen2/>

DA may promote neurotrophic processes in the adult hippocampus, as 5-HT and NA do. It is thus possible that the stimulation of multiple signalling pathways resulting from the elevation of all three monoamines may account, in part, for an accelerated and/or greater antidepressant response.<ref name=Guiard/>

Dense connections exist between monoaminergic neurons. Dopaminergic neurotransmission regulates the activity of 5-HT and NE in the dorsal raphe nucleus (DR) and locus coeruleus (LC), respectively. In turn, the ventral tegmental area (VTA) is sensitive to 5-HT and NE release.<ref name=Guiard/>

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 transporters (OCT) and the plasma membrane monoamine transporter (PMAT).<ref>{{Cite journal|pmid=19022290|year=2009|last1=Daws|first1=LC|title=Unfaithful neurotransmitter transporters: Focus on serotonin uptake and implications for antidepressant efficacy|volume=121|issue=1|pages=89–99|doi=10.1016/j.pharmthera.2008.10.004|pmc=2739988|journal=Pharmacology & Therapeutics}}</ref>

To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. The effects of DAT KO in animal models of depression 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.<ref name=Perona/>

The SSRIs 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 (and neurological) 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 state.

Most common CNS disorders are highly polygenic 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.<ref name=Musk>{{Cite journal|pmid=20704963|year=2004|last1=Musk|first1=P|title=Magic shotgun methods for developing drugs for CNS disorders|volume=4|issue=23|pages=299–302|journal=Discovery Medicine}}</ref>

Clozapine 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. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious.<ref name=Musk/><ref name=Roth>{{Cite journal|pmid=15060530|year=2004|author1-link=Bryan Roth|last1=Roth|first1=BL|last2=Sheffler|first2=DJ|last3=Kroeze|first3=WK|title=Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia|volume=3|issue=4|pages=353–9|doi=10.1038/nrd1346|journal=Nature Reviews Drug Discovery|s2cid=20913769|url=https://cdr.lib.unc.edu/concern/articles/3f4627486}}</ref><ref>{{Cite journal|pmid=19110195|pmc=5084252|year=2009|last1=Buccafusco|first1=JJ|title=Multifunctional receptor-directed drugs for disorders of the central nervous system|volume=6|issue=1|pages=4–13|doi=10.1016/j.nurt.2008.10.031|journal=Neurotherapeutics}}</ref><ref name=Enna>{{Cite journal|pmid=19182069|year=2009|last1=Enna|first1=SJ|last2=Williams|first2=M|title=Challenges in the search for drugs to treat central nervous system disorders|volume=329|issue=2|pages=404–11|doi=10.1124/jpet.108.143420|journal=The Journal of Pharmacology and Experimental Therapeutics|s2cid=11395584}}</ref><ref>{{Cite journal|pmid=16222266|year=2005|last1=Frantz|first1=S|title=Drug discovery: Playing dirty|volume=437|issue=7061|pages=942–3|doi=10.1038/437942a|journal=Nature|bibcode=2005Natur.437..942F|s2cid=4414021|doi-access=free}}</ref><ref>{{Cite journal|pmid=19907483|year=2009|last1=Hopkins|first1=AL|title=Drug discovery: Predicting promiscuity|volume=462|issue=7270|pages=167–8|doi=10.1038/462167a|journal=Nature|bibcode=2009Natur.462..167H|s2cid=4362713}}</ref><ref>{{Cite journal|pmid=16442279|year=2006|last1=Hopkins|first1=AL|last2=Mason|first2=JS|last3=Overington|first3=JP|title=Can we rationally design promiscuous drugs?|volume=16|issue=1|pages=127–36|doi=10.1016/j.sbi.2006.01.013|journal=Current Opinion in Structural Biology}}</ref><ref>{{Cite journal|pmid=18936753|year=2008|last1=Hopkins|first1=AL|title=Network pharmacology: The next paradigm in drug discovery|volume=4|issue=11|pages=682–90|doi=10.1038/nchembio.118|journal=Nature Chemical Biology}}</ref>

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.<ref>{{Cite journal|pmid=16001091|year=2004|last1=Jain|first1=R|title=Single-action versus dual-action antidepressants|volume=6|issue=Suppl 1|pages=7–11|pmc=486947|journal=Primary Care Companion to the Journal of Clinical Psychiatry}}</ref> 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 (cf. DOV 102,677)<ref name="DOV 102,677">{{Cite journal|pmid=22150508|year=2012|last1=Yang|first1=AR|last2=Yi|first2=HS|last3=Warnock|first3=KT|last4=Mamczarz|first4=J|last5=June Jr|first5=HL|last6=Mallick|first6=N|last7=Krieter|first7=PA|last8=Tonelli|first8=L|last9=Skolnick|first9=P|last10=Basile|first10=Anthony S.|last11=June|first11=Harry L.|title=Effects of the Triple Monoamine Uptake Inhibitor DOV 102,677 on Alcohol-Motivated Responding and Antidepressant Activity in Alcohol-Preferring (P) Rats|volume=36|issue=5|pages=863–73|doi=10.1111/j.1530-0277.2011.01671.x |journal=Alcoholism: Clinical and Experimental Research|pmc=3464941|display-authors=8}}</ref><ref>{{Cite journal|pmid=17908267|year=2007|last1=McMillen|first1=BA|last2=Shank|first2=JE|last3=Jordan|first3=KB|last4=Williams|first4=HL|last5=Basile|first5=AS|title=Effect of DOV 102,677 on the volitional consumption of ethanol by Myers' high ethanol-preferring rat|volume=31|issue=11|pages=1866–71|doi=10.1111/j.1530-0277.2007.00513.x|journal=Alcoholism: Clinical and Experimental Research}}</ref> * Cocaine addiction (e.g., indatraline)<ref>{{Cite journal|doi=10.1016/j.neuropharm.2006.06.009|title=A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse: Effects in laboratory rat models relating to addiction|year=2006|last1=Gardner|first1=Eliot L.|last2=Liu |first2=Xinhe|last3=Paredes|first3=William|last4=Giordano|first4=Anthony|last5=Spector|first5=Jordan |last6=Lepore|first6=Marino|last7=Wu|first7=Kuo-Ming|last8=Froimowitz|first8=Mark |journal=Neuropharmacology|volume=51|issue=5|pages=993–1003|pmid=16901516|s2cid=20465584}}</ref> * Obesity (e.g., amitifadine, tesofensine)<ref>{{Cite journal|pmid=18089843|year=2008|last1=Tizzano|first1=JP|last2=Stribling|first2=DS|last3=Perez-Tilve|first3=D|last4=Strack|first4=A|last5=Frassetto|first5=A|last6=Chen|first6=RZ|last7=Fong|first7=TM|last8=Shearman|first8=L|last9=Krieter|first9=PA|last10=Tschop|first10=M. H.|last11=Skolnick|first11=P.|last12=Basile|first12=A. S.|title=The triple uptake inhibitor (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo3.1.0 hexane hydrochloride (DOV 21947) reduces body weight and plasma triglycerides in rodent models of diet-induced obesity|volume=324|issue=3|pages=1111–26 |doi=10.1124/jpet.107.133132|journal=The Journal of Pharmacology and Experimental Therapeutics |s2cid=12020136|display-authors=8}}</ref> * Attention-deficit hyperactivity disorder (ADHD) (cf. NS-2359, EB-1020)<ref>{{Cite journal |url=http://clinicaltrials.gov/ct2/show/NCT00467428|title=Efficacy and Safety of NS2359 in Adults with Attention Deficit Hyperactivity Disorder. A Randomised, Double-Blind, Placebo-Controlled Study |date=27 April 2007|website=ClinicalTrials.gov}}</ref> * Chronic pain (cf. bicifadine)<ref>{{Cite journal|pmid=17325229|year=2007|last1=Basile |first1=AS|last2=Janowsky|first2=A|last3=Golembiowska|first3=K|last4=Kowalska|first4=M|last5=Tam |first5=E|last6=Benveniste|first6=M|last7=Popik|first7=P|last8=Nikiforuk|first8=A|last9=Krawczyk |first9=M|last10=Nowak|first10=G.|last11=Krieter|first11=P. A.|last12=Lippa|first12=A. S. |last13=Skolnick|first13=P.|last14=Koustova|first14=E.|title=Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain|volume=321|issue=3 |pages=1208–25 |doi=10.1124/jpet.106.116483|journal=The Journal of Pharmacology and Experimental Therapeutics |s2cid=17215882|display-authors=8 }}</ref> * Parkinson's disease

==List of SNDRIs==

===Approved pharmaceuticals=== * Mazindol (Mazanor, Sanorex) — anorectic; k_i is 50 nM for SERT, 18 nM for NET, 45 nM for DAT<ref name="RankovicHargreaves2012">{{cite book|author1=Zoran Rankovic|author2=Richard Hargreaves |author3=Matilda Bingham |title=Drug Discovery for Psychiatric Disorders |year=2012|publisher=Royal Society of Chemistry|isbn=978-1-84973-365-6 |url=https://books.google.com/books?id=J4Mq3Lm1R7kC&pg=PA199 |pages=199–200}}</ref> * Nefazodone (Serzone, Nefadar, Dutonin) — antidepressant; non-selective; k_i is 200 nM at SERT, 360 nM at NET, 360 nM at DAT * Nefopam — analgesic, K_i SER/NE/DA = 29/33/531 nM)<ref>{{cite journal |author=Subbaiah, M. A. M. | journal=Journal of Medicinal Chemistry | title=Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges | volume=61 | issue=6 | pages=2133–65 | date=22 March 2018 | doi=10.1021/acs.jmedchem.6b01827| pmid=28731336 }}</ref> * Toludesvenlafaxine (Ansofaxine, LY03005/LPM570065).<ref>{{Cite journal| doi=10.1371/journal.pone.0091775| pmid=24614602| title=The Effects of LPM570065, a Novel Triple Reuptake Inhibitor, on Extracellular Serotonin, Dopamine and Norepinephrine Levels in Rats| journal=PLOS ONE| volume=9| issue=3| at=e91775| year=2014| vauthors=Zhang R, Li X, Shi Y, Shao Y, Sun K, Wang A, Sun F, Liu W, Wang D, Jin J, Li Y| pmc=3948889| bibcode=2014PLoSO...991775Z| doi-access=free}}</ref> Completed Phase 2 & 3 trials. FDA accepted NDA application.<ref>{{Cite web |title=NDA Filing for Luye Pharma's Antidepressant Drug LY03005 Accepted by the U.S. FDA — Press Releases — Luye Pharma Group |url=https://www.luye.cn/lvye_en/view.php?id=1809 |access-date=2022-06-11 |website=www.luye.cn}}</ref> Approved in China.<ref name="AdisInsight">{{Cite web|url=http://adisinsight.springer.com/drugs/800039935|title = Toludesvenlafaxine extended release - Luye Pharma | work = AdisInsight | publisher = Springer Nature Switzerland AG }}</ref>

Sibutramine (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.<ref name="RankovicHargreaves2012" /> However, it appears to act as a prodrug ''in vivo'' to metabolites 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%).<ref name="KimSong2009">{{cite journal|last1=Kim|first1=K A|last2=Song|first2=W K|last3=Park|first3=J Y|title=Association of CYP2B6, CYP3A5, and CYP2C19 Genetic Polymorphisms With Sibutramine Pharmacokinetics in Healthy Korean Subjects|journal=Clinical Pharmacology & Therapeutics|volume=86|issue=5|year=2009|pages=511–8|issn=0009-9236|doi=10.1038/clpt.2009.145|pmid=19693007|s2cid=24789264}}</ref><ref name="Hofbauer2004">{{cite book | last=Hofbauer | first=Karl | title=Pharmacotherapy of obesity: options and alternatives | publisher=CRC Press | location=Boca Raton, Fla | year=2004 | isbn=978-0-415-30321-7 }}</ref>[https://web.archive.org/web/20090710173718/http://www.fda.gov/downloads/Drugs/DrugSafety/PublicHealthAdvisories/UCM130745.pdf]

Venlafaxine (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.<ref name="JohnsonLi2013">{{cite book |author1=Douglas S. Johnson|author2=Jie Jack Li|title=The Art of Drug Synthesis|url=https://books.google.com/books?id=zvruBDAulWEC&pg=SA13-PA16|date=26 February 2013|publisher=John Wiley & Sons|isbn=978-1-118-67846-6 |pages=13–}}</ref> It may weakly inhibit the reuptake of dopamine at high doses.<ref name="CNSDrugs2001-Wellington">{{cite journal |vauthors=Wellington K, Perry CM | title = Venlafaxine extended-release: a review of its use in the management of major depression | journal = CNS Drugs | volume = 15 | issue = 8 | pages = 643–69 | year = 2001 | pmid = 11524036 | doi = 10.2165/00023210-200115080-00007 | s2cid = 26795121 }}</ref>

