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Serotonin–norepinephrine–dopamine reuptake inhibitor

September 02, 2023

A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), also known as a triple reuptake inhibitor (TRI), is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It does this by concomitantly inhibiting the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT), respectively. Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and, therefore, results in an increase in serotonergic, adrenergic, and dopaminergic neurotransmission. The naturally-occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces.

Other SNDRIs were developed as potential antidepressants and treatments for other disorders, such as obesity, cocaine addiction, attention-deficit hyperactivity disorder (ADHD), and chronic pain. They are an extension of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) whereby the addition of dopaminergic action is thought to have the possibility of heightening therapeutic benefit. However, increased side effects and abuse potential are potential concerns of these agents relative to their SSRI and SNRI counterparts.

The SNDRIs are similar to non-selective monoamine oxidase inhibitors (MAOIs) such as phenelzine and tranylcypromine in that they increase the action of all three of the major monoamine neurotransmitters. They are also similar to serotonin–norepinephrine–dopamine releasing agents (SNDRAs) like MDMA ("ecstasy") and α-ethyltryptamine (αET) for the same reason, although they act via a different mechanism and have differing physiological and qualitative effects.

Although their primary mechanisms of action are as NMDA receptor antagonists, ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse.

Indications Edit

Depression Edit

Major depressive disorder (MDD) is the foremost reason supporting the need for development of an SNDRI.[1][2][3][4][5][6][7][8][9][10] 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.[11]

About 16% of the population is estimated to be affected by major depression, and another 1% is affected by bipolar disorder, one or more times throughout an individual's lifetime. 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.[12] 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.[6] Depression is often highly comorbid with other diseases, e.g. cardiovascular disease (myocardial infarction,[13] stroke),[14] diabetes,[15] cancer,[16] Depressed subjects are prone to smoking,[17] substance abuse,[18] eating disorders, obesity, high blood pressure, pathological gambling and internet addiction,[19] and on average have a 15 to 30 year shorter lifetime compared with the general population.[14]

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 prodromal phase of schizophrenia.[6]

The ability to work, familial relationships, social integration, and self-care are all severely disrupted.[6]

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.[12]

Pharmacotherapy Edit

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,[20] 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.[6]

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.[6]

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.[4] 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.[21]

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.[8]

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.[3]

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.[3]

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).[22]

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.[7]

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.[23]

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.[23][24][25][26][27][28][29][30]

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.[31] 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 Edit

List of SNDRIs Edit

Approved pharmaceuticals Edit

Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI in vitro with values of 298 nM at SERT, 5451 at NET, 943 nM at DAT.[38] 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%).[40][41][1]

Venlafaxine (Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced with values of 82 nM for SERT, 2480 nM for NET, and 7647 nM for DAT, with a ratio of 1:30:93.[42] It may weakly inhibit the reuptake of dopamine at high doses.[43]

Coincidental Edit

Undergoing clinical trials Edit

  • Ansofaxine (LY03005/LPM570065).[49] Completed Phase 2 & 3 trials. FDA accepted NDA application.[50]
  • Centanafadine (EB-1020) – see here for details 1 to 6 to 14 ratio for NDS. Completed Phase 3 trials for ADHD.[51]
  • OPC-64005 - In phase 2 trials (2022)[52]
  • Lu AA37096 – see here (SNDRI and 5-HT6 modulator)
  • NS-2360 – principle metabolite of tesofensine
  • Tesofensine (NS-2330) (2001) In trials for obesity.[53]

Failed clinical trials Edit

Designer drugs Edit

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

 
3,4-Diphenylpiperidine
 
3,4-Diphenylquinuclidine
 
MDL 47,832

Herbals Edit

Toxicological Edit

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.[158] 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.[159]

(+)-CPCA ("nocaine")[160] is the 3R,4S piperidine stereoisomer of (phenyltropane based) RTI-31.[161] It is non addictive, although this might be due to it being a NDRI, not a SNDRI. The β-naphthyl analog of "Nocaine"[93] is a SNDRI though in the case of both the SS and RR enantiomers. Consider the piperidine analogs of brasofensine[56] and tesofensine.[162] These were prepared by NeuroSearch (In Denmark) by the chemists Peter Moldt (2002),[163] and Frank Wätjen (2004–2009).[164][165] 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[166] 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 1R,2R,3S isomers).[167] While it does still have to be conceded that RTI-55 caused death at a dosage of 100 mg/kg, it's therapeutic index 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 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.[168] 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.[107][169][170]

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 Edit

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 limbic structures of the brain. Its existence was proved by demonstration of the "pleasure centers," that were discovered as the location from which electrical self-stimulation is readily evoked. The main neurotransmitter involved in the reward is dopamine, but other monoamines and acetylcholine may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens, amygdala, prefrontal cortex and other forebrain structures.[171]

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.[171][172][173]

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 PAL-287 etc.[174][175][176]

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.[169]

WIN 35428, RTI-31, RTI-51 and RTI-55 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).[161] 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,[177] and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.[178]

NET blockade is unlikely to play a major role in mediating addictive behavior. This finding is based on the premise that desipramine is not self-administered,[179] and also the fact that the NRI atomoxetine was not reinforcing.[180] However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC.

Relation to cocaine Edit

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 cardiotoxicity[181] due to its local anesthetic activity. Thousands of cocaine users are admitted to emergency units in the USA every year because of this; thus, development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health.

Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure. There has been speculation over whether the new SNDRIs will have an abuse potential 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:

... limited reinforcing properties in the context of treatment programs may be advantageous, contributing to improved patient compliance and enhanced medication effectiveness.[182]

However, not all SNDRIs are reliably self-administered by animals. Examples include:

  • PRC200-SS was not reliably self-administered.[131]
  • RTI-112 was not self-administered[169] because at low doses the compound preferentially occupies the SERT and not the DAT.[107][170]
  • Tesofensine was also not reliably self-administered by human stimulant addicts.[183]
  • 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.[95]

Legality Edit

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 that it does have medical uses.

Brasofensine was made "class A" in the UK under the MDA (misuse of drugs act). The semi-synthetic procedure for making BF uses cocaine as the starting material.

Naphyrone 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.[70] 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.[184] 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.[71] NRG-1 was promptly illegalized, although it is not known if its use resulted in any hospitalizations or deaths.

Role of monoamine neurotransmitters Edit

Monoamine hypothesis Edit

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;[12][185] it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways.[186]

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.[187]

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.[188][189]

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.[185][189]

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.[189]

In 1965 Schildkraut formulated the catecholamine theory of depression.[190] This was subsequently the most widely cited article in the American Journal of Psychiatry.[191] 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.[189]

Inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more SERT selective than the parent compound.[185]

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 (c.f. talopram and melitracen). In fact, it is also believed that the selective NRI nisoxetine was discovered prior to the invention of fluoxetine.[192] 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.[193] Moreover, NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs.[194] 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.[195] 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.[196]
  • 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,[197] 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.[198]

Dopaminergic Edit

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.[199][200][201]

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.[202]
  • 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.[203]
  • Data from clinical studies have shown that DA agonists, such as bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties.[10]
  • 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.[204][205]
  • 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,[206] 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 Edit

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.[189]

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.

[207]

Serotonergic Edit

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-HT2C receptor activation as for example was reported for PAL-287 recently.

Activation of the 5-HT2C receptor has been described as "panicogen" by users of ligands for this receptor (e.g., mCPP). Antagonism of the 5-HT2C receptor is known to augment dopaminergic output. Although SSRIs with 5-HT2C antagonist actions were recommended for the treatment of depression, 5-HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless, the 5-HT2C 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-HT1A 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-HT1A receptors.[citation needed] Systemic administration of a 5-HT1A agonist also induces growth hormone and adrenocorticotropic hormone (ACTH) release through actions in the hypothalamus.[208]

Current antidepressants Edit

Most antidepressants on the market today target the monoaminergic system.

SSRIs Edit

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.[209] 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.[210]

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-HT1A receptors. 5-HT1A 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.[194]

NRIs Edit

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 (SNRI).

NDRIs Edit

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, 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 Edit

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.[211]

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.

MAOIs Edit

Monoamine oxidase inhibitors (MAOIs) were the first antidepressants to be introduced. They were discovered entirely by serendipity.[185] Iproniazide (the first MAOI) was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity.

Isoniazid also displayed activity as an antidepressant, even though it is not a MAOI.[212] This led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the MAOI activity could be a secondary side-effect. However, with the discovery of tranylcypromine (the first non-hydrazine MAOI), it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents. Etryptamine is another example of a non-hydrazine MAOI that was introduced.

The MAOIs work by inhibiting the monoamine oxidase enzymes that, as the name suggests, break down the monoamine neurotransmitters. This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain, serotonin, norepinephrine, dopamine and melatonin. The fact that they are more efficacious than the newer generation antidepressants[citation needed] is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters.[citation needed] The problem with MAOIs is that they have many potentially dangerous side-effects such as hypotension, and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis. Although selective MAOIs can reduce, if not eliminate these risks, their efficacy tends to be lower.

MAOIs may preferentially treat TCA-resistant depression, especially in patients with features such as fatigue, volition inhibition, motor retardation and hypersomnia. This may be a function of the ability of MAOIs to increase synaptic levels of DA in addition to 5-HT and NE. The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia (FM) or chronic fatigue syndrome (CFS).

Although a substantial number of MAOIs were approved in the 1960s, many of these were taken off the market as rapidly as they were introduced. The reason for this is that they were hepatotoxic and could cause jaundice.

TCAs Edit

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.[185] 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.[213]

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 Edit

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.[214] 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.[214] These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy.[214] 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.[214] Nefazodone a weak SNDRI has been successful in treating major depressive disorder which makes it unique.[215]

