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| A '''serotonin–norepinephrine–dopamine reuptake inhibitor''' ('''SNDRI'''), or '''triple reuptake inhibitor''' ('''TRI'''), is a ]/] that simultaneously acts as a ] for the ] ]s, ] (5-HT), ] (noradrenaline, NA) and ] (DA), by blocking the ] of the ] (SERT), ] (NET), and ] (DAT), respectively. This, in turn, leads to increased ] ]s of these ]s and, therefore, an increase in ], ] or ], and ] ]. In this sense, to a degree, there is ] in what these compounds do. This group of ]/] are believed to work in much the same way as the '''nonselective''' ] (] ]), ] through a differing mechanism of activity. | |||
| ] | |||
| Of course, the exact ] depends on the specific compound/s that is/are under consideration. In addition, there is the case of the '''nonselective''' MAOIs, including ] and ], to consider. These also elevate the ] concentration of (and the amount of ] signaling of) ] ] (i.e. 5-HT, NA and DA) in the CNS. Such compounds have often (derogatively/pejoratively/disparagingly) been branded the title ']s' because they recruit a ] of modes of activity. This label can be considered to be ] in so-far as it could be interpreted as meaning that the ] of the compounds is inadequate, when, in fact, this is not the point that is being labored. The most ] (and ]) example of a SNDRI is ]. According to ], it is not sufficient in calling these drugs/ligands nonselective, but that they should be referred to as '''''selectively'''''–nonselective.<ref name=Musk/><ref name=Roth/> This would tend to imply that there is a certain amount of ] involved and it is not just (simply) a ]. | |||
| ==Depression== | |||
| {{Main|Major depressive disorder}} | |||
| ] (MDD) is the foremost reason supporting the need for development of an SNDRI.<ref name=Millan2>{{Cite pmid|19110199}}</ref><ref name=Kulkarni>{{Cite pmid|19426122}}</ref><ref name=Guiard>{{Cite pmid|19702555}}</ref><ref name=Marks>{{Cite pmid|19587855}}</ref><ref name=Chen>{{Cite pmid|17714023}}</ref><ref name=Millan1>{{Cite pmid|16522330}}</ref><ref name=Perona>{{Cite pmid|18690111}}</ref><ref name=Chen2>{{Cite pmid|18311656}}</ref><ref name=Perovic>{{Cite pmid|20856599}}</ref><ref name="Emerging">{{Cite pmid|19501541}}</ref> According to the ], ] is the leading cause of ] and the 4th leading contributor to the ] in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of ].<ref>{{cite web|url=http://www.who.int/mental_health/management/depression/definition/en/|title=Depression|work=]|publisher=WHO|archiveurl=http://www.webcitation.org/5rOPueDPS|archivedate=2010-07-21}}</ref> | |||
| About 16% and 1% of the population are estimated to be affected by major depression and bipolar disorder one or more times during their lifetime, respectively. The presence of the common symptoms of these disorders are collectively called ‘depressive syndrome’ and includes a long-lasting depressed mood, feelings of guilt, anxiety, and recurrent thoughts of death and suicide.<ref name=Saebom>{{Cite pmid|20219105}}</ref> Other symptoms including poor concentration, a disturbance of sleep rhythms (insomnia or hypersomnia), and severe fatigue may also occur. 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 ] with other diseases, e.g. ] (], ]),<ref>{{Cite pmid|22496274}}</ref> ],<ref>{{Cite pmid|21474250}}</ref> ],<ref>{{Cite pmid|22412144}}</ref> Evidence suggests that depressed subjects are more likely to be smokers,<ref>{{Cite|22526528}}</ref> substance abuse,<ref>{{Cite pmid|19945804}}</ref> ] and obesity, high blood pressure, exercise, pathological gambling and internet addiction,<ref>{{Cite pmid|22516274}}</ref> and to have a 15 to 30 year shorter lifetime compared with the general population.<ref>{{Cite pmid|19748369}}</ref> | |||
| Major depression can strike at virtually any time of life as a function of genetic and developmental pre-disposition in interaction with adverse life-events. Although common in the elderly, over the course of the last century, the average age for a first episode has fallen to ~30 years. However, depressive states (with subtly different characteristics) are now frequently identified in adolescents and even children. The differential diagnosis (and management) of depression in young populations requires considerable care and experience; for example, apparent depression in teenagers may later transpire to represent a ] phase of ].<ref name=Millan1/> | |||
| The ability to work, familial relationships, social integration, and self-care are all severely disrupted.<ref name=Millan1/> | |||
| The genetic contribution has been estimated as 40-50%. However, combinations of multiple genetic factors may be involved because a defect in a single gene usually fails to induce the multifaceted symptoms of depression.<ref name=Saebom/> | |||
| ==Pharmacotherapy== | |||
| Currently available antidepressants are effective in many patients. However, all elicit undesirable side-effects. Further, remission is frequently sub-maximal (‘‘residual’’ symptoms), and 30% of patients remain refractory to pharmacotherapy. In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy (‘‘]’’). It is, then, widely appreciated that there remains a need for more efficacious antidepressant agents in terms of: an increase in the proportion of patients responsive to treatment, a greater degree of remission in individual subjects, and more effective prevention of relapse. Novel agents should be divested of the distressing side-effects of both first and second-generation antidepressants.<ref name=Millan1/> | |||