====Coincidental==== * Esketamine (Ketanest S) — anesthetic; ''S''-enantiomer of ketamine; weak SNDRI action likely contributes to effects and abuse potential * Ketamine (Ketalar) — anesthetic and dissociative drug of abuse; weak SNDRI action likely contributes to effects and abuse potential * Phencyclidine (Sernyl) — discontinued anesthetic and dissociative psychostimulant drug of abuse; SNDRI action likely contributes to effects and abuse potential<ref>{{Cite journal | pmid = 24251803| year = 2014| last1 = Ahmadi| first1 = A| title = Synthesis and pain perception of new analogues of phencyclidine in NMRI male mice| journal = Mini Reviews in Medicinal Chemistry| volume = 14| issue = 1| pages = 64–71| last2 = Khalili| first2 = M| last3 = Marami| first3 = S| last4 = Ghadiri| first4 = A| last5 = Nahri-Niknafs| first5 = B| doi=10.2174/1389557513666131119203551}}</ref> * Tripelennamine (Pyribenzamine) — antihistamine; weak SNDRI; sometimes abused for this reason<ref name="pmid7513381">{{cite journal |vauthors=Oishi R, Shishido S, Yamori M, Saeki K | title = Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 349 | issue = 2 | pages = 140–4 |date=February 1994 | pmid = 7513381 | doi = 10.1007/bf00169830| s2cid = 20653998 }}</ref><ref name="pmid8791174">{{cite journal|date=May 1996|title=Potentiation of L-dopa-induced behavioral excitement by histamine H1-receptor antagonists in mice|journal=Japanese Journal of Pharmacology|volume=71|issue=1|pages=81–4|doi=10.1254/jjp.71.81|pmid=8791174|vauthors=Sato T, Suemaru K, Matsunaga K, Hamaoka S, Gomita Y, Oishi R |doi-access=free}}</ref><ref name="pmid10420168">{{cite journal |vauthors=Yeh SY, Dersch C, Rothman R, Cadet JL | title = Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion of serotonin in rats | journal = Synapse | volume = 33 | issue = 3 | pages = 207–17 |date=September 1999 | pmid = 10420168 | doi = 10.1002/(SICI)1098-2396(19990901)33:3<207::AID-SYN5>3.0.CO;2-8 | s2cid = 16399789 | url = https://zenodo.org/record/1235502}}</ref><ref name="urlLet them eat Prozac: the unhealthy ... - Google Books">{{cite book | url = https://books.google.com/books?id=5w64WC_-jbMC&q=let%20them%20eat%20prozac&pg=RA1-PA295 | title = Let them eat Prozac: the unhealthy ... - Google Books | isbn = 978-0-8147-3669-2 | author1 = David Healy | date = January 2004 | publisher = NYU Press }}</ref> * Lamotrigine (Lamictal) — Anticonvulsant; weak SNDRI; IC₅₀ is 240μM (human platelets) / 474 μM (rat brain synaptosomes) for SERT, 239 μM for NET, 322 μM for DAT<ref>{{cite journal | vauthors = Southam E, Kirkby D, Higgins GA, Hagan RM | title = Lamotrigine inhibits monoamine uptake in vitro and modulates 5-hydroxytryptamine uptake in rats | journal = European Journal of Pharmacology | volume = 358 | issue = 1 | pages = 19–24 | date = September 1998 | pmid = 9809864 | doi = 10.1016/s0014-2999(98)00580-9 }}</ref> *Mepiprazole

===Undergoing clinical trials=== * [https://pubchem.ncbi.nlm.nih.gov/compound/49765424 BMS-866949] (made from diclofensine precursor) * Cendifensine (NOE-115)<ref>George GARIBALDI, WO2023161533 (to Noema Pharma AG).</ref><ref>Jean-Michel Adam, et al. WO2013160273 (to F Hoffmann La Roche AG).</ref><ref>Pravin Iyer, et al. WO2008074703 (to Roche Palo Alto LLC).</ref><ref name="Lucas, M. C. 2010">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.</ref><ref>{{cite web | url=https://noemapharma.com/pipeline/ | title=Noema Pharma | date=18 June 2021 }}</ref><ref>{{cite web | url=https://www.pharmaceutical-technology.com/data-insights/noe-115-noema-pharma-vasomotor-symptoms-of-menopause-hot-flashes-likelihood-of-approval/ | title=NOE-115 by Noema Pharma for Vasomotor Symptoms of Menopause (Hot Flashes): Likelihood of Approval | date=19 June 2024 }}</ref> * Centanafadine (EB-1020) — [http://euthymics.com/our-programs/adhd-and-eb-1020/ see here for details] {{Webarchive|url=https://web.archive.org/web/20120531034819/http://euthymics.com/our-programs/adhd-and-eb-1020/ |date=2012-05-31 }} 1 to 6 to 14 ratio for NDS. Completed Phase 3 trials for ADHD.<ref>{{Cite journal |date=2021-09-20 |title=A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel-group Trial Evaluating the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release Tablets in Adults With Attention-deficit/Hyperactivity Disorder |website=ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT03605836}}</ref> * OPC-64005 — In phase 2 trials (2022)<ref>{{Cite web |title=OPC 64005 — AdisInsight |url=https://adisinsight.springer.com/drugs/800045471 |access-date=2022-12-19 |website=adisinsight.springer.com}}</ref> * Lu AA37096 — [https://books.google.com/books?id=zqvVZOea2JAC&pg=PA206 see here] (SNDRI and 5-HT₆ modulator) * NS-2360 — principle metabolite of tesofensine *Pudafensine * Tesofensine (NS-2330) (2001) In trials for obesity.<ref>{{Cite web |title=Tesofensine — Saniona — AdisInsight |url=https://adisinsight.springer.com/drugs/800009013 |access-date=2022-06-11 |website=adisinsight.springer.com}}</ref> * SEP-432 was in stage 1 clinical trials but not yet in stage 2 or stage 3.<ref>{{cite journal |author=Sramek, J. J. |author2=Hardy, L. W. |author3=Bieck, P. |author4=Zamora, C. |author5=Versavel, M. |author6=Kharidia, J. |author7=Grinnell, T. |author8=Chen, Y. |author9=Sullivan, M. |author10=Ding, H. |author11=Cutler, N. R. | journal=CNS Neuroscience & Therapeutics | title=Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP-432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects | volume=22 | issue=5 | pages=404–412 | date= May 2016 | doi=10.1111/cns.12513 | pmid=26849844 | pmc=6492792 }}</ref> **IC50 values in patent for compound 225: hSERT=7nM, hNET= 23nM, hDAT=167nM.<ref>Liming Shao, et al. {{US patent|9868718}} (2018 to Sunovion Pharmaceuticals Inc).</ref> Although in the earlier patent (277 on scheme 36) IC50 values (nM) of hSERT=34, NET=13 & DAT=41.<ref>Liming Shao, 11 More », WO2007081857 (2007 to Sepracor Inc.).</ref> **SEP-432 has a chemistry that is related to sibutramine and bromadol & Levocabastine & 3',4'-dichloromeperidine. [[File:SEP-432.svg|thumb|center|class=skin-invert-image|SEP-432]]

===Failed clinical trials=== * Bicifadine (DOV-220,075) (1981)<ref>{{Cite journal|pmid=7241504|year=1981|last1=Epstein|first1=JW|last2=Brabander|first2=HJ|last3=Fanshawe|first3=WJ|last4=Hofmann|first4=CM|last5=McKenzie|first5=TC|last6=Safir|first6=SR|last7=Osterberg|first7=AC|last8=Cosulich|first8=DB|last9=Lovell|first9=FM|title=1-Aryl-3-azabicyclo3.1.0hexanes, a new series of nonnarcotic analgesic agents|volume=24|issue=5|pages=481–90|journal=Journal of Medicinal Chemistry|doi=10.1021/jm00137a002}}</ref><ref name="ol">{{Cite journal|doi=10.1021/ol061650w|title=Stereocontrolled Synthesis of Trisubstituted Cyclopropanes: Expedient, Atom-Economical, Asymmetric Syntheses of (+)-Bicifadine and DOV21947|year=2006|last1=Xu|first1=Feng|last2=Murry|first2=Jerry A.|last3=Simmons|first3=Bryon|last4=Corley|first4=Edward|last5=Fitch|first5=Kenneth|last6=Karady|first6=Sandor|last7=Tschaen|first7=David|journal=Organic Letters|volume=8|issue=17|pages=3885–8|pmid=16898842}}</ref> * Brasofensine (NS-2214, BMS-204,756) (1995)<ref name=brasofensinepatent>{{Cite patent|country=EP|number=0756596|title=Tropane-2-aldoxine derivatives as neurotransmitter reuptake inhibitors|pubdate=1997-02-05 |assign=Neurosearch AS|inventor1-last=Moldi |inventor1-first=Peter|inventor2-last=Watjen |inventor2-first=Frank|inventor3-last=Scheel-Krueger |inventor3-first=Jorgen}}</ref> * Diclofensine (Ro 8–4650) (1982)<ref>{{Cite journal|pmid=6979165|year=1982|last1=Keller|first1=HH |last2=Schaffner|first2=R|last3=Carruba|first3=MO|last4=Burkard|first4=WP|last5=Pieri|first5=M |last6=Bonetti|first6=EP|last7=Scherschlicht|first7=R|last8=Da Prada|first8=M|last9=Haefely|first9=WE |title=Diclofensine (Ro 8-4650)--a potent inhibitor of monoamine uptake: Biochemical and behavioural effects in comparison with nomifensine|volume=31|pages=249–63|journal=Advances in Biochemical Psychopharmacology}}</ref><ref>{{Cite journal|pmid=7107085|year=1982|last1=Omer|first1=LM|title=Pilot trials with diclofensine, a new psychoactive drug in depressed patients|volume=20|issue=7|pages=320–6 |journal=International Journal of Clinical Pharmacology, Therapy, and Toxicology}}</ref> * DOV-216,303 (2004)<ref>{{Cite journal |pmid=15545306 |year=2004 |vauthors=Beer B, Stark J, Krieter P, Czobor P, Beer G, Lippa A, Skolnick P |title=DOV 216,303, a "triple" reuptake inhibitor: Safety, tolerability, and pharmacokinetic profile |volume=44 |issue=12 |pages=1360–7 |doi=10.1177/0091270004269560 |journal=Journal of Clinical Pharmacology |s2cid=26944976}}</ref><ref>{{Cite journal |pmid=20934452 |year=2011 |vauthors=Prins J, Westphal KG, Korte-Bouws GA, Quinton MS, Schreiber R, Olivier B, Korte SM |title=The potential and limitations of DOV 216,303 as a triple reuptake inhibitor for the treatment of major depression: A microdialysis study in olfactory bulbectomized rats |volume=97 |issue=3 |pages=444–452 |doi=10.1016/j.pbb.2010.10.001 |journal=Pharmacology Biochemistry and Behavior |s2cid=20809504}}</ref> * EXP-561 (1965)<ref>{{US patent|3308160}}PHENYLBICYCLO[Z.Z.Z]OCTANE-L-AMINES AND SALTS THEREOF.</ref> 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".<ref>Fuller, R. W.; Snoddy, H. D.; Perry, K. W.; Bymaster, F. P.; Wong, D. T. (1978). "Studies on 4-(p-bromophenyl)-bicyclo (2,2,2) octan-1-amine as an inhibitor of uptake into serotonin neurones". Neuropharmacology 17 (10): 815–818. doi:10.1016/0028-3908(78)90069-2.</ref> * Liafensine (BMS-820,836) * NS-2359 (GSK-372,475)<ref>{{Cite journal|pmid=22048884|year=2012|vauthors=Learned S, Graff O, Roychowdhury S, Moate R, Krishnan KR, Archer G, Modell JG, Alexander R, Zamuner S, Lavergne A, Evoniuk G, Ratti E |title=Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: Two randomized, placebo- and active-controlled clinical trials |volume=26 |issue=5 |pages=653–662 |doi=10.1177/0269881111424931 |journal=Journal of Psychopharmacology|s2cid=9365152|display-authors=8}}</ref> * SEP-227,162 * SEP-228,425 * Amitifadine (DOV-21,947, EB-1010) (2003)<ref>{{Cite press release |title=EUTHYMICS REPORTS TOP-LINE RESULTS FROM TRIADE TRIAL OF AMITIFADINE FOR MAJOR DEPRESSIVE DISORDER |date=May 29, 2013 |publisher=Euthymics Bioscience, Inc. |url=http://euthymics.com/wp-content/uploads/2013/05/FINAL_Euthymics_TRIADE_Results_052913.pdf |access-date=2022-06-11 |archive-url=https://web.archive.org/web/20170924095823/http://euthymics.com/wp-content/uploads/2013/05/FINAL_Euthymics_TRIADE_Results_052913.pdf |archive-date=2017-09-24}}</ref> * Dasotraline (SEP-225,289)<ref>{{Cite web |date=2020-05-13 |title=Sunovion Discontinues Dasotraline Program |url=https://www.businesswire.com/news/home/20200513005363/en/Sunovion-Discontinues-Dasotraline-Program |access-date=2022-06-11 |website=www.businesswire.com}}</ref> * Lu AA34893 — [http://www.gipsicopatol.it/issues/early-view/Fornaro%202B.pdf see here]{{Dead link|date=October 2023 |bot=InternetArchiveBot |fix-attempted=yes }} (SNDRI and 5-HT_2A, α₁, and 5-HT₆ modulator)<ref>{{Cite journal |date=2010-09-28 |title=Efficacy and Safety of Lu AA34893 in Patients With Major Depressive Disorder |website=ClinicalTrials.gov |url=https://clinicaltrials.gov/ct2/show/NCT00766870 |last1=a/s |first1=H. Lundbeck }}</ref> * Tedatioxetine (Lu AA24530) — SNDRI and 5-HT_2C, 5-HT₃, 5-HT_2A, and α₁ modulator<ref>{{cite web |title=Development programme — Lundbeck |url=http://www.lundbeck.com/investor/pipeline/development_programs/default.asp?investors |access-date=2012-04-18 |archive-date=2011-09-29 |archive-url=https://web.archive.org/web/20110929184731/http://www.lundbeck.com/investor/pipeline/development_programs/default.asp?investors }}</ref><ref>{{cite web |title=Search of: Lu AA24530 — List Results |website=ClinicalTrials.gov |url=http://clinicaltrials.gov/ct2/results?term=Lu+AA24530}}</ref><ref>{{Cite web |title=Tedatioxetine — AdisInsight |url=https://adisinsight.springer.com/drugs/800023694 |access-date=2022-06-11 |website=adisinsight.springer.com}}</ref>