See also Edit

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September 02, 2023
serotonin, norepinephrine, dopamine, reuptake, inhibitor, this, article, multiple, issues, please, help, improve, discuss, these, issues, talk, page, learn, when, remove, these, template, messages, this, article, includes, list, general, references, lacks, suf. This article has multiple issues Please help improve it or discuss these issues on the talk page Learn how and when to remove these template messages This article includes a list of general references but it lacks sufficient corresponding inline citations Please help to improve this article by introducing more precise citations January 2014 Learn how and when to remove this template message This article is full of jargon abbreviations that make it difficult to read and understand may be too technical for most readers to understand Please help improve it to make it understandable to non experts without removing the technical details August 2018 Learn how and when to remove this template message Learn how and when to remove this template message A serotonin norepinephrine dopamine reuptake inhibitor SNDRI also known as a triple reuptake inhibitor TRI is a type of drug that acts as a combined reuptake inhibitor of the monoamine neurotransmitters serotonin norepinephrine and dopamine It does this by concomitantly inhibiting the serotonin transporter SERT norepinephrine transporter NET and dopamine transporter DAT respectively Inhibition of the reuptake of these neurotransmitters increases their extracellular concentrations and therefore results in an increase in serotonergic adrenergic and dopaminergic neurotransmission The naturally occurring and potent SNDRI cocaine is widely used recreationally and often illegally for the euphoric effects it produces Other SNDRIs were developed as potential antidepressants and treatments for other disorders such as obesity cocaine addiction attention deficit hyperactivity disorder ADHD and chronic pain They are an extension of selective serotonin reuptake inhibitors SSRIs and serotonin norepinephrine reuptake inhibitors SNRIs whereby the addition of dopaminergic action is thought to have the possibility of heightening therapeutic benefit However increased side effects and abuse potential are potential concerns of these agents relative to their SSRI and SNRI counterparts The SNDRIs are similar to non selective monoamine oxidase inhibitors MAOIs such as phenelzine and tranylcypromine in that they increase the action of all three of the major monoamine neurotransmitters They are also similar to serotonin norepinephrine dopamine releasing agents SNDRAs like MDMA ecstasy and a ethyltryptamine aET for the same reason although they act via a different mechanism and have differing physiological and qualitative effects Although their primary mechanisms of action are as NMDA receptor antagonists ketamine and phencyclidine are also SNDRIs and are similarly encountered as drugs of abuse Contents 1 Indications 1 1 Depression 1 2 Pharmacotherapy 1 3 Applications other than depression 2 List of SNDRIs 2 1 Approved pharmaceuticals 2 1 1 Coincidental 2 2 Undergoing clinical trials 2 3 Failed clinical trials 2 4 Designer drugs 2 5 Research compounds no record of having been taken by humans 2 6 Herbals 3 Toxicological 4 Addiction 4 1 Relation to cocaine 5 Legality 6 Role of monoamine neurotransmitters 6 1 Monoamine hypothesis 6 2 Dopaminergic 6 3 Noradrenergic 6 4 Serotonergic 7 Current antidepressants 7 1 SSRIs 7 2 NRIs 7 3 NDRIs 7 4 SNRIs 7 5 MAOIs 7 6 TCAs 8 Failure of SNDRIs for depression 9 See also 10 References 11 External linksIndications EditDepression Edit Major depressive disorder MDD is the foremost reason supporting the need for development of an SNDRI 1 2 3 4 5 6 7 8 9 10 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 11 About 16 of the population is estimated to be affected by major depression and another 1 is affected by bipolar disorder one or more times throughout an individual s lifetime 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 12 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 6 Depression is often highly comorbid with other diseases e g cardiovascular disease myocardial infarction 13 stroke 14 diabetes 15 cancer 16 Depressed subjects are prone to smoking 17 substance abuse 18 eating disorders obesity high blood pressure pathological gambling and internet addiction 19 and on average have a 15 to 30 year shorter lifetime compared with the general population 14 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 prodromal phase of schizophrenia 6 The ability to work familial relationships social integration and self care are all severely disrupted 6 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 12 Pharmacotherapy Edit 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 20 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 6 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 6 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 4 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 21 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 8 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 3 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 3 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 22 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 7 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 23 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 23 24 25 26 27 28 29 30 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 31 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 Edit Alcoholism c f DOV 102 677 32 33 Cocaine addiction e g indatraline 34 Obesity e g amitifadine tesofensine 