| Although two-thirds of patients will ultimately respond to anti-depressant treatment, one-third of the patients respond to placebo.<ref name=Belmaker>{{Cite pmid|18704023}}</ref> | |||
| A 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 ] and ], the induction of ], and modifications in synaptic architecture and signaling.<ref name=Millan1/> | |||
| Depression has been associated with impaired ] of ], ], and ] pathways, although most pharmacologic treatment strategies directly enhance only 5HT 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 ], ], and ].<ref>{{Cite pmid|17339521}}</ref> | |||
| ] and ] indicates that drugs inhibiting the reuptake of ''all'' (3?) of these ]s can produce a more rapid onset of action and greater efficacy than traditional antidepressants.<ref name=Chen2/> | |||
| DA may promote ] processes in the adult ], as 5-HT and NA do. It is thus possible that the stimulation of multiple ]s resulting from the elevation of all three ] 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 ] (DR) and ] (LC), respectively. In turn, the ] (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 ]s (OCT) and the ] (PMAT).<ref>{{Cite pmid|19022290}}</ref> | |||
| To examine the role of ]s in models of depression DAT, NET, and SERT ] (KO) mice and ] littermates were studied in the ] (FST), the ], 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 ] 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 ] (and ]) diseases are easily solved by such a ]. 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 ] state. | |||
| Most common CNS disorders are highly ] 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 ]"). 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 pmid|20704963}}</ref> | |||
| ] and ] are examples of drugs used in the treatment of CNS disorders that have a superior efficacy precisely ''because'' of their "multifarious" broadspectrum mode of activity. 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 pmid|15060530}}</ref><ref>{{Cite pmid|19110195}}</ref><ref name=Enna>{{Cite pmid|19182069}}</ref><ref>{{Cite pmid|16222266}}</ref><ref>{{Cite pmid|19907483}}</ref><ref>{{Cite pmid|16442279}}</ref><ref>{{Cite pmid|18936753}}</ref> | |||
| Examples of "promiscuous" cancer drugs include: ], ], ], and ]. | |||
| In addition, the nonselective MAOIs and the TCA SNRIs are widely believed to have an '''efficacy''' that is superior to the SSRIs that are normally picked as the first-line choice of agents for/in the treatment of MDD and related disorders. Why then is the situation this way around and not vice versa? The answer to this question lies in the fact that SSRIs are safer than nonselective MAOIs and TCAs. This is both in terms of there being less chance of death in the event of overdose (be it intentional or accidental poisoning), but also less risk in terms of dietary restrictions (in the case of the nonselective MAOIs), and also no chance of hepatotoxicity (in the case of the MAOIs) or cardiotoxicity (in the case of the TCAs). | |||
| ==Applications other than for treating Depression== | |||
| ]]] | |||
| *] (c.f. ]),<ref name=DOV 102,677>{{Cite pmid|22150508}}</ref><ref>{{Cite pmid|17908267}}</ref> | |||
| *] (e.g. ]),<ref>{{Cite doi|10.1016/j.neuropharm.2006.06.009}}</ref> | |||
| *] (e.g. ]),<ref>{{Cite pmid|18089843}}</ref> also tesofensine | |||
| *] (c.f. ]),<ref>http://clinicaltrials.gov/ct2/show/NCT00467428</ref> ] | |||
| *] (c.f. ]),<ref>{{Cite pmid|17325229}}</ref> | |||
| *Neurodegeneration? (] and ]) (c.f. tesofensine and brasofensine). | |||
| The role of serendipity in drug discovery is worth considering. Several of the drugs that are used today in the field of neuropsychopharmacology are the result of "chance" discoveries.<ref>{{Cite pmid|20628954}}</ref> | |||
| *In the case of cocaine, this compound is a well-known ] with medical uses. Often used ] but chewing coca leaves is thought to be taken ] to safeguard against ]. | |||
| ==Examples== | |||
| ]]] | |||
| SNDRIs are not new drugs; Many of them first came to light in the 1980's and 1990's. EXP-561 first appears in the literature as far back as 1967. None of them have been ] for ] so far, although several of the newer agents are under active ] and are currently in ]s. If they are successful, they could become available within the next few years. Drugs like ], ], and ], and the SEP compounds did not pass their clinical trials, either due to lack of efficacy, although in the case of diclofensine it may have been due to its addictive properties. ] has also been the subject of clinical trials, and according to the it has a favorable efficacy in comparing it to the existing compounds which are already on the market. | |||
| Under certain conditions (such as in drug ] subjects or if used at higher than normal dosage), ]<ref>{{US Patent|4535186}}</ref> and also the use of ]<ref>James E. Jeffery, Antonin Kozlik, Eric C. Wilmshurst, {{US Patent|4746680}}, (1988).</ref><ref>James E. Jeffery, Antonin Kozlik, Eric C. Wilmshurst, {{US Patent|4806570}}, (1989).</ref> are said to behave as SNDRIs (although the citation for this can no longer be located). These two agents are more widely thought to behave as ]s though. If one is looking to obtain the elevations in mood felt by all three neurotransmitters, there are certain ways of going about it. Taking ] or ] is one such way. Alternatively, one could try coadministering an ] with ]. | |||
