Wikipedia

Serotonin–norepinephrine–dopamine reuptake inhibitor

(Redirected from SNDRI)

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
  • Mazindol (Mazanor, Sanorex) — anorectic; ki is 50 nM for SERT, 18 nM for NET, 45 nM for DAT[38]
  • Nefazodone (Serzone, Nefadar, Dutonin) — antidepressant; non-selective; ki is 200 nM at SERT, 360 nM at NET, 360 nM at DAT
  • Nefopam (ki SER/NE/DA = 29/33/531 nM) Informative review:[39]

Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI in vitro with ki 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 ki 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

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, its therapeutic index of safety is still much better than the corresponding trans isomers because it is a more potent compound.

In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased appetite (and hence weight loss), increased locomotor activity (LMA) etc. In the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose.[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 (an 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, but it is presumed owing to its psychomotor activating effects and it functioning as a positive reinforcer. There are also reports of methylphenidate being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter.

SNRIs

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] Despite being a weak SNDRI, nefazodone has been successful in treating major depressive disorder.[215]

See also

edit

References

edit
  1. ^ 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.
  2. ^ 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.
  3. ^ a b c Guiard, BP; El Mansari, M; Blier, P (2009). "Prospect of a dopamine contribution in the next generation of antidepressant drugs: The triple reuptake inhibitors". Current Drug Targets. 10 (11): 1069–84. doi:10.2174/138945009789735156. PMID 19702555.
  4. ^ a b Marks, DM; Pae, CU; Patkar, AA (2008). "Triple reuptake inhibitors: The next generation of antidepressants". Current Neuropharmacology. 6 (4): 338–43. doi:10.2174/157015908787386078. PMC 2701280. PMID 19587855.
  5. ^ Chen, Z; Skolnick, P (2007). "Triple uptake inhibitors: Therapeutic potential in depression and beyond". Expert Opinion on Investigational Drugs. 16 (9): 1365–77. doi:10.1517/13543784.16.9.1365. PMID 17714023. S2CID 20271918.
  6. ^ a b c d e f Millan, MJ (2006). "Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application". Pharmacology & Therapeutics. 110 (2): 135–370. doi:10.1016/j.pharmthera.2005.11.006. PMID 16522330.
  7. ^ a b Perona, MT; Waters, S; Hall, FS; Sora, I; Lesch, KP; Murphy, DL; Caron, M; Uhl, GR (2008). "Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: Prominent effects of dopamine transporter deletions". Behavioural Pharmacology. 19 (5–6): 566–74. doi:10.1097/FBP.0b013e32830cd80f. PMC 2644662. PMID 18690111.
  8. ^ a b Chen, Z; Yang, J; Tobak, A (2008). "Designing new treatments for depression and anxiety". IDrugs: The Investigational Drugs Journal. 11 (3): 189–97. PMID 18311656.
  9. ^ Perović, B; Jovanović, M; Miljković, B; Vezmar, S (2010). "Getting the balance right: Established and emerging therapies for major depressive disorders". Neuropsychiatric Disease and Treatment. 6: 343–64. doi:10.2147/ndt.s10485. PMC 2938284. PMID 20856599.
  10. ^ a b Rakofsky, JJ; Holtzheimer, PE; Nemeroff, CB (2009). "Emerging targets for antidepressant therapies". Current Opinion in Chemical Biology. 13 (3): 291–302. doi:10.1016/j.cbpa.2009.04.617. PMC 4410714. PMID 19501541.
  11. ^ "Depression". World Health Organization. WHO. Archived from the original on 2010-07-17.
  12. ^ a b c Lee, S; Jeong, J; Kwak, Y; Park, SK (2010). "Depression research: Where are we now?". Molecular Brain. 3: 8. doi:10.1186/1756-6606-3-8. PMC 2848031. PMID 20219105.
  13. ^ Larsen, KK; Vestergaard, M; Søndergaard, J; Christensen, B (2012). "Screening for depression in patients with myocardial infarction by general practitioners". European Journal of Preventive Cardiology. 20 (5): 800–6. doi:10.1177/2047487312444994. PMID 22496274. S2CID 24986156.
  14. ^ a b Saravane, D; Feve, B; Frances, Y; Corruble, E; Lancon, C; Chanson, P; Maison, P; Terra, JL; et al. (2009). "Drawing up guidelines for the attendance of physical health of patients with severe mental illness". L'Encéphale. 35 (4): 330–9. doi:10.1016/j.encep.2008.10.014. PMID 19748369.
  15. ^ Rustad, JK; Musselman, DL; Nemeroff, CB (2011). "The relationship of depression and diabetes: Pathophysiological and treatment implications". Psychoneuroendocrinology. 36 (9): 1276–86. doi:10.1016/j.psyneuen.2011.03.005. PMID 21474250. S2CID 32439196.
  16. ^ Li, M; Fitzgerald, P; Rodin, G (2012). "Evidence-based treatment of depression in patients with cancer". Journal of Clinical Oncology. 30 (11): 1187–96. doi:10.1200/JCO.2011.39.7372. PMID 22412144.
  17. ^ Tsuang, MT; Francis, T; Minor, K; Thomas, A; Stone, WS (2012). "Genetics of smoking and depression". Human Genetics. 131 (6): 905–15. doi:10.1007/s00439-012-1170-6. PMID 22526528. S2CID 11532256.
  18. ^ Davis, LL; Wisniewski, SR; Howland, RH; Trivedi, MH; Husain, MM; Fava, M; McGrath, PJ; Balasubramani, GK; et al. (2010). "Does comorbid substance use disorder impair recovery from major depression with SSRI treatment? An analysis of the STAR*D level one treatment outcomes". Drug and Alcohol Dependence. 107 (2–3): 161–70. doi:10.1016/j.drugalcdep.2009.10.003. PMID 19945804.
  19. ^ Barrault, S; Varescon, I (2012). "Psychopathology in online pathological gamblers: A preliminary study". L'Encéphale. 38 (2): 156–63. doi:10.1016/j.encep.2011.01.009. PMID 22516274.
  20. ^ Belmaker, RH (2008). "The future of depression psychopharmacology". CNS Spectrums. 13 (8): 682–7. doi:10.1017/S1092852900013766. PMID 18704023. S2CID 33347610.
  21. ^ Dunlop, BW; Nemeroff, CB (2007). "The role of dopamine in the pathophysiology of depression". Archives of General Psychiatry. 64 (3): 327–37. doi:10.1001/archpsyc.64.3.327. PMID 17339521. S2CID 26550661.
  22. ^ Daws, LC (2009). "Unfaithful neurotransmitter transporters: Focus on serotonin uptake and implications for antidepressant efficacy". Pharmacology & Therapeutics. 121 (1): 89–99. doi:10.1016/j.pharmthera.2008.10.004. PMC 2739988. PMID 19022290.