35 Attention deficit hyperactivity disorder ADHD c f NS 2359 EB 1020 36 Chronic pain c f bicifadine 37 Parkinson s diseaseList of SNDRIs EditApproved pharmaceuticals Edit Mazindol Mazanor Sanorex anorectic 50 nM for SERT 18 nM for NET 45 nM for DAT 38 Nefazodone Serzone Nefadar Dutonin antidepressant non selective 200 nM at SERT 360 nM at NET 360 nM at DAT Nefopam Ki SER NE DA 29 33 531nM Informative review 39 Sibutramine Meridia is a withdrawn anorectic that is an SNDRI in vitro with values of 298 nM at SERT 5451 at NET 943 nM at DAT 38 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 40 41 1 Venlafaxine Effexor is sometimes referred to as an SNDRI but is extremely imbalanced with values of 82 nM for SERT 2480 nM for NET and 7647 nM for DAT with a ratio of 1 30 93 42 It may weakly inhibit the reuptake of dopamine at high doses 43 Coincidental Edit 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 44 Tripelennamine Pyribenzamine antihistamine weak SNDRI sometimes abused for this reason 45 46 47 48 MepiprazoleUndergoing clinical trials Edit Ansofaxine LY03005 LPM570065 49 Completed Phase 2 amp 3 trials FDA accepted NDA application 50 Centanafadine EB 1020 see here for details 1 to 6 to 14 ratio for NDS Completed Phase 3 trials for ADHD 51 OPC 64005 In phase 2 trials 2022 52 Lu AA37096 see here SNDRI and 5 HT6 modulator NS 2360 principle metabolite of tesofensine Tesofensine NS 2330 2001 In trials for obesity 53 Failed clinical trials Edit Bicifadine DOV 220 075 1981 54 55 BMS 866 949 Brasofensine NS 2214 BMS 204 756 1995 56 Diclofensine Ro 8 4650 1982 57 58 DOV 216 303 2004 59 60 EXP 561 1965 61 Liafensine BMS 820 836 NS 2359 GSK 372 475 62 RG 7166 2009 2012 SEP 227 162 SEP 228 425 SEP 432 aka SEP 228432 CID 58954867 Amitifadine DOV 21 947 EB 1010 2003 63 Dasotraline SEP 225 289 64 Lu AA34893 see here SNDRI and 5 HT2A a1 and 5 HT6 modulator 65 Tedatioxetine Lu AA24530 SNDRI and 5 HT2C 5 HT3 5 HT2A and a1 modulator 66 67 68 Designer drugs Edit 3 Methyl PCPy 69 Naphyrone O 2482 naphthylpyrovalerone NRG 1 2006 70 71 72 5 APBResearch compounds no record of having been taken by humans Edit nbsp 3 4 Diphenylpiperidine nbsp 3 4 Diphenylquinuclidine nbsp MDL 47 832 3 4 Diphenylquinuclidine HCl salt 72811 36 0 73 3 4 Diphenylpiperidines a panoply of analogs was disclosed by French Hoechst Ref 74 75 Patents 76 77 The 3 4 Dichloro lactam was the most powerful psychostimulant tested Its SAR can be compared to a similar French Hoechst compound called Lomevactone MDL 47 832 52423 89 9 78 Patent 79 80 SAR is similar to RG 7166 amp Amitifadine For SAR study see under Osanetant 3 3 Diphenylcyclobutanamine 1978 81 AK Dutta D 161 2008 82 D 473 1632000 05 5 amp D 578 Informative review 83 DOV 102 677 2006 2011 32 Informative reviews 84 85 Fezolamine Win 41 528 2 GlaxoSmithKline Italia GSK1360707F 2010 86 87 CID 46866510 88 HP 505 89 Lundbeck group Indatraline 1985 90 Lu AA42202 amp CID 11515108 874296 10 3 91 JNJ 7925476 2008 first appeared in 1987 92 Mcn 5707 96795 88 9 amp Mcn 5292 105234 89 7 Kozikowski group DMNPC 2000 93 JZ IV 10 2005 94 amp JZAD IV 22 2010 95 Lilly group LR 5182 maybe only NDRI 1978 CID 9903806 96 CID 11335177 97 CID 9867350 98 CID 11234430 99 HM Deutsch group Methylnaphthidate HDMP 28 2001 100 MI 4 101 102 MI 4 is the same compound as Ro 25 6981 169274 78 6 103 104 This is NMDA antagonist Benzazepine derivatives SKF 83 959 2013 105 amp Nor Trepipam 20569 49 7 106 Various phenyltropanes such as WF 23 dichloropane and RTI 55 107 NeuroSearch group NS9775 108 NS18283 109 amp 4 Benzhydryl 1 2 3 6 tetrahydropyridine 1186529 81 6 CID 54673194 S N D 0 26 6 0 4 8nM 110 CID 9921901 387869 25 2 111 3 3 4 Dichlorophenyl tropan 2 ene S N D 4 7 26 79nM 112 Liming Shao Sepracor Sunovion 3 4 Dichlorotramadol 113 CID 53321058 S N D 19 04 01nM 114 115 A patent review was also disclosed 116 CID 66809062 117 118 CID 46870521 119 CID 10151573 120 CID 46701015 121 Takeda group CID 44629033 S N D 11 14 190nM Ref 122 Patent 123 Trudell group HK3 263 S N D 0 3 20 16nM 124 Pfizer group CP 607366 amp CP 939689 Desmethylsertraline active metabolite of sertraline 76 nM for SERT 420 nM for NET 440 nM for DAT 125 3 4 Dichlorotametraline trans 1R 4S sertraline 1980 126 Venlafaxine analogues LPM580098 127 amp LPM580153 128 And TP1 129 later reassigned name to PA01 130 PRC Carlier group PRC200 SS 2008 131 PRC050 and PRC025 132 Albany Molecular Research group Bruce Molino AMR 2 DAT 3 1nM SERT 8 3nM NET 3 0nM 133 CID 49765424 S enantiomer 1254941 82 6 134 SK Group CID 44555333 135 amp CID 49866033 136 137 Boots UK BTS 74 398 SPD 473 citrate 161190 26 7 Pridefine SMe1EC2M3 138 SIPI5357 CID 52939791 139 23j S S N D 83 3 8 160nM 140 Tetrazoles ROK 141 142 143 10dl CID 118713802 S N D 7 6 45 2 330nM 144 2at CID 118706539 145 THIQ Derivatives AN12 CID 10380161 146 Patent 147 CID 9839278 148 2j CID 66572162 S N D 411 71 159nM 149 6aq CID 70676472 S N D 44 10 32nM 150 Naphthyl milnacipran analog 2007 CID 17748230 S N D 18 05 140nM 151 Herbals Edit The coca flour contains cocaine natural alkaloid and drug of abuse Ginkgo biloba extract EGb761 The norepinephrine NET the serotonin SERT the dopamine DAT uptake transporters and MAO activity are inhibited by EGb761 in vitro 152 St John s Wort natural product and over the counter herbal antidepressant Hyperforin Adhyperforin Uliginosin B IC50 DA 90 nM 5 HT 252 nM NE 280 nM 153 154 Oregano extract 155 Although not specifically a SNDRI Rosmarinus officinalis is one of the trimonoamine modulator TMM that affect SER CAs 156 Hederagenin 157 Toxicological EditToxicological 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 158 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 159 CPCA nocaine 160 is the 3R 