| ] ],<ref>http://www.bindingdb.org/data/mols/tenK5033/MolStructure_50337829.html</ref><ref>{{Cite pmid|21310609}}</ref><ref>{{Cite pmid|21310612}}</ref> prepared by ] ''et al.'' at ] (formally ]).]] | |||
| ;Actual Licensed Pharmaceuticals | |||
| *] | |||
| ; Currently in (or was previously in) clinical trials being tested on humans: | |||
| *] (DOV 21,947 or EB-1010) (2003).<ref name="pmid12586204">{{Cite pmid|12586204}}</ref><ref>{{Cite pmid|22213370}}</ref><ref>{{Cite pmid|21925682}}</ref> | |||
| *] | |||
| *] (NS-2330) (2001).<ref name="tesofensinepatent">{{US patent|6395748}}</ref><ref name="Tesofensine">{{Cite pmid|19548858}}</ref><ref>{{Cite pmid|21889317}}</ref> This is also said to have an ] component to it in addition to behaving as a functional SNDRI. | |||
| *] | |||
| *] (DOV-220,075) (1981).<ref>{{Cite pmid|7241504}}</ref><ref>{{Cite pmid|7241504}}</ref><ref name="ol">Xu F, Murry JA, Simmons B, Corley E, Fitch K, Karady S, Tschaen D. Stereocontrolled synthesis of trisubstituted cyclopropanes: expedient, atom-economical, asymmetric syntheses of (+)-Bicifadine and DOV21947. ''Organic Letters''. 2006 Aug 17;8(17):3885-8.</ref> | |||
| *].<ref>http://www.evaluatepharma.com/Universal/View.aspx?type=Entity&entityType=Product&id=42857&lType=modData&componentID=1002</ref> | |||
| *],<ref>{{cite web|url=http://www.sepracor.com/products/sep225289.html|title=SEP-225289 |accessdate=7 February 2010}} {{Dead link|date=October 2010|bot=H3llBot}}</ref> ].<ref name="pmid17714023">{{cite pmid|17714023}}</ref><ref name="pmid21680689">{{cite pmid|21680689}}</ref> | |||
| *] (Lu AA24530).<ref name="urlDevelopment programme - Lundbeck">{{cite web | url = http://www.lundbeck.com/investor/pipeline/development_programs/default.asp?investors | title = Development programme - Lundbeck | format = | work = | accessdate = }}</ref><ref name="urlSearch of: Lu AA24530 - List Results - ClinicalTrials.gov">{{cite web | url = http://clinicaltrials.gov/ct2/results?term=Lu+AA24530 | title = Search of: Lu AA24530 - List Results - ClinicalTrials.gov | format = | work = | accessdate = }}</ref> | |||
| *] (2004).<ref>{{Cite pmid|15545306}}</ref><ref>{{Cite pmid|20934452}}</ref> | |||
| *] (NS-2214 or BMS-204756) (1995).<ref name=brasofensinepatent>{{Cite patent|EP|0756596}}</ref> | |||
| *] (GSK-372,475).<ref>{{Cite pmid|22048884}}</ref> | |||
| *] (Ro 8-4650) (1982).<ref>{{Cite pmid|6979165}}</ref><ref>{{Cite pmid|7107085}}</ref> 4-aryl-] based. | |||
| *] (1965).<ref>{{US Patent|3308160}}PHENYLBICYCLOOCTANE-L-AMINES AND SALTS THEREOF.</ref> | |||
| ] (4-phenylbicyclooctan-1-amine).]] | |||
| ]".<ref name=Keverline>{{Cite pmid|9457247}}</ref><ref>{{Cite pmid|12027674}}</ref><ref>{{Cite pmid|15755646}}</ref> (1''R'',2''S'',3''S'' ] ] of (] based) ] (Prepared by ] ''et al.'' of ])]] | |||
| ; Clandestine drugs tested on humans | |||
| * ] (aka O-2482, naphthylpyrovalerone and NRG-1) (2006).<ref name=Meltzer>{{Cite pmid|16480278}}</ref><ref name=NRG1>{{cite news|author=Alan Travis, home affairs editor |url=http://www.guardian.co.uk/politics/2010/apr/01/nrg1-legal-high-ban-considered |title=NRG-1 may be next legal high to face ban by ministers | Politics |publisher=The Guardian |date=2010-04-01 |accessdate=2010-04-03}}</ref><ref>{{Cite pmid|22092008}}</ref> | |||
| ; Research compounds (with no written record of ever having been taken by humans): | |||
| *] (2006–2011).<ref name=DOV 102,677/> | |||
| *] (1985).<ref>{{Cite pmid|2999402}}</ref> | |||
| *] (''trans''-(RS)-]) (1980).<ref>{{Us patent|4556676}}</ref> | |||
| *] (2005),<ref>{{Cite patent|WO|2005041875}}</ref> and, more recently (2010), ].<ref name=JZAD-IV-22>{{Cite pmid|20864506}}</ref> | |||
| *] (]) (2001).<ref>{{Cite pmid|12954808}}</ref> | |||
| *] (2008),<ref name=PRC200-SS>{{Cite pmid|18689611}}</ref> ], and ]. | |||
| *] (1978).<ref>{{Cite pmid|22757}}</ref> | |||
| *] analogs (2002).<ref>{{Cite pmid|12213054}}{{Cite pmid|12213053}}</ref> | |||
| *] (2008),<ref name=Alusio>{{Cite pmid|18499098}}</ref> (first appeared in the 1987) structurally related to simpler 4-aryl ] compounds including ]. | |||
| *] (2010).<ref>{{Cite pmid|21174473}}</ref><ref>{{Cite pmid|20527970}}</ref> | |||
| *3,4-disubstituted pyrrolidines (2001).<ref>{{Cite pmid|11354356}}</ref> | |||
| *3,3-disubstituted pyrrolidine (2008).<ref>{{Cite pmid|18954985}}</ref> | |||
| *2- and 3-ketopyrrolidines (2010).<ref name="Lucas2010">{{Cite pmid|20691589}}</ref> | |||
| *] (2008).<ref>{{Cite pmid|18561912}}</ref> | |||
| *Naphthyl ] analog (2007).<ref>{{Cite pmid|17350257}}</ref> (also NMDA receptor antagonist) | |||
| *] (1978).<ref name=LR5182one>{{Cite pmid|713683}}</ref><ref name=LR5182two>{{Cite pmid|460546}}</ref><ref>{{Cite pmid|7381469}}</ref> | |||
| *A host of ] including ], ] and ].<ref name=Carroll>{{Cite pmid|12723940}}</ref> | |||
| *3-aryl-3-azolylpropan-1-amines (2010).<ref>{{Cite pmid|20724153}}</ref> | |||
| *2-Substituted N-aryl piperazines (2010).<ref name="Lucas2010" /> | |||
| *TP1 (2011).<ref>{{Cite pmid|21925241}}</ref> | |||
| *1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicycloheptane (2011).<ref>{{Cite pmid|21550808}}</ref> | |||
| *4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol (2011).<ref>{{Cite pmid|21446715}}</ref> | |||