  23. ^ a b Musk, P (2004). "Magic shotgun methods for developing drugs for CNS disorders". Discovery Medicine. 4 (23): 299–302. PMID 20704963.
  24. ^ Roth, BL; Sheffler, DJ; Kroeze, WK (2004). "Magic shotguns versus magic bullets: Selectively non-selective drugs for mood disorders and schizophrenia". Nature Reviews Drug Discovery. 3 (4): 353–9. doi:10.1038/nrd1346. PMID 15060530. S2CID 20913769.
  25. ^ Buccafusco, JJ (2009). "Multifunctional receptor-directed drugs for disorders of the central nervous system". Neurotherapeutics. 6 (1): 4–13. doi:10.1016/j.nurt.2008.10.031. PMC 5084252. PMID 19110195.
  26. ^ Enna, SJ; Williams, M (2009). "Challenges in the search for drugs to treat central nervous system disorders". The Journal of Pharmacology and Experimental Therapeutics. 329 (2): 404–11. doi:10.1124/jpet.108.143420. PMID 19182069. S2CID 11395584.
  27. ^ Frantz, S (2005). "Drug discovery: Playing dirty". Nature. 437 (7061): 942–3. Bibcode:2005Natur.437..942F. doi:10.1038/437942a. PMID 16222266. S2CID 4414021.
  28. ^ Hopkins, AL (2009). "Drug discovery: Predicting promiscuity". Nature. 462 (7270): 167–8. Bibcode:2009Natur.462..167H. doi:10.1038/462167a. PMID 19907483. S2CID 4362713.
  29. ^ Hopkins, AL; Mason, JS; Overington, JP (2006). "Can we rationally design promiscuous drugs?". Current Opinion in Structural Biology. 16 (1): 127–36. doi:10.1016/j.sbi.2006.01.013. PMID 16442279.
  30. ^ Hopkins, AL (2008). "Network pharmacology: The next paradigm in drug discovery". Nature Chemical Biology. 4 (11): 682–90. doi:10.1038/nchembio.118. PMID 18936753.
  31. ^ Jain, R (2004). "Single-action versus dual-action antidepressants". Primary Care Companion to the Journal of Clinical Psychiatry. 6 (Suppl 1): 7–11. PMC 486947. PMID 16001091.
  32. ^ a b Yang, AR; Yi, HS; Warnock, KT; Mamczarz, J; June Jr, HL; Mallick, N; Krieter, PA; Tonelli, L; et al. (2012). "Effects of the Triple Monoamine Uptake Inhibitor DOV 102,677 on Alcohol-Motivated Responding and Antidepressant Activity in Alcohol-Preferring (P) Rats". Alcoholism: Clinical and Experimental Research. 36 (5): 863–73. doi:10.1111/j.1530-0277.2011.01671.x. PMC 3464941. PMID 22150508.
  33. ^ McMillen, BA; Shank, JE; Jordan, KB; Williams, HL; Basile, AS (2007). "Effect of DOV 102,677 on the volitional consumption of ethanol by Myers' high ethanol-preferring rat". Alcoholism: Clinical and Experimental Research. 31 (11): 1866–71. doi:10.1111/j.1530-0277.2007.00513.x. PMID 17908267.
  34. ^ Gardner, Eliot L.; Liu, Xinhe; Paredes, William; Giordano, Anthony; Spector, Jordan; Lepore, Marino; Wu, Kuo-Ming; Froimowitz, Mark (2006). "A slow-onset, long-duration indanamine monoamine reuptake inhibitor as a potential maintenance pharmacotherapy for psychostimulant abuse: Effects in laboratory rat models relating to addiction". Neuropharmacology. 51 (5): 993–1003. doi:10.1016/j.neuropharm.2006.06.009. PMID 16901516. S2CID 20465584.
  35. ^ Tizzano, JP; Stribling, DS; Perez-Tilve, D; Strack, A; Frassetto, A; Chen, RZ; Fong, TM; Shearman, L; et al. (2008). "The triple uptake inhibitor (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo3.1.0 hexane hydrochloride (DOV 21947) reduces body weight and plasma triglycerides in rodent models of diet-induced obesity". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 1111–26. doi:10.1124/jpet.107.133132. PMID 18089843. S2CID 12020136.
  36. ^ "Efficacy and Safety of NS2359 in Adults with Attention Deficit Hyperactivity Disorder. A Randomised, Double-Blind, Placebo-Controlled Study". ClinicalTrials.gov. 27 April 2007.
  37. ^ Basile, AS; Janowsky, A; Golembiowska, K; Kowalska, M; Tam, E; Benveniste, M; Popik, P; Nikiforuk, A; et al. (2007). "Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain". The Journal of Pharmacology and Experimental Therapeutics. 321 (3): 1208–25. doi:10.1124/jpet.106.116483. PMID 17325229. S2CID 17215882.
  38. ^ a b Zoran Rankovic; Richard Hargreaves; Matilda Bingham (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 199–200. ISBN 978-1-84973-365-6.
  39. ^ Subbaiah, M. A. M. (22 March 2018). "Triple Reuptake Inhibitors as Potential Therapeutics for Depression and Other Disorders: Design Paradigm and Developmental Challenges". Journal of Medicinal Chemistry. 61 (6): 2133–65. doi:10.1021/acs.jmedchem.6b01827. PMID 28731336.
  40. ^ Kim, K A; Song, W K; Park, J Y (2009). "Association of CYP2B6, CYP3A5, and CYP2C19 Genetic Polymorphisms With Sibutramine Pharmacokinetics in Healthy Korean Subjects". Clinical Pharmacology & Therapeutics. 86 (5): 511–8. doi:10.1038/clpt.2009.145. ISSN 0009-9236. PMID 19693007. S2CID 24789264.
  41. ^ Hofbauer, Karl (2004). Pharmacotherapy of obesity: options and alternatives. Boca Raton, Fla: CRC Press. ISBN 978-0-415-30321-7.
  42. ^ Douglas S. Johnson; Jie Jack Li (26 February 2013). The Art of Drug Synthesis. John Wiley & Sons. pp. 13–. ISBN 978-1-118-67846-6.
  43. ^ Wellington K, Perry CM (2001). "Venlafaxine extended-release: a review of its use in the management of major depression". CNS Drugs. 15 (8): 643–69. doi:10.2165/00023210-200115080-00007. PMID 11524036. S2CID 26795121.
  44. ^ Ahmadi, A; Khalili, M; Marami, S; Ghadiri, A; Nahri-Niknafs, B (2014). "Synthesis and pain perception of new analogues of phencyclidine in NMRI male mice". Mini Reviews in Medicinal Chemistry. 14 (1): 64–71. doi:10.2174/1389557513666131119203551. PMID 24251803.