4S piperidine stereoisomer of phenyltropane based RTI 31 161 It is non addictive although this might be due to it being a NDRI not a SNDRI The b naphthyl analog of Nocaine 93 is a SNDRI though in the case of both the SS and RR enantiomers Consider the piperidine analogs of brasofensine 56 and tesofensine 162 These were prepared by NeuroSearch In Denmark by the chemists Peter Moldt 2002 163 and Frank Watjen 2004 2009 164 165 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 166 et at revealed that the bb isomers were less likely to cause convulsions tremor and death than the corresponding trans isomers more specifically what is meant is the 1R 2R 3S isomers 167 While it does still have to be conceded that RTI 55 caused death at a dosage of 100 mg kg it s therapeutic index 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 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 168 People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety amp 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 112 107 169 170 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 EditDrug 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 limbic structures of the brain Its existence was proved by demonstration of the pleasure centers that were discovered as the location from which electrical self stimulation is readily evoked The main neurotransmitter involved in the reward is dopamine but other monoamines and acetylcholine may also participate The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens amygdala prefrontal cortex and other forebrain structures 171 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 171 172 173 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 PAL 287 etc 174 175 176 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 169 WIN 35428 RTI 31 RTI 51 and RTI 55 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 161 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 177 and the phen fen combination was also shown to have limited abuse potential relative to administration of phentermine only 178 NET blockade is unlikely to play a major role in mediating addictive behavior This finding is based on the premise that desipramine is not self administered 179 and also the fact that the NRI atomoxetine was not reinforcing 180 However it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC Relation to cocaine Edit 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 cardiotoxicity 181 due to its local anesthetic activity Thousands of cocaine users are admitted to emergency units in the USA every year because of this thus development of safer substitute medications for cocaine abuse could potentially have significant benefits for public health Many of the SNDRIs currently being developed have varying degrees of similarity to cocaine in terms of their chemical structure There has been speculation over whether the new SNDRIs will have an abuse potential 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 limited reinforcing properties in the context of treatment programs may be advantageous contributing to improved patient compliance and enhanced medication effectiveness 182 However not all SNDRIs are reliably self administered by animals Examples include PRC200 SS was not reliably self administered 131 RTI 112 was not self administered 169 because at low doses the compound preferentially occupies the SERT and not the DAT 107 170 Tesofensine was also not reliably self administered by human stimulant addicts 183 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 95 Legality EditCocaine 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 that it does have medical uses Brasofensine was made class A in the UK under the MDA misuse of drugs act The semi synthetic procedure for making BF uses cocaine as the starting material Naphyrone 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 70 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 184 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 71 NRG 1 was promptly illegalized although it is not known if its use resulted in any hospitalizations or deaths Role of monoamine neurotransmitters EditMonoamine hypothesis Edit 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 12 185 it has since evolved into the notion that depression arises through alterations in target neurons specifically the dendrites in monoamine pathways 186 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 187 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 188 189 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 185 189 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 189 In 1965 Schildkraut formulated the catecholamine theory of depression 190 This was subsequently the most widely cited article in the American Journal of Psychiatry 191 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 189 Inserting a chlorine atom into imipramine leads to clomipramine a drug that is much more SERT selective than the parent compound 185 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 c f talopram and melitracen In fact it is also believed that the selective NRI nisoxetine was discovered prior to the invention of fluoxetine 192 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 193 Moreover NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs 194 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 195 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 196 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 197 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 198 Dopaminergic Edit 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 199 200 201 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 202 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 