===Designer drugs=== * 3-Methyl-PCPy<ref>{{cite book |vauthors=Wallach J, Brandt SD |title=New Psychoactive Substances |year=2018 |chapter=Phencyclidine-Based New Psychoactive Substances |series=Handbook of Experimental Pharmacology |volume=252 |pages=261–303 |doi=10.1007/164_2018_124 |pmid=30105474 |isbn=978-3-030-10560-0}}</ref> * Naphyrone (O-2482, naphthylpyrovalerone, NRG-1) (2006)<ref name=Meltzer>{{Cite journal |pmid=16480278 |year=2006 |vauthors=Meltzer PC, Butler D, Deschamps JR, Madras BK |title=1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: A promising class of monoamine uptake inhibitors |volume=49 |issue=4 |pages=1420–32 |doi=10.1021/jm050797a |pmc=2602954 |journal=Journal of Medicinal Chemistry}}</ref><ref name=NRG1>{{cite news|author=Alan Travis |url=https://www.theguardian.com/politics/2010/apr/01/nrg1-legal-high-ban-considered |title=NRG-1 may be next legal high to face ban by ministers &#124; Politics |work=The Guardian |date=2010-04-01 |access-date=2010-04-03}}</ref><ref>{{Cite journal |pmid=22092008 |year=2012 |vauthors=Carroll FI, Lewin AH, Mascarella SW, Seltzman HH, Reddy PA |title=Designer drugs: A medicinal chemistry perspective |volume=1248 |issue=1 |pages=18–38 |doi=10.1111/j.1749-6632.2011.06199.x |journal=Annals of the New York Academy of Sciences |bibcode=2012NYASA1248...18C |s2cid=5108266}}</ref> *5-APB

===Research compounds (no record of having been taken by humans)=== {{multiple image |align=center |total_width=580 |perrow=4 |image1=3,4-Diphenylpiperidines.svg|caption1=3,4-Diphenylpiperidine |image2=MDL 47,832.svg|caption2=MDL 47,832 |image3=3,4-Diphenylquinuclidine.svg|caption3=3,4-Diphenylquinuclidine }}