  45. ^ Oishi R, Shishido S, Yamori M, Saeki K (February 1994). "Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain". Naunyn-Schmiedeberg's Archives of Pharmacology. 349 (2): 140–4. doi:10.1007/bf00169830. PMID 7513381. S2CID 20653998.
  46. ^ Sato T, Suemaru K, Matsunaga K, Hamaoka S, Gomita Y, Oishi R (May 1996). "Potentiation of L-dopa-induced behavioral excitement by histamine H1-receptor antagonists in mice". Japanese Journal of Pharmacology. 71 (1): 81–4. doi:10.1254/jjp.71.81. PMID 8791174.
  47. ^ Yeh SY, Dersch C, Rothman R, Cadet JL (September 1999). "Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion of serotonin in rats". Synapse. 33 (3): 207–17. doi:10.1002/(SICI)1098-2396(19990901)33:3<207::AID-SYN5>3.0.CO;2-8. PMID 10420168. S2CID 16399789.
  48. ^ David Healy (January 2004). Let them eat Prozac: the unhealthy ... - Google Books. NYU Press. ISBN 978-0-8147-3669-2.
  49. ^ Zhang R, Li X, Shi Y, Shao Y, Sun K, Wang A, Sun F, Liu W, Wang D, Jin J, Li Y (2014). "The Effects of LPM570065, a Novel Triple Reuptake Inhibitor, on Extracellular Serotonin, Dopamine and Norepinephrine Levels in Rats". PLOS ONE. 9 (3). e91775. Bibcode:2014PLoSO...991775Z. doi:10.1371/journal.pone.0091775. PMC 3948889. PMID 24614602.
  50. ^ "NDA Filing for Luye Pharma's Antidepressant Drug LY03005 Accepted by the U.S. FDA — Press Releases — Luye Pharma Group". www.luye.cn. Retrieved 2022-06-11.
  51. ^ "A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, Parallel-group Trial Evaluating the Efficacy, Safety, and Tolerability of Centanafadine Sustained-release Tablets in Adults With Attention-deficit/Hyperactivity Disorder". ClinicalTrials.gov. 2021-09-20.
  52. ^ "OPC 64005 — AdisInsight". adisinsight.springer.com. Retrieved 2022-12-19.
  53. ^ "Tesofensine — Saniona — AdisInsight". adisinsight.springer.com. Retrieved 2022-06-11.
  54. ^ Epstein, JW; Brabander, HJ; Fanshawe, WJ; Hofmann, CM; McKenzie, TC; Safir, SR; Osterberg, AC; Cosulich, DB; Lovell, FM (1981). "1-Aryl-3-azabicyclo3.1.0hexanes, a new series of nonnarcotic analgesic agents". Journal of Medicinal Chemistry. 24 (5): 481–90. doi:10.1021/jm00137a002. PMID 7241504.
  55. ^ Xu, Feng; Murry, Jerry A.; Simmons, Bryon; Corley, Edward; Fitch, Kenneth; Karady, Sandor; Tschaen, David (2006). "Stereocontrolled Synthesis of Trisubstituted Cyclopropanes: Expedient, Atom-Economical, Asymmetric Syntheses of (+)-Bicifadine and DOV21947". Organic Letters. 8 (17): 3885–8. doi:10.1021/ol061650w. PMID 16898842.
  56. ^ a b EP 0756596, Moldi, Peter; Watjen, Frank & Scheel-Krueger, Jorgen, "Tropane-2-aldoxine derivatives as neurotransmitter reuptake inhibitors", published 1997-02-05, assigned to Neurosearch AS 
  57. ^ Keller, HH; Schaffner, R; Carruba, MO; Burkard, WP; Pieri, M; Bonetti, EP; Scherschlicht, R; Da Prada, M; Haefely, WE (1982). "Diclofensine (Ro 8-4650)--a potent inhibitor of monoamine uptake: Biochemical and behavioural effects in comparison with nomifensine". Advances in Biochemical Psychopharmacology. 31: 249–63. PMID 6979165.
  58. ^ Omer, LM (1982). "Pilot trials with diclofensine, a new psychoactive drug in depressed patients". International Journal of Clinical Pharmacology, Therapy, and Toxicology. 20 (7): 320–6. PMID 7107085.
  59. ^ Beer B, Stark J, Krieter P, Czobor P, Beer G, Lippa A, Skolnick P (2004). "DOV 216,303, a "triple" reuptake inhibitor: Safety, tolerability, and pharmacokinetic profile". Journal of Clinical Pharmacology. 44 (12): 1360–7. doi:10.1177/0091270004269560. PMID 15545306. S2CID 26944976.
  60. ^ Prins J, Westphal KG, Korte-Bouws GA, Quinton MS, Schreiber R, Olivier B, Korte SM (2011). "The potential and limitations of DOV 216,303 as a triple reuptake inhibitor for the treatment of major depression: A microdialysis study in olfactory bulbectomized rats". Pharmacology Biochemistry and Behavior. 97 (3): 444–452. doi:10.1016/j.pbb.2010.10.001. PMID 20934452. S2CID 20809504.
  61. ^ U.S. patent 3,308,160PHENYLBICYCLO[Z.Z.Z]OCTANE-L-AMINES AND SALTS THEREOF.
  62. ^ Learned S, Graff O, Roychowdhury S, Moate R, Krishnan KR, Archer G, Modell JG, Alexander R, et al. (2012). "Efficacy, safety, and tolerability of a triple reuptake inhibitor GSK372475 in the treatment of patients with major depressive disorder: Two randomized, placebo- and active-controlled clinical trials". Journal of Psychopharmacology. 26 (5): 653–662. doi:10.1177/0269881111424931. PMID 22048884. S2CID 9365152.
  63. ^ "EUTHYMICS REPORTS TOP-LINE RESULTS FROM TRIADE TRIAL OF AMITIFADINE FOR MAJOR DEPRESSIVE DISORDER" (PDF) (Press release). Euthymics Bioscience, Inc. May 29, 2013. Archived from the original (PDF) on 2017-09-24. Retrieved 2022-06-11.
  64. ^ "Sunovion Discontinues Dasotraline Program". www.businesswire.com. 2020-05-13. Retrieved 2022-06-11.
  65. ^ "Efficacy and Safety of Lu AA34893 in Patients With Major Depressive Disorder". ClinicalTrials.gov. 2010-09-28.
  66. ^ "Development programme — Lundbeck". Archived from the original on 2011-09-29. Retrieved 2012-04-18.
  67. ^ "Search of: Lu AA24530 — List Results". ClinicalTrials.gov.
  68. ^ "Tedatioxetine — AdisInsight". adisinsight.springer.com. Retrieved 2022-06-11.