| *4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines (2011).<ref>{{Cite pmid|21093273}}</ref> | |||
| *] (DMNPC) (2000).<ref name=naphthylnocaine>{{cite pmid|10737754}}</ref> | |||
| ; Natural: | |||
| *] | |||
| *Extracts of ], a preparation containing 90% of the active ingredient ] (2011).<ref>{{Cite pmid|22005599}}</ref> | |||
| *] | |||
| ; Patented material with no link to University Research Publications | |||
| *Bruce Molino ''et al.'' Aryl- and heteroaryl-substituted tetrahydrobenzazepines (2011).<ref>{{US patent|7,956,050}}</ref> | |||
| *Beck ''et al.'' Aryl and heteroaryl substituted tetrahydroisoquinolines and use thereof (2009).<ref>{{US patent|7,612,090}}</ref> | |||
| ] | |||
| The above-listed compounds constitute only a small percentage of the known triple-reuptake inhibitors that are available, and, in general, have been picked for use in research or possible ] because of their favourable ] and ] characteristics that made them stand out from the much larger pool of structurally diverse compounds that show similar high-binding affinity for the target monoamine transporter proteins ''in vitro''. | |||
| ==]== | |||
| ] screening is important to ensure safety of the drug molecules. In this regard, the ]]-di]] ] of ] was dropped from further ] after its ] ] was called into ].<ref>{{Cite doi|10.1021/jm00172a035}}</ref> The ] of this ] is still doubtful though. It was dropped for other reasons likely related to ] at which it could be released onto the ] relative to the more developed ] ]. More recently, the ] of ] was likewise ].<ref name="PRC200-SS">{{Cite pmid|21258088}}</ref> | |||
| ] ("]")<ref name=nocaine>{{Cite pmid|9599245}}</ref> is the 3''R'',4''S'' ] ] of (] based) ].<ref name=Wee>{{Cite pmid|15957006}}</ref> It is non addictive but is not a ] (it is a ]). ]<ref name=naphthylnocaine/> is a ] though in the case of both the ''SS'' and ''RR'' enantiomers. Consider the piperidine analogs of ]<ref name=brasofensinepatent/>and ].<ref name="tesofensinepatent"/> These were prepared by ] (In ]) by the ] ] (2002),<ref>{{US patent|6,376,673}}</ref> and ] (2004–2009).<ref>{{Cite patent|WO|2004039778}}</ref><ref>{{US patent|7,560,562}}</ref> Acknowledge that there are '''four''' separate isomers to consider (''SS'', ''RR'', S/R and R/S). This is because there are two ] sites of ] (means 2 to the power of n isomers to consider where n is the number of chiral carbons). We call this situation a diastereo(iso)meric pair of racemers. Say we get a ] pair of diastereomers, there is still the question of ] (]) or ] (]). 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. | |||
| ] | |||
| This is complicated situation to explain which ] we want. For example, although ] showed that R/S Nocaine is less addictive than ''SS'' Nocaine, studies on variously substituted phenyltropanes by ]<ref>http://www.youtube.com/watch?v=1ZCNaQFVkhs</ref> ''et at.'' revealed that the ββ isomers were less likely to cause ], ] and ] than the corresponding ''trans'' isomers (more specifically, what is meant is the 1''R'',2''R'',3''S'' isomers).<ref>{{Cite pmid|15566309}}</ref> While it does still have to be conceded that ] caused death at a dosage of 100mg/kg, it's ] (of safety) is still much better than the corresponding ''trans'' isomers because it is more potent compound. | |||
| In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased ] (and hence ]), increased locomotor activity (LMA) etc. Apparently in the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose. People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. Interestingly, 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 ]s 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 ].<ref name=Carroll/><ref name=faster/><ref name=RTI112/> | |||
| Another thing that is important and should be mentioned is the risk for ] when incorporating the element of 5-HT transporter inhibition into a compound that is already fully active as a ] (or vice versa). The reasons for ] are complicated and not fully understood. | |||
| ==Addiction== | |||
| Drug addiction may be regarded as a disease of the brain reward system. This system, closely related to the system of emotional arousal, is located predominantly in the ] structures of the brain. Its existence was proved by demonstration of the “pleasure centers,” that were discovered as the location from which ] is readily evoked. The main neurotransmitter involved in the reward is ], but other monoamines and ] may also participate. The anatomical core of the reward system are dopaminergic neurons of the ] that project to the ], ], ] and other forebrain structures.<ref name=Vetulani2>{{Cite pmid|11990077}}</ref> | |||
| There are several groups of substances that activate the reward system and they may produce addiction, which in humans is a chronic, recurrent disease, characterized by absolute dominance of drug-seeking behavior.<ref name=Vetulani2/> | |||
| <ref>{{Cite pmid|17825265}}</ref><ref>{{Cite pmid|19710631}}</ref> | |||
| 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. | |||
| The above finding has been found for amphetamine and some of its variously substituted analogs including ] etc.<ref>{{Cite pmid|21228061}}</ref><ref>{{Cite pmid|19086767}}</ref><ref>{{Cite pmid|19766133}}</ref> | |||
| ] 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=faster>{{Cite pmid|17258302}}</ref> | |||