* McNeil Laboratories: McN-4612, McN5652, JNJ-7925476 (2008; first appeared in 1987),<ref name=Alusio>{{Cite journal |pmid=18499098 |year=2008 |last1=Aluisio |first1=L |last2=Lord |first2=B |last3=Barbier |first3=AJ |last4=Fraser |first4=IC |last5=Wilson |first5=SJ |last6=Boggs |first6=J |last7=Dvorak |first7=LK |last8=Letavic |first8=MA |last9=Maryanoff |first9=BE |last10=Carruthers|first10=Nicholas I |last11=Bonaventure |first11=Pascal |last12=Lovenberg |first12=Timothy W. |title=In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor |volume=587 |issue=1–3 |pages=141–6 |doi=10.1016/j.ejphar.2008.04.008|journal=European Journal of Pharmacology|display-authors=8}}</ref> McN 5707 [96795-88-9] & Mcn-5292 [105234-89-7] & McN-5558<ref>{{cite book |author=Frazee, W. J. |author2=Ohnmacht, C. J. |author3=Malick, J. B. | date= 1985 | chapter=Annual Reports in Medicinal Chemistry | title=Chapter 4. Antidepressants | series= Annual Reports in Medicinal Chemistry | publisher=Elsevier | volume=20 | pages=31–40 | url=https://linkinghub.elsevier.com/retrieve/pii/S0065774308610301 | doi=10.1016/S0065-7743(08)61030-1 | isbn= 978-0-12-040520-6 }}</ref> (labelled as SNRI though). *MDL 47,832 [52423-89-9]<ref>{{cite journal |vauthors=Burkholder TP, Kudlacz EM, Tieu-Binh L, Knippenberg RW, Shatzer SA, Maynard GD, Webster ME, Horgan SW |date=April 1996 |journal=Bioorganic & Medicinal Chemistry Letters |title=Identification and chemical synthesis of MDL 105,212, a non-peptide tachykinin antagonist with high affinity for NK1 and NK2 receptors |volume=6 |issue=8 |pages=951–6 |doi=10.1016/0960-894X(96)00148-5}}</ref><ref>Xavier Emonds-Alt, Patrick Gueule, Vincenzo Proietto, Didier Van Broeck, {{US patent|5679693}} (1997 to Sanofi SA).</ref><ref>Xavier Emonds-Alt, et al. {{US patent|5554763}} (1996 to Sanofi SA).</ref> has a SAR that is similar to RG-7166 & Amitifadine. Further details of the SAR study can be seen under Osanetant. * 3,3-Diphenylcyclobutanamine (1978)<ref>{{Cite journal |pmid=22757 |year=1978 |vauthors=Carnmalm B, Rämsby S, Renyi AL, Ross SB, Ogren SO, Stjernstrom NE |title=Antidepressant agents. 9. 3,3-Diphenylcyclobutylamines, a new class of central stimulants |volume=21 |issue=1 |pages=78–82 |journal=Journal of Medicinal Chemistry |doi=10.1021/jm00199a014}}</ref> *AK Dutta: D-161 (2008)<ref>{{Cite journal |pmid=18561912 |year=2008 |vauthors=Dutta AK, Ghosh B, Biswas S, Reith ME |title=D-161, a novel pyran-based triple monoamine transporter blocker: Behavioral pharmacological evidence for antidepressant-like action|volume=589|issue=1–3|pages=73–9|doi=10.1016/j.ejphar.2008.05.008|journal=European Journal of Pharmacology}}</ref> D-473 [1632000-05-5] & D-578. ''Informative review'':<ref name="h343">{{cite journal | last1=Sharma | first1=Horrick | last2=Santra | first2=Soumava | last3=Dutta | first3=Aloke | title=Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope? | journal=Future Medicinal Chemistry | volume=7 | issue=17 | date=2015 | pmid=26619226 | pmc=4976848 | doi=10.4155/fmc.15.134 | pages=2385–2406}}</ref> * DOV-102,677 (2006–2011)<ref name="DOV 102,677"/> ''Informative reviews'':<ref name="x670">{{cite journal | last1=Chen | first1=Zhengming | last2=Skolnick | first2=Phil | title=Triple uptake inhibitors: therapeutic potential in depression and beyond | journal=Expert Opinion on Investigational Drugs | volume=16 | issue=9 | date=2007 | issn=1354-3784 | doi=10.1517/13543784.16.9.1365 | pages=1365–77| pmid=17714023 }}</ref><ref name="s366">{{cite journal |vauthors=Skolnick P, Basile AS |title=Triple reuptake inhibitors ("broad spectrum" antidepressants) |journal=CNS Neurol Disord Drug Targets |volume=6 |issue=2 |pages=141–9 |date=April 2007 |pmid=17430151 |doi=10.2174/187152707780363285 }}</ref> * Fezolamine (Win-41,528-2) * GlaxoSmithKline (Italia): GSK1360707F (2010):<ref>{{Cite journal|pmid=21174473|year=2011|vauthors=Deschamps NM, Elitzin VI, Liu B, Mitchell MB, Sharp MJ, Tabet EA |title=An enyne cycloisomerization approach to the triple reuptake inhibitor GSK1360707F |volume=76 |issue=2 |pages=712–5 |doi=10.1021/jo102098y |journal=The Journal of Organic Chemistry}}</ref><ref>{{Cite journal |pmid=20527970 |year=2010 |last1=Micheli |first1=F |last2=Cavanni |first2=P |last3=Andreotti |first3=D |last4=Arban |first4=R |last5=Benedetti |first5=R |last6=Bertani |first6=B |last7=Bettati |first7=M |last8=Bettelini |first8=L |last9=Bonanomi |first9=G |last10=Braggio |first10=Simone |last11=Carletti |first11=Renzo |last12=Checchia |first12=Anna |last13=Corsi |first13=Mauro |last14=Fazzolari |first14=Elettra |last15=Fontana |first15=Stefano |last16=Marchioro |first16=Carla |last17=Merlo-Pich |first17=Emilio |last18=Negri |first18=Michele |last19=Oliosi |first19=Beatrice |last20=Ratti |first20=Emiliangelo |last21=Read |first21=Kevin D. |last22=Roscic |first22=Maja |last23=Sartori |first23=Ilaria |last24=Spada |first24=Simone |last25=Tedesco |first25=Giovanna |last26=Tarsi |first26=Luca |last27=Terreni |first27=Silvia |last28=Visentini |first28=Filippo |last29=Zocchi |first29=Alessandro |last30=Zonzini |first30=Laura |title=6-(3,4-dichlorophenyl)-1-(methyloxy)methyl-3-azabicyclo4.1.0heptane: A new potent and selective triple reuptake inhibitor|volume=53|issue=13|pages=4989–5001 |doi=10.1021/jm100481d|journal=Journal of Medicinal Chemistry|display-authors=8}}</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/46866510 CID:46866510]:<ref name="n854">{{cite journal | last1=Bettati | first1=Michela | last2=Cavanni | first2=Paolo | last3=Di Fabio | first3=Romano | last4=Oliosi | first4=Beatrice | last5=Perini | first5=Ornella | last6=Scheid | first6=Gunther | last7=Tedesco | first7=Giovanna | last8=Zonzini | first8=Laura | last9=Micheli | first9=Fabrizio | title=Oxa-azaspiro Derivatives: a Novel Class of Triple Re-uptake Inhibitors | journal=ChemMedChem | volume=5 | issue=3 | date=2010 | issn=1860-7179 | doi=10.1002/cmdc.200900482 | pages=361–6| pmid=20112329 }}</ref> *HP-505<ref>{{cite journal |last1=Meyerson |first1=Laurence R |last2=Ong |first2=Helen H |last3=Martin |first3=Lawrence L |last4=Ellis |first4=Daniel B |title=Effect of antidepressant agents on β-adrenergic receptor and neurotransmitter regulatory systems |journal=Pharmacology Biochemistry and Behavior |date=June 1980 |volume=12 |issue=6 |pages=943–8 |doi=10.1016/0091-3057(80)90457-8|pmid=6105676 |s2cid=45400599 }}</ref> * Lundbeck group: Indatraline (1985),<ref>{{Cite journal |pmid=2999402 |year=1985 |vauthors=Bøgesø KP, Christensen AV, Hyttel J, Liljefors |first4=T |title=3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake|volume=28|issue=12|pages=1817–28 |journal=Journal of Medicinal Chemistry|doi=10.1021/jm00150a012}}</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/24886833 Lu-AA42202] & [https://pubchem.ncbi.nlm.nih.gov/compound/11515108 CID:11515108] [874296-10-3].<ref>Jan Kehler, Friedrich Kroll, & Karsten Juhl, WO2006007843 (to H Lundbeck AS).</ref> * Kozikowski group: DMNPC (2000),<ref name=naphthylnocaine>{{Cite journal |pmid=10737754 |year=2000 |vauthors=Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M, Johnson KM, Deschaux O, Tella S, Kozikowski |title=Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors |volume=43 |issue=6 |pages=1215–22 |journal=Journal of Medicinal Chemistry |doi=10.1021/jm9905561}}</ref> JZ-IV-10 (2005)<ref>{{Cite patent|country=WO|number=2005041875|title=Dopamine-, norepinephrine- and serotonin- transporter- selective heterocyclic compounds and their therapeutic applications|pubdate=2005-05-12 |assign=Georgetown University|inventor1-last=Kozikowski |inventor1-first=Alan P.|inventor2-last=Zhou |inventor2-first=Jia}}</ref> & JZAD-IV-22 (2010)<ref name=JZAD-IV-22>{{Cite journal |pmid=20864506 |year=2010 |vauthors=Caldarone BJ, Paterson NE, Zhou J, Brunner D, Kozikowski AP, Westphal KG, Korte-Bouws GA, Prins J, Korte SM, Olivier B, Ghavami A |title=The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties |volume=335 |issue=3 |pages=762–770 |doi=10.1124/jpet.110.174011|pmc=2993553 |journal=The Journal of Pharmacology and Experimental Therapeutics |display-authors=8}}</ref> * Lilly group: LR-5182 (maybe only NDRI) (1978) [https://pubchem.ncbi.nlm.nih.gov/compound/9903806 CID:9903806]:<ref>{{cite journal |author=Axford, L. |author2=Boot, J. R. |author3=Hotten, T. M. |author4=Keenan, M. |author5=Martin, F. M. |author6=Milutinovic, S. |author7=Moore, N. A. |author8=O'Neill, M. F. |author9=Pullar, I. A. |author10=Tupper, D. E. |author11=Van Belle, K. R. |author12=Vivien, V. | journal=Bioorganic & Medicinal Chemistry Letters | title=Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression | volume=13 | issue=19 | pages=3277–80 | date= October 2003 | issn=0960-894X | doi=10.1016/S0960-894X(03)00660-7| pmid=12951108 }}</ref> **[https://pubchem.ncbi.nlm.nih.gov/compound/11335177 CID:11335177]<ref>Christopher David Beadle, et al. WO2005000811 (to Eli Lilly and Co).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/9867350 CID:9867350]<ref>Clark, B. P.; Cases-Thomas, M. J.; Gallagher, P. T.; Gilmore, J.; Masters, J. J.; Timms, G. H.; Whatton, M. A.; Wood, M.Preparation of N,N-disubstituted 4-aminopiperidines as inhibitors of monoamine, in particular serotonin, norepinephrine, and dopamine reuptake. WO2004052858 (2004 to Eli Lilly and Co Ltd (GB)).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/11234430 CID:11234430]<ref>Boulet, S. L.; Clark, B. P.; Fairhurst, J.; Gallagher, P. T.; Johansson, A. M.; Whatton, M. A.; Wood, M. Preparation of 4-aminopiperidine derivatives as monoamine uptake inhibitors. WO2005092885 (2005 to Eli Lilly And Company).</ref> *HM Deutsch group: Methylnaphthidate (HDMP-28) (2001)<ref>{{Cite journal |pmid=12954808 |year=2003 |vauthors=Lile JA, Wang Z, Woolverton WL, France JE, Gregg TC, Davies HM, Nader MA |title=The reinforcing efficacy of psychostimulants in rhesus monkeys: The role of pharmacokinetics and pharmacodynamics |volume=307 |issue=1 |pages=356–366 |doi=10.1124/jpet.103.049825 |journal=The Journal of Pharmacology and Experimental Therapeutics |s2cid=5654856}}</ref> * MI-4<ref>{{cite web|url=https://www.independent.co.uk/news/science/a-fastacting-antidepressant-could-be-on-the-horizon-9313600.html|title=A fast-acting antidepressant could be on the horizon|work=The Independent|last=Criado|first=Elisa|date=2 May 2014|access-date=22 June 2014}}</ref><ref>{{Cite journal |last1=Talbot |first1=Jeffery |last2=Geffert |first2=Laura |last3=Wolters |first3=Nicholas |last4=Amos |first4=Mary |last5=Dallman |first5=Elizabeth |last6=Munro |first6=Caitlin |last7=Tolle |first7=Erica |last8=Larkey |first8=Jessica |last9=Tanda |first9=Gianluigi |last10=Katz |first10=Jonathan |last11=Indarte |first11=Martin |last12=Madura |first12=Jeffry |last13=Surratt |first13=Christopher |url=http://www.fasebj.org/content/28/1_Supplement/1144.1.short |title=A novel triple reuptake inhibitor with rapid antidepressant properties identified by virtual screening (1144.1) |journal=The FASEB Journal |date=April 2014 |volume=28 |access-date=2014-06-23 |archive-date=2015-09-24 |archive-url=https://web.archive.org/web/20150924025603/http://www.fasebj.org/content/28/1_Supplement/1144.1.short }}</ref> MI-4 is the same compound as Ro-25-6981 [169274-78-6].<ref>{{cite web | url=https://www.latimes.com/science/sciencenow/la-sci-sn-fast-antidepressant-not-ketamine-20140501-story.html | title=A new fast-acting antidepressant (That's not ketamine) shows promise | website=Los Angeles Times | date=May 2014 }}</ref><ref>{{cite web | url=https://www.sciencedaily.com/releases/2014/04/140430161301.htm | title=Fast-acting antidepressant appears within reach }}</ref> This is NMDA antagonist. * Benzazepine derivatives: SKF-83,959 (2013)<ref>{{Cite journal| doi=10.1038/aps.2013.66| pmid=23892272| title=SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity| journal=Acta Pharmacologica Sinica| volume=34| issue=9| pages=1149–55| year=2013| vauthors=Fang X, Guo L, Jia J, Jin GZ, Zhao B, Zheng YY, Li JQ, Zhang A, Zhen XC| pmc=4003162}}</ref> & ''Nor''-Trepipam [20569-49-7]:<ref name="t586">{{cite journal | last1=Mondeshka | first1=Diana | last2=Angelova | first2=Ivanka | last3=Ivanov | first3=Chavdar B. | last4=Ivanova | first4=Nedjalka S. | title=Racemische und optisch aktive 2-Chlorethylcarbamoyl-Derivate des 7,8-Dimethoxy-1-phenyl-1 H -3-benzazepins: Neue Strukturtypen von DA, NE und 5-HT Uptake Inhibitoren | journal=Archiv der Pharmazie | volume=323 | issue=10 | date=1990 | issn=0365-6233 | doi=10.1002/ardp.19903231003 | pages=829–832| pmid=2150477 }}</ref> * Various phenyltropanes, such as WF-23, dichloropane, and RTI-55<ref name=Carroll>{{Cite journal |pmid=12723940 |year=2003 |vauthors=Carroll FI |title=2002 Medicinal Chemistry Division Award address: Monoamine transporters and opioid receptors. Targets for addiction therapy |volume=46 |issue=10 |pages=1775–94 |doi=10.1021/jm030092d |journal=Journal of Medicinal Chemistry}}</ref> *NeuroSearch group: [https://pubchem.ncbi.nlm.nih.gov/compound/67403453 NS9775],<ref name="AndreasenRedrobe2013">{{cite journal |last1=Andreasen |first1=Jesper T. |last2=Redrobe |first2=John P. |last3=Nielsen |first3=Elsebet Ø. |last4=Christensen |first4=Jeppe K. |last5=Olsen |first5=Gunnar M. |last6=Peters |first6=Dan |title=A combined α7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances |journal=Neuropharmacology |volume=73 |year=2013 |pages=183–191 |issn=0028-3908 |doi=10.1016/j.neuropharm.2013.04.060 |pmid=23748055 |s2cid=6812669}}</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/75274769 NS18283].<ref name="g152">{{cite journal | last1=Hache | first1=G. | last2=Guiard | first2=B.P. | last3=Nguyen | first3=T.H. | last4=Quesseveur | first4=G. | last5=Gardier | first5=A.M. | last6=Peters | first6=D. | last7=Munro | first7=G. | last8=Coudoré | first8=F. | title=Antinociceptive activity of the new triple reuptake inhibitor NS 18283 in a mouse model of chemotherapy-induced neuropathic pain | journal=European Journal of Pain | volume=19 | issue=3 | date=2015 | issn=1090-3801 | doi=10.1002/ejp.550 | pages=322–333| pmid=25045036 }}</ref> & 4-Benzhydryl-1,2,3,6-tetrahydropyridine [1186529-81-6]. **[https://pubchem.ncbi.nlm.nih.gov/compound/54673194 CID:54673194] (k_i S/N/D = 0.26/6.0/4.8 nM)<ref>Birgitte L. Eriksen, et al. WO2008025777 (2008 to Neurosearch A/S).</ref> ** [https://pubchem.ncbi.nlm.nih.gov/compound/9921901 CID:9921901] [387869-25-2],<ref>Dan Peters, et al. {{US patent|7060699}} (2006 to NeuroSearch AS).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/10221020 3-(3,4-Dichlorophenyl)-tropan-2-ene] (S/N/D = 4.7/26/79 nM)<ref>Peter Moldt, Jørgen SCHEEL-KRÜGER, Gunnar M. Olsen, Elsebet Østergaard NIELSEN , WO1997013770 (1997 to Neurosearch A/S).</ref> *Liming Shao (Sepracor/Sunovion). 3',4'-Dichlorotramadol,<ref>Liming Shao, 12 More », WO2008151156 (to Sunovion Pharmaceuticals Inc.).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/53321058 CID:53321058] (S/N/D = 19/04/01 nM).<ref name="j398">{{cite journal | last1=Shao | first1=Liming | last2=Hewitt | first2=Michael C. | last3=Wang | first3=Fengjiang | last4=Malcolm | first4=Scott C. | last5=Ma | first5=Jianguo | last6=Campbell | first6=John E. | last7=Campbell | first7=Una C. | last8=Engel | first8=Sharon R. | last9=Spicer | first9=Nancy A. | last10=Hardy | first10=Larry W. | last11=Schreiber | first11=Rudy | last12=Spear | first12=Kerry L. | last13=Varney | first13=Mark A. | title=Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor | journal=Bioorganic & Medicinal Chemistry Letters | volume=21 | issue=5 | date=2011 | doi=10.1016/j.bmcl.2011.01.016 | pages=1438–41| pmid=21310609 }}</ref><ref>{{cite journal |vauthors=Shao L, Hewitt MC, Wang F, Malcolm SC, Ma J, Campbell JE, Campbell UC, Engel SR, Spicer NA, Hardy LW, Schreiber R, Spear KL, Varney MA |title=Discovery of N-methyl-1-(1-phenylcyclohexyl)ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor |journal=Bioorg Med Chem Lett |volume=21 |issue=5 |pages=1434–7 |date=March 2011 |pmid=21310612 |doi=10.1016/j.bmcl.2011.01.019 }}</ref> **A patent review was also disclosed:<ref>{{cite journal |vauthors=Shao L, Li W, Xie Q, Yin H |title=Triple reuptake inhibitors: a patent review (2006–2012) |journal=Expert Opin Ther Pat |volume=24 |issue=2 |pages=131–54 |date=February 2014 |pmid=24289044 |doi=10.1517/13543776.2014.859676 }}MID 24289044.</ref> **[https://pubchem.ncbi.nlm.nih.gov/compound/66809062 CID:66809062]:<ref>{{cite journal |vauthors=Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA |title=Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors |journal=Bioorg Med Chem |volume=19 |issue=1 |pages=663–76 |date=January 2011 |pmid=21093273 |doi=10.1016/j.bmc.2010.10.034 }}</ref><ref>Liming Shao, et al. WO2007081542 (Sunovion Pharmaceuticals Inc).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/46870521 CID:46870521]<ref>Liming Shao & Jianguo Ma, WO2010091268 (Sunovion Pharmaceuticals Inc).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/10151573 CID:10151573]<ref>Heike Radeke & Liming Shao, US7812035 (2003 to Sunovion Pharmaceuticals Inc).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/46701015 CID:46701015]<ref>Liming Shao, et al. US8592608, US9133117 & US9850204 (2018 to Sunovion Pharmaceuticals Inc).</ref> * Takeda group, [https://pubchem.ncbi.nlm.nih.gov/compound/44629033 CID:44629033] (k_i S/N/D = 11/14/190 nM) Ref:<ref>Ishichi, Yuji; Kimura, Eiji; Honda, Eiji; Yoshikawa, Masato; Nakahata, Takashi; Terao, Yasuko; Suzuki, Atsuko; Kawai, Takayuki; Arakawa, Yuuichi; Ohta, Hiroyuki; Kanzaki, Naoyuki; Nakagawa, Hideyuki; Terauchi, Jun (2013). "Novel triple reuptake inhibitors with low risk of CAD associated liabilities: Design, synthesis and biological activities of 4-[(1S)-1-(3,4-dichlorophenyl)-2-methoxyethyl]piperidine and related compounds". Bioorganic & Medicinal Chemistry. 21 (15): 4600–4613. doi:10.1016/j.bmc.2013.05.025.</ref> Patent:<ref>Ishichi Yuji, Kimura Eiji & Terauchi Jun, WO2010016554 (to Takeda).</ref> *Trudell group: [https://pubchem.ncbi.nlm.nih.gov/compound/10220657 HK3-263] (k_i S/N/D = 0.3/20/16 nM):<ref>{{cite journal |vauthors=Kaur H, Izenwasser S, Verma A, Wade D, Housman A, Stevens ED, Mobley DL, Trudell ML |title=Synthesis and monoamine transporter affinity of 3alpha-arylmethoxy-3beta-arylnortropanes |journal=Bioorg Med Chem Lett |volume=19 |issue=24 |pages=6865–8 |date=December 2009 |pmid=19896846 |doi=10.1016/j.bmcl.2009.10.087 |pmc=2788963}}</ref> *Pfizer group [https://pubchem.ncbi.nlm.nih.gov/compound/9861124 CP-607366] & [https://pubchem.ncbi.nlm.nih.gov/compound/16038341 CP-939689]. **Desmethylsertraline — active metabolite of sertraline; k_i is 76 nM for SERT, 420 nM for NET, 440 nM for DAT<ref name="pmid7623609">{{cite journal |vauthors=Wong DT, Bymaster FP, Engleman EA |title=Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication |journal=Life Sci. |volume=57 |issue=5 |pages=411–441 |year=1995 |pmid=7623609 |doi=10.1016/0024-3205(95)00209-o}}</ref> **3,4-Dichlorotametraline (''trans''-(1R,4S)-sertraline) (1980)<ref>{{US patent|4556676}}</ref> *Venlafaxine analogues, LPM580098<ref>{{cite journal |vauthors=Li N, Li C, Han R, Wang Y, Yang M, Wang H, Tian J |title=LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain |journal=Front Pharmacol |volume=10 |issue= |article-number=53 |date=2019 |pmid=30837867 |doi=10.3389/fphar.2019.00053 |doi-access=free |pmc=6382704}}</ref> & LPM580153.<ref>{{cite journal |vauthors=Zhang F, Shao J, Tian J, Zhong Y, Ye L, Meng X, Liu Q, Wang H |title=Antidepressant-like Effects of LPM580153, A Novel Potent Triple Reuptake Inhibitor |journal=Sci Rep |volume=6 |issue= |article-number=24233 |date=April 2016 |pmid=27052887 |doi=10.1038/srep24233 |pmc=4823741 |bibcode=2016NatSR...624233Z }}</ref> And [https://pubchem.ncbi.nlm.nih.gov/compound/56589568 TP1]<ref>{{Cite journal |pmid=21925241 |year=2011 |vauthors=Tian JW, Jiang WL, Zhong Y, Meng Q, Gai Y, Zhu HB, Hou J, Xing Y, Li YX |title=Preclinical pharmacology of TP1, a novel potent triple reuptake inhibitor with antidepressant properties |volume=196 |pages=124–130 |doi=10.1016/j.neuroscience.2011.08.064|journal=Neuroscience|s2cid=37122044}}</ref> later reassigned name to PA01.<ref>{{cite journal |vauthors=Hou J, Xing Y, Zuo D, Wu Y, Tian J, Meng Q, Yang M |title=In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor |journal=Physiol Behav |volume=138 |pages=141–9 |date=January 2015 |pmid=25447484 |doi=10.1016/j.physbeh.2014.10.007 }}</ref> **PRC (Carlier) group: PRC200-SS (2008),<ref name=PRC200-SS>{{Cite journal |pmid=18689611 |year=2008 |vauthors=Liang Y, Shaw AM, Boules M, Briody S, Robinson J, Oliveros A, Blazar E, Williams K, Zhang Y, Carlier PR, Richelson E |title=Antidepressant-like pharmacological profile of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS) |volume=327 |issue=2 |pages=573–583 |doi=10.1124/jpet.108.143610 |journal=The Journal of Pharmacology and Experimental Therapeutics |s2cid=12635418|display-authors=8}}</ref> PRC050, and [https://pubchem.ncbi.nlm.nih.gov/compound/11630988 PRC025].<ref>{{cite journal |vauthors=Shaw AM, Boules M, Zhang Y, Williams K, Robinson J, Carlier PR, Richelson E |title=Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050 |journal=Eur J Pharmacol |volume=555 |issue=1 |pages=30–6 |date=January 2007 |pmid=17109850 |doi=10.1016/j.ejphar.2006.10.004 }}</ref> *Albany Molecular Research group (Bruce Molino) [https://pubchem.ncbi.nlm.nih.gov/compound/86279074 AMR-2] (k_i is DAT 3.1 nM, SERT 8.3 nM, NET 3.0 nM):<ref>{{cite journal |vauthors=Liu S, Zha C, Nacro K, Hu M, Cui W, Yang YL, Bhatt U, Sambandam A, Isherwood M, Yet L, Herr MT, Ebeltoft S, Hassler C, Fleming L, Pechulis AD, Payen-Fornicola A, Holman N, Milanowski D, Cotterill I, Mozhaev V, Khmelnitsky Y, Guzzo PR, Sargent BJ, Molino BF, Olson R, King D, Lelas S, Li YW, Johnson K, Molski T, Orie A, Ng A, Haskell R, Clarke W, Bertekap R, O'Connell J, Lodge N, Sinz M, Adams S, Zaczek R, Macor JE |title=Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors |journal=ACS Med Chem Lett |volume=5 |issue=7 |pages=760–5 |date=July 2014 |pmid=25050161 |doi=10.1021/ml500053b |pmc=4094255 }}</ref> **[https://pubchem.ncbi.nlm.nih.gov/compound/49765424 CID:49765424] (S)-enantiomer: [1254941-82-6]:<ref>Shuang Liu, Bruce F. Molino, Kassoum Nacro, WO2010132442 (2010 to Albany Molecular Research, Inc.). Page column 32.</ref> *SK Group: [https://pubchem.ncbi.nlm.nih.gov/compound/10407800 SKL-10406] [https://pubchem.ncbi.nlm.nih.gov/compound/44555333 CID:44555333]<ref>Ki-Ho Lee, et al. WO2009148291 (to SK Biopharmaceuticals Co Ltd).</ref> & [https://pubchem.ncbi.nlm.nih.gov/compound/49866033 CID:49866033]<ref>Chun-Eung Park, et al. WO2009148290 (to SK Biopharmaceuticals Co Ltd).</ref><ref>{{cite journal |vauthors=Lee KH, Park CE, Min KH, Shin YJ, Chung CM, Kim HH, Yoon HJ, Won-Kim, Ryu EJ, Shin YJ, Nam HS, Cho JW, Lee HY |title=Synthesis and pharmacological evaluation of 3-aryl-3-azolylpropan-1-amines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors |journal=Bioorg Med Chem Lett |volume=20 |issue=18 |pages=5567–71 |date=September 2010 |pmid=20724153 |doi=10.1016/j.bmcl.2010.07.021 }}</ref> *Boots UK: BTS 74,398, SPD-473 citrate: [161190-26-7] *Pridefine *SMe1EC2M3<ref>{{cite journal |vauthors=Koprdova R, Csatlosova K, Durisova B, Bogi E, Majekova M, Dremencov E, Mach M |title=Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors |journal=Molecules |volume=24 |issue=23 |page=4218 |date=November 2019 |pmid=31757051 |doi=10.3390/molecules24234218 |pmc=6930491 |doi-access=free}}</ref> *SIPI5357 ([https://pubchem.ncbi.nlm.nih.gov/compound/52939791 CID:52939791]):<ref>{{cite journal |vauthors=Weng Z, Zheng Y, Li J |title=Synthesis, antidepressant activity, and toxicity of the erythro/threo racemates and optical isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-ol |journal=Chem Biol Drug Des |volume=85 |issue=4 |pages=454–60 |date=April 2015 |pmid=25243904 |doi=10.1111/cbdd.12438 }}</ref> & SIPI5056 ([https://pubchem.ncbi.nlm.nih.gov/compound/69055942 CID:69055942]):<ref>Weng Z, Li J. Synthesis and antidepressant activity of optical isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl) propan-1-ol (SIPI5056). Bioorg Med Chem Lett. 2010 Feb 1;20(3):1256-9. doi: 10.1016/j.bmcl.2009.11.108. Epub 2009 Nov 27. PMID 20022503.</ref> *[https://pubchem.ncbi.nlm.nih.gov/compound/91799660 23j-S] (k_i S/N/D = 83/3.8/160 nM):<ref>{{cite journal |vauthors=Honda E, Ishichi Y, Kimura E, Yoshikawa M, Kanzaki N, Nakagawa H, Terao Y, Suzuki A, Kawai T, Arakawa Y, Ohta H, Terauchi J |title=Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors |journal=Bioorg Med Chem Lett |volume=24 |issue=16 |pages=3898–902 |date=August 2014 |pmid=25017029 |doi=10.1016/j.bmcl.2014.06.046 }}</ref> *Tetrazoles (ROK):<ref>{{cite journal |vauthors=Paudel S, Acharya S, Yoon G, Kim KM, Cheon SH |title=Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors |journal=Bioorg Med Chem |volume=25 |issue=7 |pages=2266–76 |date=April 2017 |pmid=28274674 |doi=10.1016/j.bmc.2017.02.051 }}</ref><ref>{{cite journal |vauthors=Paudel S, Min X, Acharya S, Khadka DB, Yoon G, Kim KM, Cheon SH |title=Triple reuptake inhibitors: Design, synthesis and structure-activity relationship of benzylpiperidine-tetrazoles |journal=Bioorg Med Chem |volume=25 |issue=20 |pages=5278–89 |date=October 2017 |pmid=28807575 |doi=10.1016/j.bmc.2017.07.046 }}</ref><ref>Paudel S, Wang S, Kim E, Kundu D, Min X, Shin CY, Kim KM. Design, Synthesis, and Functional Evaluation of 1, 5-Disubstituted Tetrazoles as Monoamine Neurotransmitter Reuptake Inhibitors. Biomol Ther (Seoul). 2021 Nov 18. doi: 10.4062/biomolther.2021.119. Epub ahead of print. PMID 34789584.</ref> *10dl ([https://pubchem.ncbi.nlm.nih.gov/compound/118713802 CID:118713802]) (k_i S/N/D 7.6/45.2/330 nM):<ref>{{cite journal |vauthors=Han M, Song C, Jeong N, Hahn HG |title=Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine |journal=ACS Med Chem Lett |volume=5 |issue=9 |pages=999–1004 |date=September 2014 |pmid=25221656 |doi=10.1021/ml500187a |pmc=4160755 }}</ref> * 2at ([https://pubchem.ncbi.nlm.nih.gov/compound/118706539 CID:118706539]):<ref>{{cite journal |vauthors=Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG |title=Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors |journal=Bioorg Med Chem Lett |volume=24 |issue=15 |pages=3234–7 |date=August 2014 |pmid=24974340 |doi=10.1016/j.bmcl.2014.06.026 }}</ref> *THIQ Derivatives: '''AN12''' ([https://pubchem.ncbi.nlm.nih.gov/compound/10380161 CID:10380161]):<ref>{{cite journal |vauthors=Mondeshka DM, Angelova IG, Tancheva CN, Ivanov CB, Daleva LD, Ivanova NS |title=Synthesis, antiulcer and antidepressive activity of 4-(4-halophenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolines |journal=Farmaco |volume=49 |issue=7–8 |pages=475–80 |date=1994 |pmid=7945712 }}</ref> Patent:<ref>CA2015114 idem Donka M. Mondeshka, 10 More », EP0400319 (1990 to N I S Pri Vchti).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/9839278 CID:9839278]:<ref>James P. Beck, Mark A. Smith, Matt A. Curry, M. A. Aryl- and heteroarylsubstituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin. WO2001032625 (2001 to Du Pont Pharmaceuticals Company).</ref> *2j ([https://pubchem.ncbi.nlm.nih.gov/compound/66572162 CID:66572162]) (k_i S/N/D = 411/71/159 nM):<ref>{{cite journal |vauthors=Zheng YY, Guo L, Zhen XC, Li JQ |title=Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as triple reuptake inhibitors |journal=Eur J Med Chem |volume=54 |issue= |pages=123–36 |date=August 2012 |pmid=22608762 |doi=10.1016/j.ejmech.2012.04.030 }}</ref> *6aq ([https://pubchem.ncbi.nlm.nih.gov/compound/70676472 CID:70676472]) (k_i S/N/D 44/10/32 nM):<ref>{{cite journal |vauthors=Han Y, Han M, Shin D, Song C, Hahn HG |title=Exploration of novel 3-substituted azetidine derivatives as triple reuptake inhibitors |journal=J Med Chem |volume=55 |issue=18 |pages=8188–92 |date=September 2012 |pmid=22938049 |doi=10.1021/jm3008294 }}</ref> *Naphthyl milnacipran analog (2007), [https://pubchem.ncbi.nlm.nih.gov/compound/17748230 CID:17748230] (k_i S/N/D = 18/05/140 nM).<ref>{{cite journal |vauthors=Roggen H, Kehler J, Stensbøl TB, Hansen T |title=Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters |journal=Bioorg Med Chem Lett |volume=17 |issue=10 |pages=2834–7 |date=May 2007 |pmid=17350257 |doi=10.1016/j.bmcl.2007.02.054 }}</ref> *Benzazepine derivatives, e.g. Nortrepipram [20569-49-7].<ref>Mondeshka, Diana; Angelova, Ivanka; Ivanov, Chavdar B.; Ivanova, Nedjalka S. (1990). "Racemische und optisch aktive 2-Chlorethylcarbamoyl-Derivate des 7,8-Dimethoxy-1-phenyl-1H-3-benzazepins: Neue Strukturtypen von DA, NE und 5-HT Uptake Inhibitoren". Archiv der Pharmazie. 323 (10): 829–832. doi:10.1002/ardp.19903231003.</ref> SKF-83959<ref>Fang, Xing; Guo, Lin; Jia, Jia; Jin, Guo-zhang; Zhao, Bin; Zheng, Yong-yong; Li, Jian-qi; Zhang, Ao; Zhen, Xue-chu (2013). "SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity". Acta Pharmacologica Sinica. 34 (9): 1149–1155. doi:10.1038/aps.2013.66.</ref> *Roche: RG-7166 ([https://pubchem.ncbi.nlm.nih.gov/compound/44231267 PC44231267]),<ref>Bannwart, L. M., Carter, D. S., Cai, H.-Y., Choy, J. C., Greenhouse, R., Jaime-Figueroa, S., Iyer, P. S., Lin, C. J., Lee, E. K., Lucas, M. C., Lynch, S. M., Madera, A. M., Moore, A., Ozboya, K., Raptova, L., Roetz, R., Schoenfeld, R. C., Stein, K. A., Steiner, S., Villa, M., Weikert, R. J., Zhai, Y. (December 2008). "Novel 3,3-disubstituted pyrrolidines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors". Bioorganic & Medicinal Chemistry Letters. 18 (23): 6062–6066. doi:10.1016/j.bmcl.2008.10.025.</ref><ref>Matthew C. Lucas, Ryan Craig Schoenfeld, Robert James Weikert, WO2009115427 (2011 to Hoffmann-La Roche Inc).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/52950556 PC52950556]<ref>Ryan Craig Schoenfeld, WO2011067273 (2011 to F. Hoffmann-La Roche Ag).</ref> [https://pubchem.ncbi.nlm.nih.gov/compound/58017238 PC58017238]<ref name="Lucas, M. C. 2010"/> See also:<ref>Lucas, M. C., Carter, D. S., Cai, H.-Y., Lee, E. K., Schoenfeld, R. C., Steiner, S., Villa, M., Weikert, R. J., Iyer, P. S. (August 2009). "Novel, achiral aminoheterocycles as selective monoamine reuptake inhibitors". Bioorganic & Medicinal Chemistry Letters. 19 (16): 4630–4633. doi:10.1016/j.bmcl.2009.06.076.</ref><ref>Carter, D. S., Cai, H.-Y., Lee, E. K., Iyer, P. S., Lucas, M. C., Roetz, R., Schoenfeld, R. C., Weikert, R. J. (July 2010). "2-Substituted N-aryl piperazines as novel triple reuptake inhibitors for the treatment of depression". Bioorganic & Medicinal Chemistry Letters. 20 (13): 3941–3945. doi:10.1016/j.bmcl.2010.05.008.</ref> *Lafadofensine * Diphenylbutylpiperazines: FG5865, FG5891, FG-5893, FG5909.<ref>{{cite journal |author=Pettersson, E. | journal=European Journal of Pharmacology | title=Studies of four novel diphenylbutylpiperazinepyridyl derivatives on release and inhibition of reuptake of dopamine, serotonin and noradrenaline by rat brain in vitro | volume=282 | issue=1–3 | pages=131–135 | date= August 1995 | doi=10.1016/0014-2999(95)00300-A | pmid=7498267 }}</ref> *Flunamine [50366-32-0]<ref>{{cite journal |author=Vejdělek, Z. |author2=Metyš, J. |author3=Holubek, J. |author4=Svátek, E. |author5=Protiva, M. | journal=Collection of Czechoslovak Chemical Communications | title=Potential antiparkinsonic agents: Synthesis and pharmacology of some 4-fluoro-4'-halogen'benzhydryl 2-(N,N-disubstituted amino)ethyl ethers | volume=49 | issue=11 | pages=2649–2660 | date= 1984 | url=http://cccc.uochb.cas.cz/49/11/2649/ | doi=10.1135/cccc19842649}}</ref> Primary:<ref>Zee P. van der, Hespe W.: 5th Int. Symp. Med. Chem., Paris, July 1976; Abstr. p. 52 (No 053).</ref> (led to vanoxerine) *SRI-29574 [1928712-46-2] (Rothman)<ref>{{cite journal |author=Rothman, R. B. |author2=Ananthan, S. |author3=Partilla, J. S. |author4=Saini, S. K. |author5=Moukha-Chafiq, O. |author6=Pathak, V. |author7=Baumann, M. H. | journal=The Journal of Pharmacology and Experimental Therapeutics | title=Studies of the Biogenic Amine Transporters 15. Identification of Novel Allosteric Dopamine Transporter Ligands with Nanomolar Potency | volume=353 | issue=3 | pages=529–538 | date= June 2015 | url=https://linkinghub.elsevier.com/retrieve/pii/S0022356524190416 | doi=10.1124/jpet.114.222299 | pmid=25788711 }}</ref> Patent:<ref>Subramaniam Ananthan & Richard B. Rothman, WO2016090296 (to Southern Research Institute, US Department of Health and Human Services).</ref>