203 Data from clinical studies have shown that DA agonists such as bromocriptine pramipexole and ropinirole exhibit antidepressant properties 10 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 b 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 204 205 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 lt 15 minutes from administration and clear the brain rapidly to enable fast repeated administration In addition to mood they may also improve cognitive performance 206 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 Edit The decreased levels of NA proposed by Schildkraut suggested that there would be a compensatory upregulation of b adrenoceptors Despite inconsistent findings supporting this more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy ECT decrease b adrenoceptor density in the rat forebrain This led to the theory that b adrenoceptor downregulation was required for clinical antidepressant efficacy However some of the newly developed antidepressants do not alter or even increase b adrenoceptor density 189 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 207 Serotonergic Edit 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 HT2C receptor activation as for example was reported for PAL 287 recently Activation of the 5 HT2C receptor has been described as panicogen by users of ligands for this receptor e g mCPP Antagonism of the 5 HT2C receptor is known to augment dopaminergic output Although SSRIs with 5 HT2C antagonist actions were recommended for the treatment of depression 5 HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti addictive Nevertheless the 5 HT2C 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 HT1A 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 HT1A receptors citation needed Systemic administration of a 5 HT1A agonist also induces growth hormone and adrenocorticotropic hormone ACTH release through actions in the hypothalamus 208 Current antidepressants EditMost antidepressants on the market today target the monoaminergic system SSRIs Edit 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 209 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 210 SSRIs can be combined with a host of other drugs including bupropion a2 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 HT1A receptors 5 HT1A 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 194 NRIs Edit 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 SNRI NDRIs Edit 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 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 Edit 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 211 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 MAOIs Edit Monoamine oxidase inhibitors MAOIs were the first antidepressants to be introduced They were discovered entirely by serendipity 185 Iproniazide the first MAOI was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity Isoniazid also displayed activity as an antidepressant even though it is not a MAOI 212 This led some people to question whether it is some property of the hydrazine which is responsible for mediating the antidepressant effect even going as far as to state that the MAOI activity could be a secondary side effect However with the discovery of tranylcypromine the first non hydrazine MAOI it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents Etryptamine is another example of a non hydrazine MAOI that was introduced The MAOIs work by inhibiting the monoamine oxidase enzymes that as the name suggests break down the monoamine neurotransmitters This leads to increased concentrations of most of the monoamine neurotransmitters in the human brain serotonin norepinephrine dopamine and melatonin The fact that they are more efficacious than the newer generation antidepressants citation needed is what leads scientists to develop newer antidepressants that target a greater range of neurotransmitters citation needed The problem with MAOIs is that they have many potentially dangerous side effects such as hypotension and there is a risk of food and drug interactions that can result in potentially fatal serotonin syndrome or a hypertensive crisis Although selective MAOIs can reduce if not eliminate these risks their efficacy tends to be lower MAOIs may preferentially treat TCA resistant depression especially in patients with features such as fatigue volition inhibition motor retardation and hypersomnia This may be a function of the ability of MAOIs to increase synaptic levels of DA in addition to 5 HT and NE The MAOIs also seem to be effective in the treatment of fatigue associated with fibromyalgia FM or chronic fatigue syndrome CFS Although a substantial number of MAOIs were approved in the 1960s many of these were taken off the market as rapidly as they were introduced The reason for this is that they were hepatotoxic and could cause jaundice TCAs Edit 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 185 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 a1 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 213 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 EditSNDRIs 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 214 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 214 These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy 214 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 214 Nefazodone a weak SNDRI has been successful in treating major depressive disorder which makes it unique 215 See also EditMonoamine reuptake inhibitorReferences Edit Millan MJ 2009 Dual and triple acting agents for treating core and co morbid symptoms of major depression Novel concepts new drugs Neurotherapeutics 6 1 53 77 doi 10 1016 j nurt 2008 10 039 PMC 5084256 