  69. ^ Wallach J, Brandt SD (2018). "Phencyclidine-Based New Psychoactive Substances". New Psychoactive Substances. Handbook of Experimental Pharmacology. Vol. 252. pp. 261–303. doi:10.1007/164_2018_124. ISBN 978-3-030-10560-0. PMID 30105474.
  70. ^ a b Meltzer PC, Butler D, Deschamps JR, Madras BK (2006). "1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: A promising class of monoamine uptake inhibitors". Journal of Medicinal Chemistry. 49 (4): 1420–32. doi:10.1021/jm050797a. PMC 2602954. PMID 16480278.
  71. ^ a b Alan Travis (2010-04-01). "NRG-1 may be next legal high to face ban by ministers | Politics". The Guardian. Retrieved 2010-04-03.
  72. ^ Carroll FI, Lewin AH, Mascarella SW, Seltzman HH, Reddy PA (2012). "Designer drugs: A medicinal chemistry perspective". Annals of the New York Academy of Sciences. 1248 (1): 18–38. Bibcode:2012NYASA1248...18C. doi:10.1111/j.1749-6632.2011.06199.x. PMID 22092008. S2CID 5108266.
  73. ^ Petit S, Nallet J, Guillard M, Dreux J, Chermat R, Poncelet M, Bulach C, Simon P (October 1990). "Synthèses et activités psychotropes de 3,4-diarylpiperidin-2-ones: corrélation structure-activité". European Journal of Medicinal Chemistry. 25 (8): 641–652. doi:10.1016/0223-5234(90)90129-Q.
  74. ^ Petit S, Nallet J, Guillard M, Dreux J, Chermat R, Poncelet M, Bulach C, Simon P, Fontaine C, Barthelmebs M, Imbs J (January 1991). "Synthèses et activités psychotropes de 3,4-diarylpipéridines. Corrélation structure-activité et recherche d'une activité antihypertensive". European Journal of Medicinal Chemistry. 26 (1): 19–32. doi:10.1016/0223-5234(91)90209-6.
  75. ^ Jacques Dreux & Serge Petit, US4785007 (1988 to Sanofi Aventis France).
  76. ^ Serge Petit, et al. EP0273199 (1988 to Sanofi Aventis France).
  77. ^ Claude G. A. Gueremy, et al. U.S. patent 4,224,332 (1980 to Pharmindustrie).
  78. ^ Burkholder TP, Kudlacz EM, Tieu-Binh L, Knippenberg RW, Shatzer SA, Maynard GD, Webster ME, Horgan SW (April 1996). "Identification and chemical synthesis of MDL 105,212, a non-peptide tachykinin antagonist with high affinity for NK1 and NK2 receptors". Bioorganic & Medicinal Chemistry Letters. 6 (8): 951–6. doi:10.1016/0960-894X(96)00148-5.
  79. ^ Xavier Emonds-Alt, Patrick Gueule, Vincenzo Proietto, Didier Van Broeck, U.S. patent 5,679,693 (1997 to Sanofi SA).
  80. ^ Xavier Emonds-Alt, et al. U.S. patent 5,554,763 (1996 to Sanofi SA).
  81. ^ Carnmalm B, Rämsby S, Renyi AL, Ross SB, Ogren SO, Stjernstrom NE (1978). "Antidepressant agents. 9. 3,3-Diphenylcyclobutylamines, a new class of central stimulants". Journal of Medicinal Chemistry. 21 (1): 78–82. doi:10.1021/jm00199a014. PMID 22757.
  82. ^ Dutta AK, Ghosh B, Biswas S, Reith ME (2008). "D-161, a novel pyran-based triple monoamine transporter blocker: Behavioral pharmacological evidence for antidepressant-like action". European Journal of Pharmacology. 589 (1–3): 73–9. doi:10.1016/j.ejphar.2008.05.008. PMID 18561912.
  83. ^ Sharma, Horrick; Santra, Soumava; Dutta, Aloke (2015). "Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?". Future Medicinal Chemistry. 7 (17): 2385–2406. doi:10.4155/fmc.15.134. PMC 4976848. PMID 26619226.
  84. ^ Chen, Zhengming; Skolnick, Phil (2007). "Triple uptake inhibitors: therapeutic potential in depression and beyond". Expert Opinion on Investigational Drugs. 16 (9): 1365–77. doi:10.1517/13543784.16.9.1365. ISSN 1354-3784. PMID 17714023.
  85. ^ Skolnick P, Basile AS (April 2007). "Triple reuptake inhibitors ("broad spectrum" antidepressants)". CNS Neurol Disord Drug Targets. 6 (2): 141–9. doi:10.2174/187152707780363285. PMID 17430151.
  86. ^ Deschamps NM, Elitzin VI, Liu B, Mitchell MB, Sharp MJ, Tabet EA (2011). "An enyne cycloisomerization approach to the triple reuptake inhibitor GSK1360707F". The Journal of Organic Chemistry. 76 (2): 712–5. doi:10.1021/jo102098y. PMID 21174473.
  87. ^ Micheli, F; Cavanni, P; Andreotti, D; Arban, R; Benedetti, R; Bertani, B; Bettati, M; Bettelini, L; et al. (2010). "6-(3,4-dichlorophenyl)-1-(methyloxy)methyl-3-azabicyclo4.1.0heptane: A new potent and selective triple reuptake inhibitor". Journal of Medicinal Chemistry. 53 (13): 4989–5001. doi:10.1021/jm100481d. PMID 20527970.
  88. ^ Bettati, Michela; Cavanni, Paolo; Di Fabio, Romano; Oliosi, Beatrice; Perini, Ornella; Scheid, Gunther; Tedesco, Giovanna; Zonzini, Laura; Micheli, Fabrizio (2010). "Oxa-azaspiro Derivatives: a Novel Class of Triple Re-uptake Inhibitors". ChemMedChem. 5 (3): 361–6. doi:10.1002/cmdc.200900482. ISSN 1860-7179. PMID 20112329.
  89. ^ Meyerson, Laurence R; Ong, Helen H; Martin, Lawrence L; Ellis, Daniel B (June 1980). "Effect of antidepressant agents on β-adrenergic receptor and neurotransmitter regulatory systems". Pharmacology Biochemistry and Behavior. 12 (6): 943–8. doi:10.1016/0091-3057(80)90457-8. PMID 6105676. S2CID 45400599.
  90. ^ Bøgesø KP, Christensen AV, Hyttel J, Liljefors (1985). "3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibition of dopamine, norepinephrine, and serotonin uptake". Journal of Medicinal Chemistry. 28 (12): 1817–28. doi:10.1021/jm00150a012. PMID 2999402.
  91. ^ Jan Kehler, Friedrich Kroll, & Karsten Juhl, WO2006007843 (to H Lundbeck AS).