| ], ], ] and ] were all compared and it was found that there was a negative correlation between the size of the halogen atom and the rate of self-administration (on moving across the series).<ref name="Wee" /> Rate of onset was held partly accountable for this, although increasing the potency of the compounds for the serotonin transporter also played a role. | |||
| Further evidence that 5-HT dampens the reinforcing actions of dopaminergic medications comes from the co-administration of psychostimulants with SSRIs,<ref>{{Cite pmid|17105829}}</ref> and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.<ref>{{Cite pmid|9668665}}</ref> | |||
| NET blockade is unlikely to play a major role in mediating addictive behavior. This finding is based on the premise that ] is not self-administered,<ref>{{Cite pmid|16213110}}</ref> and also the fact that the NRI ] was not reinforcing.<ref>{{Cite pmid|15283948}}</ref> However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the ]. | |||
| ===Relation to cocaine=== | |||
| ].]] | |||
| ].]] | |||
| ] is a short-acting SNDRI that also exerts auxiliary pharmacological actions on other receptors. Cocaine is a relatively "balanced" inhibitor, although facilitation of dopaminergic neurotransmission is what has been linked to the reinforcing and addictive effects. In addition, cocaine has some serious limitations in terms of its ]<ref>{{Cite pmid|19463023}}</ref> due to its ] activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health. | |||
| Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their ]. There has been speculation over whether the new SNDRIs will have an ] like cocaine does. However, for pharmacotherapeutical treatment of cocaine addiction it is advantageous if a substitute medication is at least weakly reinforcing because this can serve to retain addicts in treatment programmes: | |||
| <blockquote> | |||
| ''... limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness.''<ref>{{Cite pmid|11408518}}</ref> | |||
| </blockquote> | |||
| However, not all SNDRIs are reliably self-administered by animals. Examples include: | |||
| *PRC200-SS was not reliably self-administered.<ref name=PRC200-SS/> | |||
| *] 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>{{Cite pmid|14982963}}</ref> | |||
| *] was also not reliably self-administered by ] ] ]s.<ref>{{Cite pmid|20520602}}</ref> | |||
| *The ] analog ] 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/> | |||
| ==]== | |||
| The '''rate''' of onset of the drug needs to be sufficiently rapid to ensure a ] therapeutic response. Although the rate of onset might be thought to be intrinsically related to the compounds molecular structure (c.f. the specific case of the phenytropanes) and the rate at which it penetrates the BBB, the '''route'''(or method) of administration is clearly also important. There are a number of choices: ], ], ], eyes, nose, swallow pill. Dissolving drug in mouth on tongue is the preferred choice. Particularly desirable is cases where the drug is so potent that it can be distributed on blotter paper. | |||
| The compounds duration(span) must be sufficiently long to prevent it from being repeatedly self-administered, which would tend to indicate a high propensity for abuse (e.g. nicotine). In terms of risk of overdose, a subject is less likely to redose if the effects of having taken the drug are felt immediately (or at least, within a short time afterwards) relative to a situation where there is a slower onset of action. | |||
| Compounds that are extremely lipophilic and resistant to metabolic deactivation are not necessarily desirable. Say that the user takes his drug in the morning after he(she) wakes up. They want the effects of the drug to last all day long without needing to re-dose so the effects of the medication should be long lasting. However, by the time they are thinking about going to bed at the end of the day they will want the drug to be in the stages of wearing off so that it doesn't interrupt their sleeping. Also supposing the subject accidently takes an overdose or starts experiencing a headache then they will want to abort the experience and to start returning to baseline. In the case of slow-onset, long-duration psychoactive the effects might actually intensify by the time that this point is reached and it could take several days before it is cleared from their system. | |||
| Examples of drugs that are very lipophilic and long-lasting would include such compounds as ] and ]. | |||
| ==Affordability (i.e. cost)== | |||
| ] | |||
| Obviously the more complicated the molecule and the less yielding (more difficult) the chemical reactions that lead to it, then the more expensive a given compound will be. Some chemical reactants and reagents clearly cost more than others. Consider the case where there are sites of asymmetry and more than one isomer that the chemist may need to separate in order to purify the final compound/intermediates. | |||
| ] and ] look like highly sophisticated molecules but it is still questionable how affordable they would be. | |||
| Consider the process of ]. It may be conceivable that the low energy isomers were chosen because these are cheaper and easier to obtain. | |||
| Clearly if a compound is highly potent then less of it has to be consumed for a given dose. This might off-set the increased cost of making a more complicated molecule. As an example for this consider the case of ] versus the Pyrroloisoquinoline derivative of it. The SAR for this is in the ] document. | |||