PMID 19110199 Kulkarni SK Dhir A 2009 Current investigational drugs for major depression Expert Opinion on Investigational Drugs 18 6 767 88 doi 10 1517 13543780902880850 PMID 19426122 S2CID 71382550 a b c 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1021 jm3008294 Epub 2012 Sep 11 PMID 22938049 Roggen Heidi Kehler Jan Stensbol Tine Bryan Hansen Tore 2007 Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine serotonin and norepinephrine transporters Bioorganic amp Medicinal Chemistry Letters 17 10 2834 2837 doi 10 1016 j bmcl 2007 02 054 Fehske C J Leuner K Muller W E 2009 Ginkgo biloba extract EGb761 influences monoaminergic neurotransmission via inhibition of NE uptake but not MAO activity after chronic treatment Pharmacological Research 60 1 68 73 doi 10 1016 j phrs 2009 02 012 PMID 19427589 Stein A C Viana A F Muller L G Nunes J M Stolz E D Do Rego J C Costentin J von Poser G L Rates S M 2012 Uliginosin B a phloroglucinol derivative from Hypericum polyanthemum A promising new molecular pattern for the development of antidepressant drugs Behavioural Brain Research 228 1 66 73 doi 10 1016 j bbr 2011 11 031 PMID 22155486 S2CID 1518033 US 2011313034 Rates Stela Maris Kuze Von Poser Gilsane Lino amp Viana Alice Fialho et al Neuroactive plant extract from Hypericum polyanthemum published 2011 12 22 assigned to Universidade Federal Do Rio Grande Do Sul and Universite de Rouen Mechan Annis O Fowler Ann Seifert Nicole Rieger Henry Wohrle Tina Etheve Stephane Wyss Adrian Schuler Gode Colletto Biagio Kilpert Claus Aston James Elliott J Martin Goralczyk Regina Mohajeri M Hasan 2010 Monoamine reuptake inhibition and mood enhancing potential of a specified oregano extract British Journal of Nutrition 105 8 1150 1163 doi 10 1017 S0007114510004940 ISSN 0007 1145 PMID 21205415 Sasaki Kazunori El Omri Abdelfatteh Kondo Shinji Han Junkyu Isoda Hiroko 2013 Rosmarinus officinalis polyphenols produce anti depressant like effect through monoaminergic and cholinergic functions modulation Behavioural Brain Research 238 86 94 doi 10 1016 j bbr 2012 10 010 ISSN 0166 4328 PMID 23085339 S2CID 31553844 Jin Zeng Liang Gao Nana Zhou Dan Chi Mu Gen Yang Xue Mei Xu Jiang Ping 2012 The extracts of Fructus Akebiae a preparation containing 90 of the active ingredient hederagenin Serotonin norepinephrine and dopamine reuptake inhibitor Pharmacology Biochemistry and Behavior 100 3 431 439 doi 10 1016 j pbb 2011 10 001 ISSN 0091 3057 PMID 22005599 S2CID 207331897 Yardley John P Husbands G E Morris Stack Gary Butch Jacqueline Bicksler James Moyer John A Muth Eric A Andree Terrance et al 1990 2 Phenyl 2 1 hydroxycycloalkyl ethylamine derivatives Synthesis and antidepressant activity Journal of Medicinal Chemistry 33 10 2899 905 doi 10 1021 jm00172a035 PMID 1976813 Guha M Heier A Price S Bielenstein M Caccese RG Heathcote DI Simpson TR Stong DB Bodes E 2011 Assessment of biomarkers of drug induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor Toxicological Sciences 120 2 269 83 doi 10 1093 toxsci kfr013 PMID 21258088 Kozikowski AP Araldi GL Boja J Meil WM Johnson KM Flippen Anderson JL George C Saiah E 1998 Chemistry and pharmacology of the piperidine based analogues of cocaine Identification of potent DAT inhibitors lacking the tropane skeleton Journal of Medicinal Chemistry 41 11 1962 9 doi 10 1021 jm980028 PMID 9599245 a b Wee S Carroll FI Woolverton WL 2006 A reduced rate of in vivo dopamine transporter binding is associated with lower relative reinforcing efficacy of stimulants Neuropsychopharmacology 31 2 351 62 doi 10 1038 sj npp 1300795 PMID 15957006 U S Patent 6 395 748 U S Patent 6 376 673 WO 2004039778 Watjen Frank Novel piperidine derivatives and their use as monoamine neurotransmitter re uptake inhibitors published 2004 05 13 assigned to NeuroSearch AS U S Patent 7 560 562 Archived at Ghostarchive and the Wayback Machine 2010 N C Award for Science Dr F Ivy Carroll YouTube Carroll FI Runyon SP Abraham P Navarro H Kuhar MJ Pollard GT Howard JL 2004 Monoamine transporter binding locomotor activity and drug discrimination properties of 3 4 substituted phenyl tropane 2 carboxylic acid methyl ester isomers Journal of Medicinal Chemistry 47 25 6401 9 doi 10 1021 jm0401311 PMID 15566309 Abuse National Institute on Drug Drug Related Hospital Emergency Room Visits www drugabuse gov Retrieved 2016 04 04 a b c Kimmel HL O Connor JA Carroll FI Howell LL 2007 Faster onset and dopamine transporter selectivity predict stimulant and reinforcing effects of cocaine analogs in squirrel monkeys Pharmacology Biochemistry and Behavior 86 1 45 54 doi 10 1016 j pbb 2006 12 006 PMC 1850383 PMID 17258302 a b Lindsey KP Wilcox KM Votaw JR Goodman MM Plisson C Carroll FI Rice KC Howell LL 2004 Effects of dopamine transporter inhibitors on cocaine self administration in rhesus monkeys Relationship to transporter occupancy determined by positron emission tomography neuroimaging The Journal of Pharmacology and Experimental Therapeutics 309 3 959 69 doi 10 1124 jpet 103 060293 PMID 14982963 S2CID 39794215 a b Vetulani J 2001 Drug addiction Part II Neurobiology of addiction Polish Journal of Pharmacology 53 4 303 17 PMID 11990077 Howell LL Kimmel HL 2008 Monoamine transporters and psychostimulant addiction Biochemical Pharmacology 75 1 196 217 doi 10 1016 j bcp 2007 08 003 PMID 17825265 Koob GF Volkow ND 2010 Neurocircuitry of addiction Neuropsychopharmacology 35 1 217 38 doi 10 1038 npp 2009 110 PMC 2805560 PMID 19710631 Baumann MH Clark RD Woolverton WL Wee S Blough BE Rothman RB 2011 In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat The Journal of Pharmacology and Experimental Therapeutics 337 1 218 25 doi 10 1124 jpet 110 176271 PMC 3063744 PMID 21228061 