  92. ^ Aluisio, L; Lord, B; Barbier, AJ; Fraser, IC; Wilson, SJ; Boggs, J; Dvorak, LK; Letavic, MA; et al. (2008). "In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor". European Journal of Pharmacology. 587 (1–3): 141–6. doi:10.1016/j.ejphar.2008.04.008. PMID 18499098.
  93. ^ a b Tamiz AP, Zhang J, Flippen-Anderson JL, Zhang M, Johnson KM, Deschaux O, Tella S, Kozikowski (2000). "Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors". Journal of Medicinal Chemistry. 43 (6): 1215–22. doi:10.1021/jm9905561. PMID 10737754.
  94. ^ WO 2005041875, Kozikowski, Alan P. & Zhou, Jia, "Dopamine-, norepinephrine- and serotonin- transporter- selective heterocyclic compounds and their therapeutic applications", published 2005-05-12, assigned to Georgetown University 
  95. ^ a b Caldarone BJ, Paterson NE, Zhou J, Brunner D, Kozikowski AP, Westphal KG, Korte-Bouws GA, Prins J, et al. (2010). "The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties". The Journal of Pharmacology and Experimental Therapeutics. 335 (3): 762–770. doi:10.1124/jpet.110.174011. PMC 2993553. PMID 20864506.
  96. ^ Axford, L., Boot, J. R., Hotten, T. M., Keenan, M., Martin, F. M., Milutinovic, S., Moore, N. A., O’Neill, M. F., Pullar, I. A., Tupper, D. E., Van Belle, K. R., Vivien, V. (October 2003). "Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression". Bioorganic & Medicinal Chemistry Letters. 13 (19): 3277–80. doi:10.1016/S0960-894X(03)00660-7. ISSN 0960-894X. PMID 12951108.
  97. ^ Christopher David Beadle, et al. WO2005000811 (to Eli Lilly and Co).
  98. ^ Clark, B. P.; Cases-Thomas, M. J.; Gallagher, P. T.; Gilmore, J.; Masters, J. J.; Timms, G. H.; Whatton, M. A.; Wood, M.Preparation of N,N-disubstituted 4-aminopiperidines as inhibitors of monoamine, in particular serotonin, norepinephrine, and dopamine reuptake. WO2004052858 (2004 to Eli Lilly and Co Ltd (GB)).
  99. ^ Boulet, S. L.; Clark, B. P.; Fairhurst, J.; Gallagher, P. T.; Johansson, A. M.; Whatton, M. A.; Wood, M. Preparation of 4-aminopiperidine derivatives as monoamine uptake inhibitors. WO2005092885 (2005 to Eli Lilly And Company).
  100. ^ Lile JA, Wang Z, Woolverton WL, France JE, Gregg TC, Davies HM, Nader MA (2003). "The reinforcing efficacy of psychostimulants in rhesus monkeys: The role of pharmacokinetics and pharmacodynamics". The Journal of Pharmacology and Experimental Therapeutics. 307 (1): 356–366. doi:10.1124/jpet.103.049825. PMID 12954808. S2CID 5654856.
  101. ^ Criado, Elisa (2 May 2014). "A fast-acting antidepressant could be on the horizon". The Independent. Retrieved 22 June 2014.
  102. ^ "A novel triple reuptake inhibitor with rapid antidepressant properties identified by virtual screening (1144.1)". Archived from the original on 2015-09-24. Retrieved 2014-06-23.
  103. ^ "A new fast-acting antidepressant (That's not ketamine) shows promise". Los Angeles Times. May 2014.
  104. ^ "Fast-acting antidepressant appears within reach".
  105. ^ Fang X, Guo L, Jia J, Jin GZ, Zhao B, Zheng YY, Li JQ, Zhang A, Zhen XC (2013). "SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity". Acta Pharmacologica Sinica. 34 (9): 1149–55. doi:10.1038/aps.2013.66. PMC 4003162. PMID 23892272.
  106. ^ Mondeshka, Diana; Angelova, Ivanka; Ivanov, Chavdar B.; Ivanova, Nedjalka S. (1990). "Racemische und optisch aktive 2-Chlorethylcarbamoyl-Derivate des 7,8-Dimethoxy-1-phenyl-1 H -3-benzazepins: Neue Strukturtypen von DA, NE und 5-HT Uptake Inhibitoren". Archiv der Pharmazie. 323 (10): 829–832. doi:10.1002/ardp.19903231003. ISSN 0365-6233. PMID 2150477.
  107. ^ a b c Carroll FI (2003). "2002 Medicinal Chemistry Division Award address: Monoamine transporters and opioid receptors. Targets for addiction therapy". Journal of Medicinal Chemistry. 46 (10): 1775–94. doi:10.1021/jm030092d. PMID 12723940.
  108. ^ Andreasen, Jesper T.; Redrobe, John P.; Nielsen, Elsebet Ø.; Christensen, Jeppe K.; Olsen, Gunnar M.; Peters, Dan (2013). "A combined α7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances". Neuropharmacology. 73: 183–191. doi:10.1016/j.neuropharm.2013.04.060. ISSN 0028-3908. PMID 23748055. S2CID 6812669.
  109. ^ Hache, G.; Guiard, B.P.; Nguyen, T.H.; Quesseveur, G.; Gardier, A.M.; Peters, D.; Munro, G.; Coudoré, F. (2015). "Antinociceptive activity of the new triple reuptake inhibitor NS 18283 in a mouse model of chemotherapy-induced neuropathic pain". European Journal of Pain. 19 (3): 322–333. doi:10.1002/ejp.550. ISSN 1090-3801. PMID 25045036.
  110. ^ Birgitte L. Eriksen, et al. WO2008025777 (2008 to Neurosearch A/S).
  111. ^ Dan Peters, et al. U.S. patent 7,060,699 (2006 to NeuroSearch AS).
  112. ^ Peter Moldt, Jørgen SCHEEL-KRÜGER, Gunnar M. Olsen, Elsebet Østergaard NIELSEN , WO1997013770 (1997 to Neurosearch A/S).
  113. ^ Liming Shao, 12 More », WO2008151156 (to Sunovion Pharmaceuticals Inc.).
  114. ^ Shao, Liming; Hewitt, Michael C.; Wang, Fengjiang; Malcolm, Scott C.; Ma, Jianguo; Campbell, John E.; Campbell, Una C.; Engel, Sharon R.; Spicer, Nancy A.; Hardy, Larry W.; Schreiber, Rudy; Spear, Kerry L.; Varney, Mark A. (2011). "Discovery of N-methyl-1-(1-phenylcyclohexyl)methanamine, a novel triple serotonin, norepinephrine, and dopamine reuptake inhibitor". Bioorganic & Medicinal Chemistry Letters. 21 (5): 1438–41. doi:10.1016/j.bmcl.2011.01.016. PMID 21310609.