===Herbals=== * cocaine — natural alkaloid and drug of abuse extracted from plants of the genus ''Erythroxylum'' * ''Ginkgo biloba'' extract (EGb761) — "The norepinephrine (NET), the serotonin (SERT), the dopamine (DAT) uptake transporters and MAO activity are inhibited by EGb761 in vitro"<ref>{{Cite journal | doi = 10.1016/j.phrs.2009.02.012| pmid = 19427589| title = Ginkgo biloba extract (EGb761®) influences monoaminergic neurotransmission via inhibition of NE uptake, but not MAO activity after chronic treatment| journal = Pharmacological Research| volume = 60| issue = 1| pages = 68–73| year = 2009| last1 = Fehske | first1 = C. J. | last2 = Leuner | first2 = K. | last3 = Müller | first3 = W. E. }}</ref> * St John's Wort — a natural product and over-the-counter herbal antidepressant which contains: ** Hyperforin ** Adhyperforin ** Uliginosin B — IC₅₀ DA = 90 nM, 5-HT = 252 nM, NE = 280 nM<ref>{{Cite journal | pmid = 22155486| year = 2012| last1 = Stein| first1 = A. C.| title = Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: A promising new molecular pattern for the development of antidepressant drugs| journal = Behavioural Brain Research| volume = 228| issue = 1| pages = 66–73| last2 = Viana| first2 = A. F.| last3 = Müller| first3 = L. G.| last4 = Nunes| first4 = J. M.| last5 = Stolz| first5 = E. D.| last6 = Do Rego| first6 = J. C.| last7 = Costentin| first7 = J| last8 = von Poser| first8 = G. L.| last9 = Rates| first9 = S. M.| doi = 10.1016/j.bbr.2011.11.031| s2cid = 1518033}}</ref><ref>{{Cite patent |country= US |number= 2011313034|title=Neuroactive plant extract from ''Hypericum polyanthemum''|pubdate=2011-12-22|assign1=Universidade Federal Do Rio Grande Do Sul|assign2=Universite de Rouen|inventor1-last=Rates|inventor1-first=Stela Maris Kuze |inventor2-last=Von Poser|inventor2-first=Gilsane Lino |inventor3-last=Viana|inventor3-first=Alice Fialho |inventor4=Jean Costentin & Jean-Claude Do Rego}}</ref> *Oregano extract.<ref name="MechanFowler2010">{{cite journal|last1=Mechan|first1=Annis O.|last2=Fowler|first2=Ann|last3=Seifert|first3=Nicole|last4=Rieger|first4=Henry|last5=Wöhrle|first5=Tina|last6=Etheve|first6=Stéphane|last7=Wyss|first7=Adrian|last8=Schüler|first8=Göde|last9=Colletto|first9=Biagio|last10=Kilpert|first10=Claus|last11=Aston|first11=James|last12=Elliott|first12=J. Martin|last13=Goralczyk|first13=Regina|last14=Mohajeri|first14=M. Hasan|title=Monoamine reuptake inhibition and mood-enhancing potential of a specified oregano extract|journal=British Journal of Nutrition|volume=105|issue=8|year=2010|pages=1150–63|issn=0007-1145|doi=10.1017/S0007114510004940|pmid=21205415|doi-access=free}}</ref> <!--Some language interpreters are able to spoof the words so that it becomes overheard as arecoline by accident.--> *Although not specifically a SNDRI, ''Rosmarinus officinalis'' is one of the trimonoamine modulator (TMM) that affect SER/CAs.<ref name="SasakiEl Omri2013">{{cite journal|last1=Sasaki|first1=Kazunori|last2=El Omri|first2=Abdelfatteh|last3=Kondo|first3=Shinji|last4=Han|first4=Junkyu|last5=Isoda|first5=Hiroko|title=Rosmarinus officinalis polyphenols produce anti-depressant like effect through monoaminergic and cholinergic functions modulation|journal=Behavioural Brain Research|volume=238|year=2013|pages=86–94|issn=0166-4328|doi=10.1016/j.bbr.2012.10.010|pmid=23085339|s2cid=31553844}}</ref> *Hederagenin<ref name="JinGao2012">{{cite journal|last1=Jin|first1=Zeng-Liang|last2=Gao|first2=Nana|last3=Zhou|first3=Dan|last4=Chi|first4=Mu-Gen|last5=Yang|first5=Xue-Mei|last6=Xu|first6=Jiang-Ping|title=The extracts of Fructus Akebiae, a preparation containing 90% of the active ingredient hederagenin: Serotonin, norepinephrine and dopamine reuptake inhibitor|journal=Pharmacology Biochemistry and Behavior|volume=100|issue=3|year=2012|pages=431–9|issn=0091-3057|doi=10.1016/j.pbb.2011.10.001|pmid=22005599|s2cid=207331897}}</ref> *Yuanzhi-1 (''Polygala tenuifolia'').<ref>Jin, Zeng-liang; Gao, Nana; Zhang, Jian-rui; Li, Xiao-rong; Chen, Hong-xia; Xiong, Jie; Li, Yun-feng; Tang, Yu (2014). "The discovery of Yuanzhi-1, a triterpenoid saponin derived from the traditional Chinese medicine, has antidepressant-like activity". Progress in Neuro-Psychopharmacology and Biological Psychiatry. 53: 9–14. doi:10.1016/j.pnpbp.2014.02.013.</ref><ref>Jin, Zeng-liang; Gao, Nana; Li, Xiao-rong; Tang, Yu; Xiong, Jie; Chen, Hong-xia; Xue, Rui; Li, Yun-Feng (2015). "The antidepressant-like pharmacological profile of Yuanzhi-1, a novel serotonin, norepinephrine and dopamine reuptake inhibitor". European Neuropsychopharmacology. 25 (4): 544–556. doi:10.1016/j.euroneuro.2015.01.005.</ref>