| ==Legality== | |||
| ] is obviously illegal (class A in the UK), although in the USA it is only schedule II since despite having some "abuse potential" it is recognized that it does have medical uses. | |||
| ] was made "class A" in the UK under the MDA (misuse of drugs act). BF is an interesting compound in so far as the semi-synthetic procedure for making it actually uses cocaine as the starting material. | |||
| ] first appeared in 2006 as one of quite a large number of analogs of ] designed by the well-known medicinal chemist ] ''et al.''<ref name=Meltzer/> When the ]s ] and ] 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.<ref name=mephedrone>{{Cite pmid|22169943}}</ref> Anyway, a short time after mephedrone and methylone were banned (which had become quite popular by the time they were illegalized), naphyrone appeared under the trade name NRG-1.<ref name=NRG1/> NRG-1 was promptly illegalized, although it is not known if its use resulted in any hospitalizations or deaths. | |||
| From a medical perspective considerations of health and safety are important when considering legality but there might be other factors to consider such as the impact on economical productivity given that a psychoactive drug can influence decision making processes(behaviour). | |||
| ==Role of monoamine neurotransmitters== | |||
| ===Monoamine Hypothesis=== | |||
| The ] 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=Lopez>{{Cite pmid|19442174}}</ref><ref name=Saebom/> | |||
| When ] (an ] with uses in the treatment of ] and ]) was first introduced to ] from ] 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 ], leading to their increased catabolism by monoamine oxidase. However, not everyone has been convinced by claims that reserpine is depressogenic, some authors (] in particular) have even claimed that it is antidepressant.<ref>{{Cite pmid|12953623}}</ref> | |||
| ], 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 pmid|14081399}}</ref><ref name=invited/> | |||
| ], 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=invited/><ref name=Lopez/> | |||
| 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 ] 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 pmid|14748749}}</ref> | |||
| In 1965 Schildkraut formulated the ] theory of depression.<ref>{{Cite pmid|5319766}}</ref> This was subsequently the most widely cited article in the ].<ref>http://www.fa.hms.harvard.edu/about-our-faculty/memorial-minutes/s/joseph-j-schildkraut/</ref> The theory stated that: | |||
| {{cquote|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 ], a drug that is much more SERT selective than the parent compound.<ref name=Lopez/> | |||
| Clomipramine was a precursor leading to the development of the more recent SSRIs. There was, in fact, a time prior to the SSRIs when selective NRIs were being considered (c.f. ] and ]). In fact, it is also believed that the selective NRI ] was discovered prior to the invention of ].<ref>{{Cite pmid|16121130}}</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>http://www.healyprozac.com/Book/Introduction.pdf</ref> Moreover, NRIs have the additional adverse safety risk of ] that is not seen for SSRIs.<ref name=Moltzen>{{Cite pmid|17017959}}</ref> Nevertheless NRIs have still found uses. | |||
| Further support for the monoamine hypothesis came from monoamine depletion studies: | |||
| *Alpha-methyl-''p''-tyrosine (]) is a ] ] 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 pmid|8629887}}</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 pmid|15688090}}</ref> | |||
| *Administration of ] (''para''-chlorophenylalanine) is able able to bring about a depletion of 5-HT. The mechanism of action for this is via ] inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients,<ref name="Shopsin1975">{{Cite pmid|131359}}</ref><ref name="Shopsin1975" /> but it is considered too toxic for use today. | |||
| *Although depletion of ] — 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 pmid|15738959}}</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 pmid|17050654}}</ref><ref>{{Cite pmid|16566899}}</ref><ref>{{Cite pmid|16934768}}</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 suffering from PD.<ref>{{Cite pmid|12893111}}</ref> | |||
| *Patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to suffer from symptoms of depression.<ref name="Cohen"> {{Cite pmid|17403963}}</ref> | |||
| *Data from clinical studies have shown that DA agonists, such as ], ] and ], exhibit antidepressant properties.<ref name="Emerging"/> | |||
| *], 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 ] ] (a drug developed for the treatment of PD) has now been approved for the treatment of depression in the form of a ] patch (]). For some reason, there have been numerous reports of users taking this drug in conjunction with beta-]. | |||
| *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 pmid|17338594}}</ref><ref>{{Cite pmid|18425966}}</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 pmid|12126656}}</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. | |||
| ===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 ] ] 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. | |||
| 5-HT is known to cause hallucinations through activating the 5HT<sub>2A</sub> receptor. | |||
| In most cases serotonergic activation of receptors can result in a more ] state. It is dependent upon the exact therapeutic agent under discussion. | |||