  115. ^ Shao L, Hewitt MC, Wang F, Malcolm SC, Ma J, Campbell JE, Campbell UC, Engel SR, Spicer NA, Hardy LW, Schreiber R, Spear KL, Varney MA (March 2011). "Discovery of N-methyl-1-(1-phenylcyclohexyl)ethanamine, a novel triple serotonin, norepinephrine and dopamine reuptake inhibitor". Bioorg Med Chem Lett. 21 (5): 1434–7. doi:10.1016/j.bmcl.2011.01.019. PMID 21310612.
  116. ^ Shao L, Li W, Xie Q, Yin H (February 2014). "Triple reuptake inhibitors: a patent review (2006–2012)". Expert Opin Ther Pat. 24 (2): 131–54. doi:10.1517/13543776.2014.859676. PMID 24289044.MID 24289044.
  117. ^ Shao L, Wang F, Malcolm SC, Ma J, Hewitt MC, Campbell UC, Bush LR, Spicer NA, Engel SR, Saraswat LD, Hardy LW, Koch P, Schreiber R, Spear KL, Varney MA (January 2011). "Synthesis and pharmacological evaluation of 4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalenyl amines as triple reuptake inhibitors". Bioorg Med Chem. 19 (1): 663–76. doi:10.1016/j.bmc.2010.10.034. PMID 21093273.
  118. ^ Liming Shao, et al. WO2007081542 (Sunovion Pharmaceuticals Inc).
  119. ^ Liming Shao & Jianguo Ma, WO2010091268 (Sunovion Pharmaceuticals Inc).
  120. ^ Heike Radeke & Liming Shao, US7812035 (2003 to Sunovion Pharmaceuticals Inc).
  121. ^ Liming Shao, et al. US8592608, US9133117 & US9850204 (2018 to Sunovion Pharmaceuticals Inc).
  122. ^ Ishichi, Yuji; Kimura, Eiji; Honda, Eiji; Yoshikawa, Masato; Nakahata, Takashi; Terao, Yasuko; Suzuki, Atsuko; Kawai, Takayuki; Arakawa, Yuuichi; Ohta, Hiroyuki; Kanzaki, Naoyuki; Nakagawa, Hideyuki; Terauchi, Jun (2013). "Novel triple reuptake inhibitors with low risk of CAD associated liabilities: Design, synthesis and biological activities of 4-[(1S)-1-(3,4-dichlorophenyl)-2-methoxyethyl]piperidine and related compounds". Bioorganic & Medicinal Chemistry. 21 (15): 4600–4613. doi:10.1016/j.bmc.2013.05.025.
  123. ^ Ishichi Yuji, Kimura Eiji & Terauchi Jun, WO2010016554 (to Takeda).
  124. ^ Kaur H, Izenwasser S, Verma A, Wade D, Housman A, Stevens ED, Mobley DL, Trudell ML (December 2009). "Synthesis and monoamine transporter affinity of 3alpha-arylmethoxy-3beta-arylnortropanes". Bioorg Med Chem Lett. 19 (24): 6865–8. doi:10.1016/j.bmcl.2009.10.087. PMC 2788963. PMID 19896846.
  125. ^ Wong DT, Bymaster FP, Engleman EA (1995). "Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publication". Life Sci. 57 (5): 411–441. doi:10.1016/0024-3205(95)00209-o. PMID 7623609.
  126. ^ U.S. patent 4,556,676
  127. ^ Li N, Li C, Han R, Wang Y, Yang M, Wang H, Tian J (2019). "LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain". Front Pharmacol. 10: 53. doi:10.3389/fphar.2019.00053. PMC 6382704. PMID 30837867.
  128. ^ Zhang F, Shao J, Tian J, Zhong Y, Ye L, Meng X, Liu Q, Wang H (April 2016). "Antidepressant-like Effects of LPM580153, A Novel Potent Triple Reuptake Inhibitor". Sci Rep. 6: 24233. doi:10.1038/srep24233. PMC 4823741. PMID 27052887.
  129. ^ Tian JW, Jiang WL, Zhong Y, Meng Q, Gai Y, Zhu HB, Hou J, Xing Y, Li YX (2011). "Preclinical pharmacology of TP1, a novel potent triple reuptake inhibitor with antidepressant properties". Neuroscience. 196: 124–130. doi:10.1016/j.neuroscience.2011.08.064. PMID 21925241. S2CID 37122044.
  130. ^ Hou J, Xing Y, Zuo D, Wu Y, Tian J, Meng Q, Yang M (January 2015). "In vitro and in vivo characterization of PA01, a novel promising triple reuptake inhibitor". Physiol Behav. 138: 141–9. doi:10.1016/j.physbeh.2014.10.007. PMID 25447484.
  131. ^ a b Liang Y, Shaw AM, Boules M, Briody S, Robinson J, Oliveros A, Blazar E, Williams K, et al. (2008). "Antidepressant-like pharmacological profile of a novel triple reuptake inhibitor, (1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol (PRC200-SS)". The Journal of Pharmacology and Experimental Therapeutics. 327 (2): 573–583. doi:10.1124/jpet.108.143610. PMID 18689611. S2CID 12635418.
  132. ^ Shaw AM, Boules M, Zhang Y, Williams K, Robinson J, Carlier PR, Richelson E (January 2007). "Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050". Eur J Pharmacol. 555 (1): 30–6. doi:10.1016/j.ejphar.2006.10.004. PMID 17109850.
  133. ^ Liu S, Zha C, Nacro K, Hu M, Cui W, Yang YL, Bhatt U, Sambandam A, Isherwood M, Yet L, Herr MT, Ebeltoft S, Hassler C, Fleming L, Pechulis AD, Payen-Fornicola A, Holman N, Milanowski D, Cotterill I, Mozhaev V, Khmelnitsky Y, Guzzo PR, Sargent BJ, Molino BF, Olson R, King D, Lelas S, Li YW, Johnson K, Molski T, Orie A, Ng A, Haskell R, Clarke W, Bertekap R, O'Connell J, Lodge N, Sinz M, Adams S, Zaczek R, Macor JE (July 2014). "Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors". ACS Med Chem Lett. 5 (7): 760–5. doi:10.1021/ml500053b. PMC 4094255. PMID 25050161.
  134. ^ Shuang Liu, Bruce F. Molino, Kassoum Nacro, WO2010132442 (2010 to Albany Molecular Reserch, Inc.). Page column 32.
  135. ^ Ki-Ho Lee, et al. WO2009148291 (to SK Biopharmaceuticals Co Ltd).
  136. ^ Chun-Eung Park, et al. WO2009148290 (to SK Biopharmaceuticals Co Ltd).