Rothman RB Blough BE Baumann MH 2008 Dual dopamine serotonin releasers Potential treatment agents for stimulant addiction Experimental and Clinical Psychopharmacology 16 6 458 74 doi 10 1037 a0014103 PMC 2683464 PMID 19086767 Kimmel HL Manvich DF Blough BE Negus SS Howell LL 2009 Behavioral and neurochemical effects of amphetamine analogs that release monoamines in the squirrel monkey Pharmacology Biochemistry and Behavior 94 2 278 84 doi 10 1016 j pbb 2009 09 007 PMC 2763934 PMID 19766133 Howell LL Carroll FI Votaw JR Goodman MM Kimmel HL 2007 Effects of combined dopamine and serotonin transporter inhibitors on cocaine self administration in rhesus monkeys The Journal of Pharmacology and Experimental Therapeutics 320 2 757 65 doi 10 1124 jpet 106 108324 PMID 17105829 S2CID 9205978 Rothman RB Elmer GI Shippenberg TS Rea W Baumann MH 1998 Phentermine and fenfluramine Preclinical studies in animal models of cocaine addiction Annals of the New York Academy of Sciences 844 1 59 74 Bibcode 1998NYASA 844 59R doi 10 1111 j 1749 6632 1998 tb08222 x PMID 9668665 S2CID 205929292 Wee S Wang Z He R Zhou J Kozikowski AP Woolverton WL 2006 Role of the increased noradrenergic neurotransmission in drug self administration Drug and Alcohol Dependence 82 2 151 7 doi 10 1016 j drugalcdep 2005 09 002 PMID 16213110 Wee S Woolverton WL 2004 Evaluation of the reinforcing effects of atomoxetine in monkeys Comparison to methylphenidate and desipramine Drug and Alcohol Dependence 75 3 271 6 doi 10 1016 j drugalcdep 2004 03 010 PMID 15283948 Phillips K Luk A Soor GS Abraham JR Leong S Butany J 2009 Cocaine cardiotoxicity A review of the pathophysiology pathology and treatment options American Journal of Cardiovascular Drugs 9 3 177 96 doi 10 1007 bf03256574 PMID 19463023 S2CID 70385136 Howell LL Wilcox KM 2001 The dopamine transporter and cocaine medication development Drug self administration in nonhuman primates The Journal of Pharmacology and Experimental Therapeutics 298 1 1 6 PMID 11408518 Schoedel KA Meier D Chakraborty B Manniche PM Sellers EM 2010 Subjective and objective effects of the novel triple reuptake inhibitor tesofensine in recreational stimulant users Clinical Pharmacology and Therapeutics 88 1 69 78 doi 10 1038 clpt 2010 67 PMID 20520602 S2CID 39849071 Baumann MH Ayestas Jr MA Partilla JS Sink JR Shulgin AT Daley PF Brandt SD Rothman RB et al 2012 The designer methcathinone analogs mephedrone and methylone are substrates for monoamine transporters in brain tissue Neuropsychopharmacology 37 5 1192 203 doi 10 1038 npp 2011 304 PMC 3306880 PMID 22169943 a b c d e Lopez Munoz F Alamo C 2009 Monoaminergic neurotransmission The history of the discovery of antidepressants from 1950s until today Current Pharmaceutical Design 15 14 1563 86 doi 10 2174 138161209788168001 PMID 19442174 Malenka RC Nestler EJ Hyman SE 2009 Chapter 14 Neuropharmacology of Neural Systems and Disorders In Sydor A Brown RY eds Molecular Neuropharmacology A Foundation for Clinical Neuroscience 2nd ed New York McGraw Hill Medical pp 355 360 ISBN 9780071481274 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 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 Baumeister AA Hawkins MF Uzelac SM 2003 The myth of reserpine induced depression Role in the historical development of the monoamine hypothesis Journal of the History of the Neurosciences 12 2 207 20 doi 10 1076 jhin 12 2 207 15535 PMID 12953623 S2CID 42407412 Lingjaerde O 1963 Tetrabenazine Nitoman in the Treatment of Psychoses With a Discussion on the Central Mode of Action of Tetrabenazine and Reserpine Acta Psychiatrica Scandinavica 39 SUPPL170 1 109 doi 10 1111 j 1600 0447 1963 tb07906 x PMID 14081399 S2CID 221395033 a b c d e 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Aarre T Bourin M Canonico PL Carrasco JL Stahl S 2007 The other face of depression reduced positive affect The role of catecholamines in causation and cure Journal of Psychopharmacology 21 5 461 71 doi 10 1177 0269881106069938 PMID 17050654 S2CID 2139339 Nestler EJ Carlezon Jr WA 2006 The mesolimbic dopamine reward circuit in depression Biological Psychiatry 59 12 1151 9 doi 10 1016 j biopsych 2005 09 018 PMID 16566899 S2CID 18005398 Papakostas GI Nutt DJ Hallett LA Tucker VL Krishen A Fava M 2006 Resolution of sleepiness and fatigue in major depressive disorder A comparison of bupropion and the selective serotonin reuptake inhibitors Biological Psychiatry 60 12 1350 5 doi 10 1016 j biopsych 2006 06 015 PMID 16934768 S2CID 6886384 McDonald WM Richard IH Delong MR 2003 Prevalence etiology and treatment of depression in Parkinson s disease Biological Psychiatry 54 3 363 75 doi 10 1016 S0006 3223 03 00530 4 PMID 12893111 S2CID 45520438 Cohen BM Carlezon Jr WA 2007 Can t get enough of that 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1960s to the 1990s Journal of Psychiatric Practice 16 6 413 5 doi 10 1097 01 pra 0000390760 12204 99 PMID 21107146 a b c d Dale Elena Bang Andersen Benny Sanchez Connie 2015 Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs Biochemical Pharmacology 95 2 81 97 doi 10 1016 j bcp 2015 03 011 ISSN 0006 2952 PMID 25813654 Davis R Whittington R Bryson H M April 1997 Nefazodone A review of its pharmacology and clinical efficacy in the management of major depression Drugs 53 4 608 636 doi 10 2165 00003495 199753040 00006 ISSN 0012 6667 PMID 9098663 S2CID 239077479 External links Edit nbsp Media related to Serotonin norepinephrine dopamine reuptake inhibitors at Wikimedia Commons Retrieved from https en wikipedia org w index php title Serotonin norepinephrine dopamine reuptake inhibitor amp oldid 1170218576, wikipedia, wiki, book, books, library,

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