| Appetite suppression is related to 5-HT<sub>2C</sub> receptor activation as for example was reported for PAL-287 recently. | |||
| Activation of the 5HT<sub>2C</sub> receptor has been described as "panicogen" by users of ligands for this receptor (e.g., ]). Antagonism of the 5HT<sub>2C</sub> receptor is known to augment dopaminergic output. Although SSRIs with 5HT<sub>2C</sub> antagonist actions were recommended for the treatment of depression, 5HT<sub>2C</sub> receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless the 5HT<sub>2C</sub> is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonized. | |||
| Azapirone-type drugs (e.g., ]), which act as 5-HT<sub>1A</sub> receptor agonists and partial agonists have been developed as novel 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<sub>1A</sub> receptors. Systemic administration of a 5-HT<sub>1A</sub> agonist also induces ] and ] (ACTH) release through actions in the ].<ref name=nichols>{{Cite pmid|18476671}}</ref> | |||
| ===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 a2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of a2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of a2-adrenoceptor activity) although platelet studies proved inconsistent. This | |||
| supersensitivity of a2-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, a2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of a2-adrenoceptors present on 5-HT nerve terminals. | |||
| <ref>{{Cite pmid|21155988}}</ref> | |||
| ===Anxiety=== | |||
| The ] of fear appears to focus on the ]. The amygdala receives noradrenergic innervation from the ] and serotonergic projections from the midbrain ]. High levels of amygdala activation are associated with an increased prevalence of anxiety symptoms and dispositional negative affect. Electrical stimulation of the amygdala can evoke emotional experiences, especially fear and anxiety, and vivid recall of emotional life events. | |||
| ===Neurotrophins and CREB=== | |||
| A SNDRI may also possibly be considered ]. There is evidence linking the use of ] to increased expression of ] (in particular, ]).<ref>{{Cite pmid|18571629}}</ref><ref>{{Cite pmid|17634380}}</ref><ref name=Malberg2005>{{Cite pmid|16246434}}</ref> These are believed to be ]. | |||
| However, although tranylcypromine and ECS increase BDNF mRNA levels, the more selective antidepressants such as desipramine and fluoxetine have variable effects.<ref name=Malberg2005/> Thus, because nonselective SNDRIs recruit a plurality of modes of activity, they are more likely to be effective at elevating BDNF RNA. | |||
| The ] is one of several limbic brain structures implicated in the pathophysiology and treatment of mood disorders. Preclinical and clinical studies demonstrate that stress and depression lead to reductions of the total volume of this structure and ] and loss of neurons in the adult hippocampus. One of the cellular mechanisms that might account for alterations in hippocampal structure as well as function is the regulation of adult ]. Stress exerts a profound effect on neurogenesis, leading to a rapid and prolonged decrease in the rate of cell proliferation in the adult hippocampus. In contrast, chronic antidepressant treatment up-regulates hippocampal neurogenesis, and could thereby block or reverse the atrophy and damage caused by stress. Recent studies show that neurogenesis is also requisite for the actions of antidepressants in behavioral models of depression.<ref>{{Cite pmid|16425236}}</ref> | |||
| ==Current antidepressants== | |||
| Most antidepressants on the market today target the monoaminergic system. | |||
| ===SSRIs=== | |||
| The most commonly prescribed class of antidepressants in the USA today are the ]s. 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 ] and ] 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 pmid|16429123}}</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 pmid|12650947}}</ref> | |||
| SSRIs can be combined with a host of other drugs including bupropion, alpha-2 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<sub>1A</sub> receptors. 5-HT<sub>1A</sub> receptors are located presynaptically as well as post-synaptically. It is the presynaptic receptors that are believed to function as ] (cf. studies done with ]). 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=== | |||
| ]s 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, ] has found use in the treatment of ] as a non-addictive alternative to ]. The chemical structure of atomoxetine is closely related to that of fluoxetine (an SSRI) and also duloxetine (SNRI). | |||
| ===NDRIs=== | |||
| Bupropion is a commonly prescribed antidepressant that acts as an ]. 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. ] is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Ritalin is used in the treatment of ], its use in treating depression is not known to have been reported, it is presumed owing to its psychomotor activating effects and it functioning as a ]. There are also reports of Ritalin 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. | |||
| ===SNRI=== | |||
| ] such as ] (trade name "Effexor"), its active metabolite ] ("Pristiq"), and ] ("Cymbalta") prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the SSRIs.<ref>{{Cite pmid|17588546}}</ref> | |||