  137. ^ Lee KH, Park CE, Min KH, Shin YJ, Chung CM, Kim HH, Yoon HJ, Won-Kim, Ryu EJ, Shin YJ, Nam HS, Cho JW, Lee HY (September 2010). "Synthesis and pharmacological evaluation of 3-aryl-3-azolylpropan-1-amines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors". Bioorg Med Chem Lett. 20 (18): 5567–71. doi:10.1016/j.bmcl.2010.07.021. PMID 20724153.
  138. ^ Koprdova R, Csatlosova K, Durisova B, Bogi E, Majekova M, Dremencov E, Mach M (November 2019). "Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors". Molecules. 24 (23): 4218. doi:10.3390/molecules24234218. PMC 6930491. PMID 31757051.
  139. ^ Weng Z, Zheng Y, Li J (April 2015). "Synthesis, antidepressant activity, and toxicity of the erythro/threo racemates and optical isomers of 2-(4-benzylpiperazin-1-yl)-1-(5-chloro-6-methoxynaphthalen-2-yl)hexan-1-ol". Chem Biol Drug Des. 85 (4): 454–60. doi:10.1111/cbdd.12438. PMID 25243904.
  140. ^ Honda E, Ishichi Y, Kimura E, Yoshikawa M, Kanzaki N, Nakagawa H, Terao Y, Suzuki A, Kawai T, Arakawa Y, Ohta H, Terauchi J (August 2014). "Design, synthesis, and biological activities of 1-aryl-1,4-diazepan-2-one derivatives as novel triple reuptake inhibitors". Bioorg Med Chem Lett. 24 (16): 3898–902. doi:10.1016/j.bmcl.2014.06.046. PMID 25017029.
  141. ^ Paudel S, Acharya S, Yoon G, Kim KM, Cheon SH (April 2017). "Design, synthesis and in vitro activity of 1,4-disubstituted piperazines and piperidines as triple reuptake inhibitors". Bioorg Med Chem. 25 (7): 2266–76. doi:10.1016/j.bmc.2017.02.051. PMID 28274674.
  142. ^ Paudel S, Min X, Acharya S, Khadka DB, Yoon G, Kim KM, Cheon SH (October 2017). "Triple reuptake inhibitors: Design, synthesis and structure-activity relationship of benzylpiperidine-tetrazoles". Bioorg Med Chem. 25 (20): 5278–89. doi:10.1016/j.bmc.2017.07.046. PMID 28807575.
  143. ^ Paudel S, Wang S, Kim E, Kundu D, Min X, Shin CY, Kim KM. Design, Synthesis, and Functional Evaluation of 1, 5-Disubstituted Tetrazoles as Monoamine Neurotransmitter Reuptake Inhibitors. Biomol Ther (Seoul). 2021 Nov 18. doi: 10.4062/biomolther.2021.119. Epub ahead of print. PMID 34789584.
  144. ^ Han M, Song C, Jeong N, Hahn HG (September 2014). "Exploration of 3-Aminoazetidines as Triple Reuptake Inhibitors by Bioisosteric Modification of 3-α-Oxyazetidine". ACS Med Chem Lett. 5 (9): 999–1004. doi:10.1021/ml500187a. PMC 4160755. PMID 25221656.
  145. ^ Yun J, Han M, Song C, Cheon SH, Choi K, Hahn HG (August 2014). "Synthesis and biological evaluation of 3-phenethylazetidine derivatives as triple reuptake inhibitors". Bioorg Med Chem Lett. 24 (15): 3234–7. doi:10.1016/j.bmcl.2014.06.026. PMID 24974340.
  146. ^ Mondeshka DM, Angelova IG, Tancheva CN, Ivanov CB, Daleva LD, Ivanova NS (1994). "Synthesis, antiulcer and antidepressive activity of 4-(4-halophenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolines". Farmaco. 49 (7–8): 475–80. PMID 7945712.
  147. ^ CA2015114 idem Donka M. Mondeshka, 10 More », EP0400319 (1990 to N I S Pri Vchti).
  148. ^ James P. Beck, Mark A. Smith, Matt A. Curry, M. A. Aryl- and heteroarylsubstituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine and serotonin. WO2001032625 (2001 to Du Pont Pharmaceuticals Company).
  149. ^ Zheng YY, Guo L, Zhen XC, Li JQ (August 2012). "Synthesis and antidepressant activity of arylalkanol-piperidine derivatives as triple reuptake inhibitors". Eur J Med Chem. 54: 123–36. doi:10.1016/j.ejmech.2012.04.030. PMID 22608762.
  150. ^ Han Y, Han M, Shin D, Song C, Hahn HG (September 2012). "Exploration of novel 3-substituted azetidine derivatives as triple reuptake inhibitors". J Med Chem. 55 (18): 8188–92. doi:10.1021/jm3008294. PMID 22938049.
  151. ^ Roggen H, Kehler J, Stensbøl TB, Hansen T (May 2007). "Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters". Bioorg Med Chem Lett. 17 (10): 2834–7. doi:10.1016/j.bmcl.2007.02.054. PMID 17350257.
  152. ^ Fehske, C. J.; Leuner, K.; Müller, 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.
  153. ^ Stein, A. C.; Viana, A. F.; Müller, 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.
  154. ^ US 2011313034, Rates, Stela Maris Kuze; Von Poser, Gilsane Lino & 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 
  155. ^ Mechan, Annis O.; Fowler, Ann; Seifert, Nicole; Rieger, Henry; Wöhrle, Tina; Etheve, Stéphane; Wyss, Adrian; Schüler, Göde; 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): 1150–63. doi:10.1017/S0007114510004940. ISSN 0007-1145. PMID 21205415.
  156. ^ 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.
  157. ^ 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): 431–9. doi:10.1016/j.pbb.2011.10.001. ISSN 0091-3057. PMID 22005599. S2CID 207331897.
  158. ^ 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.
  159. ^ 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.
  160. ^ 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.
  161. ^ 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.
  162. ^ U.S. patent 6,395,748
  163. ^ U.S. patent 6,376,673
  164. ^ WO 2004039778, Wätjen, Frank, "Novel piperidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", published 2004-05-13, assigned to NeuroSearch AS 
  165. ^ U.S. patent 7,560,562
  166. ^ Archived at Ghostarchive and the Wayback Machine: "2010 N.C. Award for Science: Dr. F. Ivy Carroll". YouTube. 8 April 2011.
  167. ^ 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.
  168. ^ Abuse, National Institute on Drug. "Drug-Related Hospital Emergency Room Visits". www.drugabuse.gov. Retrieved 2016-04-04.
  169. ^ 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.
  170. ^ 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.
  171. ^ a b Vetulani, J (2001). "Drug addiction. Part II. Neurobiology of addiction". Polish Journal of Pharmacology. 53 (4): 303–17. PMID 11990077.
  172. ^ 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.