==Toxicological== Toxicological screening is important to ensure safety of the drug molecules. In this regard, the p m-dichloro phenyl analog of venlafaxine was dropped from further development after its potential mutagenicity was called into question.<ref>{{Cite journal|doi=10.1021/jm00172a035|title=2-Phenyl-2-(1-hydroxycycloalkyl)ethylamine derivatives: Synthesis and antidepressant activity|year=1990|last1=Yardley|first1=John P.|last2=Husbands|first2=G. E. Morris|last3=Stack|first3=Gary|last4=Butch|first4=Jacqueline|last5=Bicksler|first5=James|last6=Moyer|first6=John A.|last7=Muth|first7=Eric A.|last8=Andree|first8=Terrance|last9=Fletcher|first9=Horace|last10=James|first10=M. N.|journal=Journal of Medicinal Chemistry|volume=33|issue=10|pages=2899–905|pmid=1976813|display-authors=8}}</ref> The mutagenicity of this compound 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 of PRC200-SS was likewise reported.<ref>{{Cite journal|pmid=21258088|year=2011|last1=Guha|first1=M|last2=Heier|first2=A|last3=Price|first3=S|last4=Bielenstein|first4=M|last5=Caccese|first5=RG|last6=Heathcote|first6=DI|last7=Simpson|first7=TR|last8=Stong|first8=DB|last9=Bodes|first9=E|title=Assessment of biomarkers of drug-induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor|volume=120|issue=2|pages=269–83|doi=10.1093/toxsci/kfr013|journal=Toxicological Sciences|doi-access=free}}</ref>

(+)-CPCA ("nocaine")<ref name=nocaine>{{Cite journal|pmid=9599245|year=1998|last1=Kozikowski|first1=AP|last2=Araldi|first2=GL|last3=Boja|first3=J|last4=Meil|first4=WM|last5=Johnson|first5=KM|last6=Flippen-Anderson|first6=JL|last7=George|first7=C|last8=Saiah|first8=E|title=Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton|volume=41|issue=11|pages=1962–9|doi=10.1021/jm980028+|journal=Journal of Medicinal Chemistry}}</ref> is the 3''R'',4''S'' piperidine stereoisomer of (phenyltropane based) RTI-31.<ref name=Wee>{{Cite journal|pmid=15957006|year=2006|last1=Wee|first1=S|last2=Carroll|first2=FI|last3=Woolverton|first3=WL|title=A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants|volume=31|issue=2|pages=351–62|doi=10.1038/sj.npp.1300795|journal=Neuropsychopharmacology|doi-access=free}}</ref> It is non addictive, although this might be due to it being a NDRI, not a SNDRI. The β-naphthyl analog of "Nocaine"<ref name=naphthylnocaine/> is a SNDRI though in the case of both the ''SS'' and ''RR'' enantiomers. Consider the piperidine analogs of brasofensine<ref name=brasofensinepatent/> and tesofensine.<ref name="tesofensinepatent">{{US patent|6395748}}</ref> These were prepared by NeuroSearch (In Denmark) by the chemists Peter Moldt (2002),<ref>{{US patent|6,376,673}}</ref> and Frank Wätjen (2004–2009).<ref>{{Cite patent|country=WO|number=2004039778|title=Novel piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors|pubdate=2004-05-13|assign=NeuroSearch AS|inventor1-last=Wätjen|inventor1-first=Frank}}</ref><ref>{{US patent|7,560,562}}</ref> 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 (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 pair of diastereomers, there is still the question of syn (cis) or anti (trans). 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 isomers are desired. For example, although Alan P. Kozikowski showed that ''R/S'' nocaine is less addictive than ''SS'' Nocaine, studies on variously substituted phenyltropanes by F. Ivy Carroll<ref>Archived at [https://ghostarchive.org/varchive/youtube/20211205/1ZCNaQFVkhs Ghostarchive]{{cbignore}} and the [https://web.archive.org/web/20120324002347/http://www.youtube.com/watch?v=1ZCNaQFVkhs Wayback Machine]{{cbignore}}: {{cite web| url = https://www.youtube.com/watch?v=1ZCNaQFVkhs| title = 2010 N.C. Award for Science: Dr. F. Ivy Carroll | website=YouTube| date = 8 April 2011 }}{{cbignore}}</ref> ''et at.'' revealed that the ββ isomers were less likely to cause convulsions, tremor and death than the corresponding ''trans'' isomers (more specifically, what is meant is the 1''R'',2''R'',3''S'' isomers).<ref>{{Cite journal|pmid=15566309|year=2004|last1=Carroll|first1=FI|last2=Runyon|first2=SP|last3=Abraham|first3=P|last4=Navarro|first4=H|last5=Kuhar|first5=MJ|last6=Pollard|first6=GT|last7=Howard|first7=JL|title=Monoamine transporter binding, locomotor activity, and drug discrimination properties of 3-(4-substituted-phenyl)tropane-2-carboxylic acid methyl ester isomers|volume=47|issue=25|pages=6401–9|doi=10.1021/jm0401311|journal=Journal of Medicinal Chemistry}}</ref> While it does still have to be conceded that RTI-55 caused death at a dosage of 100&nbsp;mg/kg, its therapeutic index 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 (and hence weight loss), 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.<ref>{{Cite web|url=https://www.drugabuse.gov/publications/drugfacts/drug-related-hospital-emergency-room-visits|title=Drug-Related Hospital Emergency Room Visits|last=Abuse|first=National Institute on Drug|website=www.drugabuse.gov|access-date=2016-04-04}}</ref> 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.<ref name=Carroll/><ref name="faster">{{Cite journal |last1=Kimmel |first1=HL |last2=O'Connor |first2=JA |last3=Carroll |first3=FI |last4=Howell |first4=LL |year=2007 |title=Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys |journal=Pharmacology Biochemistry and Behavior |volume=86 |issue=1 |pages=45–54 |doi=10.1016/j.pbb.2006.12.006 |pmc=1850383 |pmid=17258302}}</ref><ref name="RTI112">{{Cite journal |last1=Lindsey |first1=KP |last2=Wilcox |first2=KM |last3=Votaw |first3=JR |last4=Goodman |first4=MM |last5=Plisson |first5=C |last6=Carroll |first6=FI |last7=Rice |first7=KC |last8=Howell |first8=LL |year=2004 |title=Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: Relationship to transporter occupancy determined by positron emission tomography neuroimaging |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=309 |issue=3 |pages=959–69 |doi=10.1124/jpet.103.060293 |pmid=14982963 |s2cid=39794215}}</ref>

Another thing that is important and should be mentioned is the risk for serotonin syndrome 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 serotonin syndrome are complicated and not fully understood.