| ] is the name of an SNRI based appetite suppressant with use in the treatment of ]. This was explored in the treatment of depression, but was shown not to be effective. | |||
| Both sibutramine and venlafaxine are ] based. At high doses, both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA re-uptake is unlikely to be relevant at clinically approved doses. | |||
| These drugs all feel markedly different, although the fact that they are all branded as SNRIs might lead some people into believing that they are similar. One must consider structure-activity-relationships in accounting for this. It is likely that duloxetine is antihistaminergic whereas sibutramine causes hypertension. | |||
| A number of analogs of sibutramine are known that behave as SNDRIs, changing the aromatic substituent in venlafaxine can also affect the degree of noradrenergic activation, although it is unclear to what extent the dopaminergic pathways can also be affected. | |||
| D Wong was unaware of any analogs of fluoxetine/atomoxetine/nisoxetine/duloxetine based on the same structural motifs that displayed dopaminergic activity. | |||
| ] is a further example of an SNRI. | |||
| ===NaSSAs=== | |||
| The ] (TeCAs), or, to be more specific, the ] (NaSSAs), such as mirtazapine, antagonise various serotonergic and noradrenergic receptors leading to a greater outflow of these neurotransmitters. However mirtazapine's strong antagonism of the ] can result in sedation, and the drug often causes significant ]. | |||
| ===Atypical=== | |||
| Agomelatine also targets various serotonin receptors and uniquely the melatonin receptors, another monoamine neurotransmitter. | |||
| It is interesting to note that ] enhances the reuptake of serotonin (according to earlier studies but disputed later), yet has comparable efficacy to the other antidepressants and an excellent side-effect profile. | |||
| Consider also ] and ]. | |||
| ] are also being explored within the context of treating ] and related conditions.<ref>{{Cite pmid|15738862}}</ref> | |||
| ===MAOIs=== | |||
| The first antidepressant agents were discovered entirely by serendipity.<ref name=Lopez/> ] (the first ]) was originally developed as an ] agent but was then unexpectedly found to display antidepressant activity. | |||
| It is interesting to note that ] also displayed activity as an antidepressant, even though it is not a MAOI.<ref>{{Cite pmid|11478422}}</ref> This led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the MAOI activity could be a secondary side-effect. However, with the discovery of tranylcypromine (the first non-hydrazine MAOI), it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents. ] is another example of a non-hydrazine MAOI that was introduced. | |||
| The MAOIs work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. The fact that they are more efficacious than the newer generation antidepressants is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters. The problem with MAOIs is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. Although selective MAOIs can reduce, if not eliminate these risks, their efficacy tends to be lower. | |||
| MAOIs may preferentially treat TCA-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. This may be a function of the | |||
| ability of MAOIs to increase synaptic levels of DA in addition to 5-HT and NE. The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia (FM) or chronic fatigue syndrome (CFS). | |||
| Although a substantial number of MAOIs were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. The reason for this is that they were ] and could cause ]. | |||
| ===TCAs=== | |||
| The first ] (]) was derived from the ] drug ], which was developed as a useful ] agent with possible use as a hypnotic sedative.<ref name=Lopez/> Imipramine is an iminodibenzyl (]). | |||
| 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 (α-1) 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 pmid|21107146}}</ref> | |||
| Another example of an interesting TCA is ] which is the only one believed to function as a ]. Although this used to be available it is no longer available now and was replaced with ] instead. | |||
| ==Beyond Monoamines== | |||
| Certain studies have suggested the inclusion of other neurotransmitters and molecular targets than just the monoamines in the treatment of depression.<ref>{{Cite pmid|19442173}}</ref><ref name="Berton2006" /><ref name=Millan1/><ref>{{Cite pmid|15330686}}</ref> | |||
| Cocaine also has auxiliary actions on other receptors: it has muscarinic activity, is a sigma agonist and has sodium channel blocking activity. | |||
| Ketamine is antidepressant and behaves as a NMDA antagonist. | |||
| Both the ] (c.f. ketamine) and GABA neurotransmitters are involved in depression.<ref>{{Cite pmid|16400244}}</ref> | |||
| Opiates are known to exhibit antidepressant activities.<ref name="opiates"> {{Cite pmid|18956529}}</ref> | |||
| Lots of new targets for depression are emerging. ] | |||
| ==See also== | |||
| * ] | |||
| * ] (SRI) | |||
| * ] (SSRI) | |||
| * ] (NRI) | |||
| * ] (SNRI) | |||
| * ] (DRI) | |||
| * ] (NDRI) | |||
| == References == | |||
| {{reflist|32em}} | |||
| {{Antidepressants}} | |||
| {{Anxiolytics}} | |||
| {{Stimulants}} | |||
| {{Psychostimulants, agents used for ADHD and nootropics}} | |||
| {{Anorectics}} | |||
| ] | |||
Revision as of 08:45, 12 May 2012
My previous usernames are Nuklear and Yid. I got banned with both of these names.