  173. ^ Koob, GF; Volkow, ND (2010). "Neurocircuitry of addiction". Neuropsychopharmacology. 35 (1): 217–38. doi:10.1038/npp.2009.110. PMC 2805560. PMID 19710631.
  174. ^ 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.
  175. ^ 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.
  176. ^ 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.
  177. ^ 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.
  178. ^ 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.
  179. ^ 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.
  180. ^ 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.
  181. ^ 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.
  182. ^ 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.
  183. ^ 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.
  184. ^ 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.
  185. ^ a b c d e López-Muñoz, 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.
  186. ^ 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 978-0-07-148127-4. 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.
  187. ^ 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.
  188. ^ 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.
  189. ^ a b c d e Slattery, DA; Hudson, AL; Nutt, DJ (2004). "Invited review: The evolution of antidepressant mechanisms". Fundamental & Clinical Pharmacology. 18 (1): 1–21. doi:10.1111/j.1472-8206.2004.00195.x. PMID 14748749. S2CID 29459098.
  190. ^ Schildkraut, JJ (1965). "The catecholamine hypothesis of affective disorders: A review of supporting evidence". The American Journal of Psychiatry. 122 (5): 509–22. doi:10.1176/ajp.122.5.509. PMID 5319766.
  191. ^ "Joseph J. Schildkraut | Harvard Medical School Office for Faculty Affairs". Archived from the original on 2011-07-19. Retrieved 2011-03-09.
  192. ^ Wong, DT; Perry, KW; Bymaster, FP (2005). "Case history: The discovery of fluoxetine hydrochloride (Prozac)". Nature Reviews Drug Discovery. 4 (9): 764–74. doi:10.1038/nrd1821. PMID 16121130.
  193. ^ "'Let Them Eat Prozac' — Introduction: The SSRI Issues" (PDF). 'Let them Eat Prozac' Website. Retrieved 2024-07-12.
  194. ^ a b Moltzen, EK; Bang-Andersen, B (2006). "Serotonin reuptake inhibitors: The corner stone in treatment of depression for half a century--a medicinal chemistry survey". Current Topics in Medicinal Chemistry. 6 (17): 1801–23. doi:10.2174/156802606778249810. PMID 17017959.
  195. ^ Miller, HL; Delgado, PL; Salomon, RM; Berman, R; Krystal, JH; Heninger, GR; Charney, DS (1996). "Clinical and biochemical effects of catecholamine depletion on antidepressant-induced remission of depression". Archives of General Psychiatry. 53 (2): 117–28. doi:10.1001/archpsyc.1996.01830020031005. PMID 8629887.
  196. ^ Roiser, JP; McLean, A; Ogilvie, AD; Blackwell, AD; Bamber, DJ; Goodyer, I; Jones, PB; Sahakian, BJ (2005). "The subjective and cognitive effects of acute phenylalanine and tyrosine depletion in patients recovered from depression". Neuropsychopharmacology. 30 (4): 775–85. doi:10.1038/sj.npp.1300659. PMC 2631648. PMID 15688090.
  197. ^ Shopsin, B; Gershon, S; Goldstein, M; Friedman, E; Wilk, S (1975). "Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients". Psychopharmacology Communications. 1 (2): 239–49. PMID 131359.
  198. ^ Castrén, E (2005). "Is mood chemistry?". Nature Reviews Neuroscience. 6 (3): 241–6. doi:10.1038/nrn1629. PMID 15738959. S2CID 34523310.
  199. ^ Nutt, D; Demyttenaere, K; Janka, Z; 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.
  200. ^ 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.
  201. ^ 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.
  202. ^ 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.
  203. ^ Cohen, BM; Carlezon Jr, WA (2007). "Can't get enough of that dopamine". The American Journal of Psychiatry. 164 (4): 543–6. doi:10.1176/appi.ajp.164.4.543. PMID 17403963.
  204. ^ Orr, K; Taylor, D (2007). "Psychostimulants in the treatment of depression: A review of the evidence". CNS Drugs. 21 (3): 239–57. doi:10.2165/00023210-200721030-00004. PMID 17338594. S2CID 35761979.
  205. ^ Candy, M; Jones, L; Williams, R; Tookman, A; King, M (2008). Candy, Bridget (ed.). "Psychostimulants for depression". Cochrane Database of Systematic Reviews (2): CD006722. doi:10.1002/14651858.CD006722.pub2. PMID 18425966.
  206. ^ Nieoullon, A (2002). "Dopamine and the regulation of cognition and attention". Progress in Neurobiology. 67 (1): 53–83. doi:10.1016/S0301-0082(02)00011-4. PMID 12126656. S2CID 206054231.
  207. ^ Dell'Osso, B; Palazzo, MC; Oldani, L; Altamura, AC (2011). "The noradrenergic action in antidepressant treatments: Pharmacological and clinical aspects". CNS Neuroscience & Therapeutics. 17 (6): 723–32. doi:10.1111/j.1755-5949.2010.00217.x. PMC 6493872. PMID 21155988.
  208. ^ Nichols, DE; Nichols, CD (2008). "Serotonin receptors". Chemical Reviews. 108 (5): 1614–41. doi:10.1021/cr078224o. PMID 18476671.
  209. ^ Berton, O; Nestler, EJ (2006). "New approaches to antidepressant drug discovery: Beyond monoamines". Nature Reviews Neuroscience. 7 (2): 137–51. doi:10.1038/nrn1846. PMID 16429123. S2CID 10488057.
  210. ^ Blier, P (2003). "The pharmacology of putative early-onset antidepressant strategies". European Neuropsychopharmacology. 13 (2): 57–66. doi:10.1016/S0924-977X(02)00173-6. PMID 12650947. S2CID 38643068.
  211. ^ Papakostas, GI; Thase, ME; Fava, M; Nelson, JC; Shelton, RC (2007). "Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents". Biological Psychiatry. 62 (11): 1217–27. doi:10.1016/j.biopsych.2007.03.027. PMID 17588546. S2CID 45621773.
  212. ^ Ban, TA (2001). "Pharmacotherapy of depression: A historical analysis". Journal of Neural Transmission. 108 (6): 707–16. doi:10.1007/s007020170047. PMID 11478422. S2CID 19966517.
  213. ^ Preskorn, SH (2010). "CNS drug development: Part II: Advances from the 1960s to the 1990s". Journal of Psychiatric Practice. 16 (6): 413–5. doi:10.1097/01.pra.0000390760.12204.99. PMID 21107146.
  214. ^ a b c d Dale, Elena; Bang-Andersen, Benny; Sánchez, 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.
  215. ^ 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.
edit
Retrieved from "https://en.wikipedia.org/w/index.php?title=Serotonin–norepinephrine–dopamine_reuptake_inhibitor&oldid=1254281942"