== Addiction == thumb|The limbic system is the part of the brain associated with emotion and reward. Drug addiction may be regarded as a disease of the brain's reward system.<ref>{{Cite web |last=Abuse |first=National Institute on Drug |date=2020-07-06 |title=Drug Misuse and Addiction {{!}} National Institute on Drug Abuse (NIDA) |url=https://nida.nih.gov/publications/drugs-brains-behavior-science-addiction/drug-misuse-addiction#:~:text=It%20is%20considered%20a%20brain,person%20has%20stopped%20taking%20drugs.&text=Addiction%20is%20a%20lot%20like%20other%20diseases,%20such%20as%20heart%20disease. |archive-url=https://web.archive.org/web/20220127050433/https://nida.nih.gov/publications/drugs-brains-behavior-science-addiction/drug-misuse-addiction#:~:text=It%20is%20considered%20a%20brain,person%20has%20stopped%20taking%20drugs.&text=Addiction%20is%20a%20lot%20like%20other%20diseases,%20such%20as%20heart%20disease. |archive-date=January 27, 2022 |access-date=2025-03-09 |website=nida.nih.gov |language=en}}</ref> This system, closely related to the system of emotional arousal, is located predominantly in the limbic 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.<ref>{{Cite journal |last=Vetulani |first=J. |date=2001 |title=Drug addiction. Part II. Neurobiology of addiction |journal=Polish Journal of Pharmacology |volume=53 |issue=4 |pages=303–317 |issn=1230-6002 |pmid=11990077}}</ref> 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.<ref>{{Cite web |last=curen |date=2021-02-24 |title=Researchers Analyze Cocaine-induced Adaptations in the Medial Prefrontal Cortex |url=https://med.umn.edu/news/researchers-analyze-cocaine-induced-adaptations-medial-prefrontal-cortex#:~:text=Growing%20evidence%20suggests%20that%20chronic,seeking%20and%20drug-taking%20behaviors. |access-date=2025-03-03 |website=Medical School |language=en}}</ref> Dopamine is the primary neurotransmitter involved in the reward mechanism of the limbic system.<ref>{{Cite journal |last1=Del Arco |first1=Alberto |last2=Mora |first2=Francisco |date=August 2009 |title=Neurotransmitters and prefrontal cortex-limbic system interactions: implications for plasticity and psychiatric disorders |journal=Journal of Neural Transmission (Vienna, Austria: 1996) |volume=116 |issue=8 |pages=941–952 |doi=10.1007/s00702-009-0243-8 |issn=1435-1463 |pmid=19475335}}</ref>

== Cocaine == thumb|Cocaine in powder form. Cocaine is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors.<ref name="pmc.ncbi.nlm.nih.gov" /> 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.<ref>{{Cite web |title=Cocaine |url=https://www.dea.gov/factsheets/cocaine |archive-url=https://web.archive.org/web/20250214050740/https://www.dea.gov/factsheets/cocaine |archive-date=2025-02-14 |access-date=2025-03-03 |website=DEA |language=en}}</ref> In addition, cocaine has some serious limitations in terms of its cardiotoxicity due to its local anesthetic activity.<ref>{{Cite journal |title= Cocaine and Cardiotoxicity: A Literature Review|date=2021 |pmc=8136464 |last1=Pergolizzi Jr |first1=J. V. |last2=Magnusson |first2=P. |last3=Lequang |first3=J. A. |last4=Breve |first4=F. |last5=Varrassi |first5=G. |journal=Cureus |volume=13 |issue=4 |article-number=e14594 |doi=10.7759/cureus.14594 |doi-access=free |pmid=34036012 }}</ref> 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.<ref>{{Cite journal |title= Trends of Cocaine Use and Manifestations in Hospitalized Patients: A Cross-Sectional Study|date=2022 |pmc=8830384 |last1=Gangu |first1=K. |last2=Bobba |first2=A. |last3=Basida |first3=S. D. |last4=Avula |first4=S. |last5=Chela |first5=H. |last6=Singh |first6=S. |journal=Cureus |volume=14 |issue=2 |article-number=e22090 |doi=10.7759/cureus.22090 |doi-access=free |pmid=35165645 }}</ref>

Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure.<ref>{{Cite journal |last1=Elfers |first1=Kristin |last2=Menne |first2=Laura |last3=Colnaghi |first3=Luca |last4=Hoppe |first4=Susanne |last5=Mazzuoli-Weber |first5=Gemma |date=2023-02-10 |title=Short- and Long-Term Effects of Cocaine on Enteric Neuronal Functions |journal=Cells |language=en |volume=12 |issue=4 |page=577 |doi=10.3390/cells12040577 |doi-access=free |pmid=36831246 |pmc=9954635 }}</ref> There has been speculation over whether the new SNDRIs will have an abuse potential 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.<ref>{{Cite journal |last1=Rush |first1=Craig R |last2=Stoops |first2=William W |date=February 2012 |title=Agonist Replacement Therapy for Cocaine Dependence: A Translational Review |journal=Future Medicinal Chemistry |language=en |volume=4 |issue=2 |pages=245–265 |doi=10.4155/fmc.11.184 |pmid=22300101 |pmc=3292908 |issn=1756-8919 }}</ref>

{{blockquote| ''... limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness.''<ref>{{Cite journal|pmid=11408518|year=2001|last1=Howell|first1=LL|last2=Wilcox|first2=KM|title=The dopamine transporter and cocaine medication development: Drug self-administration in nonhuman primates|volume=298|issue=1|pages=1–6|journal=The Journal of Pharmacology and Experimental Therapeutics|doi=10.1016/S0022-3565(24)29344-7 }}</ref> }}

== Legality == thumb|Cocaine can be used as a local anesthetic for certain surgeries.<ref name="Cocaine topical route">{{Cite web |title=Cocaine (topical route) |url=https://www.mayoclinic.org/drugs-supplements/cocaine-topical-route/description/drg-20063139 |access-date=2025-03-03 |website=Mayo Clinic |language=en}}</ref> Cocaine 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.<ref name="Cocaine topical route"/>

Brasofensine, 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.<ref>{{Cite web |last=PubChem |title=Brasofensine |url=https://pubchem.ncbi.nlm.nih.gov/compound/Brasofensine |access-date=2025-03-03 |website=pubchem.ncbi.nlm.nih.gov |language=en}}</ref>

Naphyrone, a drug that inhibits monoamine transporters, first appeared in 2006 as one of quite a large number of analogs of pyrovalerone designed by the well-known medicinal chemist P. Meltzer ''et al.''<ref>{{Cite journal |last1=Pinterova-Leca |first1=Nikola |last2=Horsley |first2=Rachel R. |last3=Danda |first3=Hynek |last4=Žídková |first4=Monika |last5=Lhotková |first5=Eva |last6=Šíchová |first6=Klára |last7=Štefková |first7=Kristýna |last8=Balíková |first8=Marie |last9=Kuchař |first9=Martin |last10=Páleníček |first10=Tomáš |date=March 2021 |title=Naphyrone (naphthylpyrovalerone): Pharmacokinetics, behavioural effects and thermoregulation in Wistar rats |journal=Addiction Biology |volume=26 |issue=2 |article-number=e12906 |doi=10.1111/adb.12906 |issn=1369-1600 |pmid=32378298}}</ref> When the designer drugs mephedrone and methylone 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.<ref>{{Cite journal |last1=Vardakou |first1=Ioanna |last2=Pistos |first2=Constantinos |last3=Dona |first3=Artemis |last4=Spiliopoulou |first4=Chara |last5=Athanaselis |first5=Sotiris |date=October 2012 |title=Naphyrone: a "legal high" not legal any more |journal=Drug and Chemical Toxicology |volume=35 |issue=4 |pages=467–471 |doi=10.3109/01480545.2011.642381 |issn=1525-6014 |pmid=22168347}}</ref><ref>{{Cite journal |last1=López-Arnau |first1=Raul |last2=Martínez-Clemente |first2=Jose |last3=Pubill |first3=David |last4=Escubedo |first4=Elena |last5=Camarasa |first5=Jorge |date=2012-08-22 |title=Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone |journal=British Journal of Pharmacology |language=en |volume=167 |issue=2 |pages=407–420 |doi=10.1111/j.1476-5381.2012.01998.x |pmid=22509960 |pmc=3481047 |issn=0007-1188 }}</ref>

=== 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.<ref>{{Cite journal |title= Dopamine dysfunction in stimulant-use disorders: Mechanistic comparisons and implications for treatment|date=2021 |pmc=8664889 |last1=Kohno |first1=M. |last2=Dennis |first2=L. E. |last3=McCready |first3=H. |last4=Hoffman |first4=W. F. |journal=Molecular Psychiatry |volume=27 |issue=1 |pages=220–229 |doi=10.1038/s41380-021-01180-4 |pmid=34117366 }}</ref> This finding has been found for amphetamine and some of its variously substituted analogs including PAL-287 etc. RTI-112 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.<ref name=":0">{{Cite journal |last1=Negus |first1=S.S. |last2=Mello |first2=N.K. |last3=Kimmel |first3=H.L. |last4=Howell |first4=L.L. |last5=Carroll |first5=F.I. |date=January 2009 |title=Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys |journal=Pharmacology Biochemistry and Behavior |language=en |volume=91 |issue=3 |pages=333–338 |doi=10.1016/j.pbb.2008.08.002 |pmid=18755212 |pmc=2645592 |issn=0091-3057 }}</ref>

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.<ref>{{Cite journal |last1=Baumann |first1=M. H. |last2=Ayestas |first2=M. A. |last3=Dersch |first3=C. M. |last4=Brockington |first4=A. |last5=Rice |first5=K. C. |last6=Rothman |first6=R. B. |date=May 2000 |title=Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications |journal=Synapse (New York, N.Y.) |volume=36 |issue=2 |pages=102–113 |doi=10.1002/(SICI)1098-2396(200005)36:2<102::AID-SYN3>3.0.CO;2-# |issn=0887-4476 |pmid=10767057}}</ref> However, not all SNDRIs are reliably self-administered by animals. Examples include: * PRC200-SS was not reliably self-administered.<ref name="PRC200-SS" /> * RTI-112 was not self-administered<ref name="faster" /> because at low doses the compound preferentially occupies the SERT and not the DAT.<ref name="Carroll" /><ref name="RTI112" /> * Tesofensine was also not reliably self-administered by human stimulant addicts.<ref>{{Cite journal |last1=Schoedel |first1=KA |last2=Meier |first2=D |last3=Chakraborty |first3=B |last4=Manniche |first4=PM |last5=Sellers |first5=EM |year=2010 |title=Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users |journal=Clinical Pharmacology and Therapeutics |volume=88 |issue=1 |pages=69–78 |doi=10.1038/clpt.2010.67 |pmid=20520602 |s2cid=39849071}}</ref> * The nocaine 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.<ref name="JZAD-IV-22" />

==Role of monoamine neurotransmitters==

===Monoamine hypothesis=== The original monoamine hypothesis 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;<ref name="Saebom">{{Cite journal |last1=Lee |first1=S |last2=Jeong |first2=J |last3=Kwak |first3=Y |last4=Park |first4=SK |year=2010 |title=Depression research: Where are we now? |journal=Molecular Brain |volume=3 |article-number=8 |doi=10.1186/1756-6606-3-8 |pmc=2848031 |pmid=20219105 |doi-access=free}}</ref><ref name=Lopez>{{Cite journal|pmid=19442174|year=2009|last1=López-Muñoz|first1=F|last2=Alamo|first2=C|title=Monoaminergic neurotransmission: The history of the discovery of antidepressants from 1950s until today|volume=15|issue=14|pages=1563–86|journal=Current Pharmaceutical Design|doi=10.2174/138161209788168001}}</ref> it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways.<ref name="NHM-evolved monoamine hypothesis">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-148127-4 | pages = 355–360 | edition = 2nd | chapter = Chapter 14:Neuropharmacology of Neural Systems and Disorders | quote= Pharmacologic observations such as these led to a simple hypothesis: depression is the result of inadequate monoamine neurotransmission, and clinically effective antidepressants work by increasing the availability of monoamines. Yet this hypothesis has failed to explain the observation that weeks of treatment with antidepressants are required before clinical efficacy becomes apparent, despite the fact that the inhibitory actions of these agents—whether in relation to reuptake or monoamine oxidase—are immediate. This delay in therapeutic effect eventually led investigators to theorize that long-term adaptations in brain function, rather than increases in synaptic norepinephrine and serotonin per se, most likely underlie the therapeutic effects of antidepressant drugs. Consequently, the focus of research on antidepressants has shifted from the study of their immediate effects to the investigation of effects that develop more slowly. The anatomic focus of research on antidepressants also has shifted. Although monoamine synapses are believed to be the immediate targets of antidepressant drugs, more attention is given to the target neurons of monoamines, where chronic alterations in monoaminergic inputs caused by antidepressant drugs presumably lead to long-lasting adaptations that underlie effective treatment of depression. The identification of molecular and cellular adaptations that occur in response to antidepressants, and the location of the cells and circuits in which they occur, are the chief goals that guide current research. The work described toward the beginning of the chapter on mood-regulating circuits that involve the subgenual cingulate gyrus, for instance, represent a significant advance over a narrow focus on monoamine neuron function.&nbsp;...<br />The several weeks latency in onset of the therapeutic actions of antidepressants contributes to distress and clinical risk for those with severe depression. In the search for treatments of more rapid onset, great effort has gone into trying to understand the delay in efficacy of current antidepressants. All current ideas posit that antidepressant-induced increases in synaptic monoamine concentrations cause slowly accumulating adaptive changes in target neurons. Two broad classes of theories have emerged: (1) Changes in protein phosphorylation, gene expression, and protein translation occur in target neurons that ultimately alter synaptic structure or function in a way that relieves symptoms; and (2) antidepressant-induced neurogenesis in the hippocampus and the incorporation of those new neurons into functional circuits is a required step in the therapeutic response. Before considering specific hypotheses, however, it is important to discuss obstacles in relating research in animal models to human depression.}}</ref>

When reserpine (an alkaloid with uses in the treatment of hypertension and psychosis) was first introduced to the West from India 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, 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.<ref>{{Cite journal|pmid=12953623|year=2003|last1=Baumeister|first1=AA|last2=Hawkins|first2=MF|last3=Uzelac|first3=SM|title=The myth of reserpine-induced depression: Role in the historical development of the monoamine hypothesis|volume=12|issue=2|pages=207–20|doi=10.1076/jhin.12.2.207.15535|journal=Journal of the History of the Neurosciences|s2cid=42407412}}</ref>

Tetrabenazine, 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.<ref>{{Cite journal|pmid=14081399|year=1963|last1=Lingjaerde|first1=O|title=Tetrabenazine (Nitoman) in the Treatment of Psychoses. With a Discussion on the Central Mode of Action of Tetrabenazine and Reserpine|volume=39|pages=SUPPL170:1–109|journal=Acta Psychiatrica Scandinavica|doi=10.1111/j.1600-0447.1963.tb07906.x|s2cid=221395033}}</ref><ref name=invited/>

Iproniazid, 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.<ref name=Lopez/><ref name=invited/>

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.<ref name=invited>{{Cite journal|pmid=14748749|year=2004|last1=Slattery|first1=DA|last2=Hudson|first2=AL|last3=Nutt|first3=DJ|title=Invited review: The evolution of antidepressant mechanisms| volume=18|issue=1|pages=1–21|journal=Fundamental & Clinical Pharmacology|doi=10.1111/j.1472-8206.2004.00195.x|s2cid=29459098}}</ref>

In 1965 Schildkraut formulated the catecholamine theory of depression.<ref>{{Cite journal|pmid=5319766|year=1965|last1=Schildkraut|first1=JJ|title=The catecholamine hypothesis of affective disorders: A review of supporting evidence|volume=122|issue=5|pages=509–22|journal=The American Journal of Psychiatry|doi=10.1176/ajp.122.5.509}}</ref> This was subsequently the most widely cited article in the American Journal of Psychiatry.<ref>{{Cite web |url=http://www.fa.hms.harvard.edu/about-our-faculty/memorial-minutes/s/joseph-j-schildkraut/ |title=Joseph J. Schildkraut &#124; Harvard Medical School Office for Faculty Affairs |access-date=2011-03-09 |archive-date=2011-07-19 |archive-url=https://web.archive.org/web/20110719204521/http://www.fa.hms.harvard.edu/about-our-faculty/memorial-minutes/s/joseph-j-schildkraut/ }}</ref> 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.<ref name=invited/>

Inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more SERT selective than the parent compound.<ref name=Lopez/>

Clomipramine 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). In fact, it is also believed that the selective NRI nisoxetine was discovered prior to the invention of fluoxetine.<ref>{{Cite journal|pmid=16121130|year=2005|last1=Wong|first1=DT|last2=Perry|first2=KW|last3=Bymaster|first3=FP|title=Case history: The discovery of fluoxetine hydrochloride (Prozac)|volume=4|issue=9|pages=764–74|doi=10.1038/nrd1821|journal=Nature Reviews Drug Discovery|doi-access=free}}</ref> 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.<ref name="n373">{{cite web | title='Let Them Eat Prozac' — Introduction: The SSRI Issues | website='Let them Eat Prozac' Website | url=https://www.healyprozac.com/Book/Introduction.pdf | access-date=2024-07-12}}</ref> Moreover, NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs.<ref name=Moltzen>{{Cite journal|pmid=17017959|year=2006|last1=Moltzen|first1=EK|last2=Bang-Andersen|first2=B|title=Serotonin reuptake inhibitors: The corner stone in treatment of depression for half a century--a medicinal chemistry survey|volume=6|issue=17|pages=1801–23|journal=Current Topics in Medicinal Chemistry|doi=10.2174/156802606778249810}}</ref> 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 enzyme inhibitor 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.<ref>{{Cite journal|pmid=8629887|year=1996|last1=Miller|first1=HL|last2=Delgado|first2=PL|last3=Salomon|first3=RM|last4=Berman|first4=R|last5=Krystal|first5=JH|last6=Heninger|first6=GR|last7=Charney|first7=DS|title=Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression|volume=53|issue=2|pages=117–28|journal=Archives of General Psychiatry|doi=10.1001/archpsyc.1996.01830020031005}}</ref> 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.<ref>{{Cite journal|pmid=15688090|year=2005|last1=Roiser|first1=JP|last2=McLean|first2=A|last3=Ogilvie|first3=AD|last4=Blackwell|first4=AD|last5=Bamber|first5=DJ|last6=Goodyer|first6=I|last7=Jones|first7=PB|last8=Sahakian|first8=BJ|title=The subjective and cognitive effects of acute phenylalanine and tyrosine depletion in patients recovered from depression|volume=30|issue=4|pages=775–85|doi=10.1038/sj.npp.1300659|pmc=2631648|journal=Neuropsychopharmacology}}</ref> * Administration of fenclonine (''para''-chlorophenylalanine) is able to bring about a depletion of 5-HT. The mechanism of action for this is via tryptophan hydroxylase inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients,<ref name="Shopsin1975">{{Cite journal|pmid=131359|year=1975|last1=Shopsin|first1=B|last2=Gershon|first2=S|last3=Goldstein|first3=M|last4=Friedman|first4=E|last5=Wilk|first5=S|title=Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients|volume=1|issue=2|pages=239–49|journal=Psychopharmacology Communications}}</ref> but it is considered too toxic for use today. * Although depletion of tryptophan — 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.<ref>{{Cite journal|pmid=15738959|year=2005|last1=Castrén|first1=E|title=Is mood chemistry?|volume=6|issue=3|pages=241–6|doi=10.1038/nrn1629|journal=Nature Reviews Neuroscience|s2cid=34523310}}</ref>

===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.<ref name=Nutt>{{Cite journal|pmid=17050654|year=2007|last1=Nutt|first1=D|last2=Demyttenaere|first2=K|last3=Janka|first3=Z|last4=Aarre|first4=T|last5=Bourin|first5=M|last6=Canonico|first6=PL|last7=Carrasco|first7=JL|last8=Stahl|first8=S|title=The other face of depression, reduced positive affect: The role of catecholamines in causation and cure|volume=21|issue=5|pages=461–71|doi=10.1177/0269881106069938|journal=Journal of Psychopharmacology|s2cid=2139339}}</ref><ref>{{Cite journal|pmid=16566899|year=2006|last1=Nestler |first1=EJ |last2=Carlezon Jr|first2=WA |title=The mesolimbic dopamine reward circuit in depression|volume=59|issue=12|pages=1151–9|doi=10.1016/j.biopsych.2005.09.018|journal=Biological Psychiatry|s2cid=18005398}}</ref><ref>{{Cite journal|pmid=16934768|year=2006|last1=Papakostas|first1=GI|last2=Nutt |first2=DJ|last3=Hallett|first3=LA|last4=Tucker|first4=VL|last5=Krishen|first5=A|last6=Fava|first6=M |title=Resolution of sleepiness and fatigue in major depressive disorder: A comparison of bupropion and the selective serotonin reuptake inhibitors|volume=60|issue=12|pages=1350–5|doi=10.1016/j.biopsych.2006.06.015|journal=Biological Psychiatry|s2cid=6886384}}</ref>

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.<ref>{{Cite journal|pmid=12893111|year=2003|last1=McDonald|first1=WM|last2=Richard|first2=IH|last3=Delong|first3=MR|title=Prevalence, etiology, and treatment of depression in Parkinson's disease|volume=54|issue=3|pages=363–75|journal=Biological Psychiatry|doi=10.1016/S0006-3223(03)00530-4|s2cid=45520438}}</ref> * 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.<ref name="Cohen">{{Cite journal|pmid=17403963|year=2007|last1=Cohen|first1=BM|last2=Carlezon Jr|first2=WA|title=Can't get enough of that dopamine|volume=164|issue=4|pages=543–6|doi=10.1176/appi.ajp.164.4.543|journal=The American Journal of Psychiatry}}</ref> * Data from clinical studies have shown that DA agonists, such as bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties.<ref name="Emerging"/> * Amineptine, 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 selegiline (a drug developed for the treatment of PD) has now been approved for the treatment of depression in the form of a transdermal patch (Emsam). For some reason, there have been numerous reports of users taking this drug in conjunction with β-phenethylamine. * 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.<ref>{{Cite journal|pmid=17338594|year=2007|last1=Orr|first1=K|last2=Taylor|first2=D|title=Psychostimulants in the treatment of depression: A review of the evidence|volume=21|issue=3|pages=239–57|journal=CNS Drugs|doi=10.2165/00023210-200721030-00004|s2cid=35761979}}</ref><ref>{{Cite journal|pmid=18425966|year=2008|last1=Candy|first1=M|last2=Jones|first2=L|last3=Williams|first3=R|last4=Tookman|first4=A|last5=King|first5=M|title=Psychostimulants for depression|issue=2|article-number=CD006722|doi=10.1002/14651858.CD006722.pub2|journal=Cochrane Database of Systematic Reviews|editor1-last=Candy|editor1-first=Bridget}}</ref> * 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,<ref>{{Cite journal|pmid=12126656|year=2002|last1=Nieoullon|first1=A|title=Dopamine and the regulation of cognition and attention|volume=67|issue=1|pages=53–83|journal=Progress in Neurobiology|doi=10.1016/S0301-0082(02)00011-4|s2cid=206054231}}</ref> 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.<ref name=invited/>

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.<ref>{{Cite journal|pmid=21155988|pmc=6493872|year=2011|last1=Dell'Osso|first1=B|last2=Palazzo|first2=MC|last3=Oldani|first3=L|last4=Altamura|first4=AC|title=The noradrenergic action in antidepressant treatments: Pharmacological and clinical aspects|volume=17|issue=6|pages=723–32|doi=10.1111/j.1755-5949.2010.00217.x|journal=CNS Neuroscience & Therapeutics}}</ref>

===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 melatonin 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), 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.{{Citation needed|date=December 2015}} Systemic administration of a 5-HT_1A agonist also induces growth hormone and adrenocorticotropic hormone (ACTH) release through actions in the hypothalamus.<ref name=nichols>{{Cite journal|pmid=18476671|year=2008|last1=Nichols|first1=DE|last2=Nichols|first2=CD|title=Serotonin receptors|volume=108|issue=5|pages=1614–41|doi=10.1021/cr078224o|journal=Chemical Reviews}}</ref>

==Current antidepressants== The majority of antidepressants on the market today are a type of Monoamine reuptake inhibitor.

===SSRIs=== The most commonly prescribed class of antidepressants in the USA today are the selective serotonin reuptake inhibitors (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 and weight gain 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.<ref name="Berton2006">{{Cite journal|pmid=16429123|year=2006|last1=Berton|first1=O|last2=Nestler|first2=EJ|title=New approaches to antidepressant drug discovery: Beyond monoamines|volume=7|issue=2|pages=137–51|doi=10.1038/nrn1846|journal=Nature Reviews Neuroscience|s2cid=10488057}}</ref> 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.<ref>{{Cite journal|pmid=12650947|year=2003|last1=Blier|first1=P|title=The pharmacology of putative early-onset antidepressant strategies|volume=13|issue=2|pages=57–66|journal=European Neuropsychopharmacology|doi=10.1016/S0924-977X(02)00173-6|s2cid=38643068}}</ref>

SSRIs can be combined with a host of other drugs including bupropion, 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 (cf. studies done with pindolol). 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.<ref name=Moltzen/>

===NRIs=== Norepinephrine reuptake inhibitors (NRIs) such as reboxetine 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 has found use in the treatment of ADHD as a non-addictive alternative to Ritalin. The chemical structure of atomoxetine is closely related to that of fluoxetine (an SSRI) and also duloxetine (an SNRI).

===NDRIs=== Bupropion is a commonly prescribed antidepressant that acts as a norepinephrine–dopamine reuptake inhibitor (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 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 ADHD; 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. 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 inhibitors (SNRIs) such as venlafaxine (Effexor), its active metabolite desvenlafaxine (Pristiq), and duloxetine (Cymbalta) prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the SSRIs.<ref>{{Cite journal|pmid=17588546|year=2007|last1=Papakostas|first1=GI|last2=Thase|first2=ME|last3=Fava|first3=M|last4=Nelson|first4=JC|last5=Shelton|first5=RC|title=Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents|volume=62|issue=11|pages=1217–27|doi=10.1016/j.biopsych.2007.03.027|journal=Biological Psychiatry|s2cid=45621773}}</ref>

Sibutramine is the name of an SNRI based appetite suppressant with use in the treatment of obesity. This was explored in the treatment of depression, but was shown not to be effective.

Both sibutramine and venlafaxine are phenethylamine-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.

===TCAs=== The first tricyclic antidepressant (TCA), imipramine (Tofranil), was derived from the antipsychotic drug chlorpromazine, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative.<ref name=Lopez/> Imipramine is an iminodibenzyl (dibenzazepine).

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.<ref>{{Cite journal|pmid=21107146|year=2010|last1=Preskorn|first1=SH|title=CNS drug development: Part II: Advances from the 1960s to the 1990s|volume=16|issue=6|pages=413–5|doi=10.1097/01.pra.0000390760.12204.99|journal=Journal of Psychiatric Practice}}</ref>

Another example of a TCA is amineptine 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 trials.<ref name="DaleBang-Andersen2015">{{cite journal|last1=Dale|first1=Elena|last2=Bang-Andersen|first2=Benny|last3=Sánchez|first3=Connie|title=Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs|journal=Biochemical Pharmacology|volume=95|issue=2|year=2015|pages=81–97|issn=0006-2952|doi=10.1016/j.bcp.2015.03.011|pmid=25813654|doi-access=free}}</ref> In addition, the augmentation of a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor with lisdexamfetamine, a norepinephrine–dopamine releasing agent, recently failed to separate from placebo in phase III clinical trials of individuals with treatment-resistant depression, and clinical development was subsequently discontinued.<ref name="DaleBang-Andersen2015" /> These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy.<ref name="DaleBang-Andersen2015" /> As such, skepticism has been cast on the promise of the remaining SNDRIs that are still being trialed, such as ansofaxine (currently in phase II trials), in the treatment of depression.<ref name="DaleBang-Andersen2015" /> Despite being a weak SNDRI, nefazodone has been successful in treating major depressive disorder.<ref>{{Cite journal |last1=Davis |first1=R. |last2=Whittington |first2=R. |last3=Bryson |first3=H. M. |date=April 1997 |title=Nefazodone. A review of its pharmacology and clinical efficacy in the management of major depression |journal=Drugs |volume=53 |issue=4 |pages=608–636 |doi=10.2165/00003495-199753040-00006 |issn=0012-6667 |pmid=9098663|s2cid=239077479 }}</ref>

==See also== * List of antidepressants * Selective serotonin reuptake inhibitor (SSRI) * Serotonin–norepinephrine reuptake inhibitor (SNRI) * Monoamine reuptake inhibitor (MRI)

==References== {{Reflist|30em}}

==External links== *{{Commons category-inline|Serotonin–norepinephrine–dopamine reuptake inhibitors}}

{{Monoamine reuptake inhibitors}}

{{DEFAULTSORT:Serotonin-norepinephrine-dopamine reuptake inhibitor}} Category:Serotonin–norepinephrine–dopamine reuptake inhibitors