Serotonin–norepinephrine–dopamine reuptake inhibitor

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.

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 very 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. One of the ways in which this is so is that SNDRIs lack the entactogenic, psychedelic, and neurotoxic effects of SNDRAs like MDMA and αET.

Cocaine is a naturally-occurring SNDRI with a fast onset and short duration (about two hours) that is widely encountered as a drug of abuse. 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

Depression

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

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, noradrenergic, and dopaminergic 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 and dimebon are examples of drugs used in the treatment of CNS disorders that have a superior efficacy precisely because of their "multifarious" broadspectrum mode of activity. Likewise, in cancer chemotherapeutics, it has been recognized that drugs active at more than one target have a higher probability of being efficacious.[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

List of SNDRIs

Approved pharmaceuticals

Sibutramine (Meridia) is a withdrawn anorectic that is an SNDRI in vitro with values of 298 nM at SERT, 5451 at NET, 943 nM at DAT.[38] However, it appears to act as a prodrug in vivo to metabolites that are considerably more potent and possess different ratios of monoamine reuptake inhibition in comparison, and in accordance, sibutramine behaves contrarily as an SNRI (73% and 54% for norepinephrine and serotonin reuptake inhibition, respectively) in human volunteers with only very weak and probably inconsequential inhibition of dopamine reuptake (16%).[39][40]

Venlafaxine (Effexor) is sometimes referred to as an SNDRI, but is extremely imbalanced. 82 nM at SERT, 2480 nM at NET, 7647 at DAT, with a ratio of 1:30:93.[41] It may weakly inhibit the reuptake of dopamine at high doses.[42]

Coincidental

Undergoing clinical trials

Failed clinical trials

Designer drugs

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

Other SNDRIs

Toxicological

Toxicological screening is important to ensure safety of the drug molecules. In this regard, the p m-dichloro phenyl analog of venlafaxine was dropped from further development after its potential mutagenicity was called into question.[91] 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.[92]

(+)-CPCA ("nocaine")[93] is the 3R,4S piperidine stereoisomer of (phenyltropane based) RTI-31.[94] It is non addictive but is not a SNDRI (it is a NDRI). The β-naphthyl analog of "Nocaine"[72] is a SNDRI though in the case of both the SS and RR enantiomers. Consider the piperidine analogs of brasofensine[58] and tesofensine.[95] These were prepared by NeuroSearch (In Denmark) by the chemists Peter Moldt (2002),[96] and Frank Wätjen (2004–2009).[97][98] 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[99] 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).[100] While it does still have to be conceded that RTI-55 caused death at a dosage of 100 mg/kg, it's therapeutic index of safety is still much better than the corresponding trans isomers because it is more potent compound.

In discussing cocaine and related compounds such as amphetamines, it is clear that these psychostimulants cause increased blood pressure, decreased appetite (and hence weight loss), increased locomotor activity (LMA) etc. In the United States, cocaine overdose is one of the leading causes of ER admissions each year due to drug overdose.[101] People are at increased risk of heart attack and stroke and also present with an array of psychiatric symptoms including anxiety & paranoia etc. Interestingly, on removal of the 2C tropane bridge and on going from RTI-31 to the simpler SS and RS Nocaine it was seen that these compounds still possessed activity as 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.[88][102][103]

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

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.[104]

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.[104][105][106]

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.[107][108][109]

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.[102]

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).[94] 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,[110] and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.[111]

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,[112] and also the fact that the NRI atomoxetine was not reinforcing.[113] However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC.

Relation to cocaine

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[114] 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.[115]

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

Legality

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). BF is an interesting compound in so far as the semi-synthetic procedure for making it actually 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.[65] 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.[117] Anyway, a short time after mephedrone and methylone were banned (which had become quite popular by the time they were illegalized), naphyrone appeared under the trade name NRG-1.[66] NRG-1 was promptly illegalized, although it is not known if its use resulted in any hospitalizations or deaths.

Role of monoamine neurotransmitters

Monoamine hypothesis

The original monoamine hypothesis postulates that depression is caused by a deficiency or imbalances in the monoamine neurotransmitters (5-HT, NE, and DA). This has been the central topic of depression research for approximately the last 50 years;[12][118] it has since evolved into the notion that depression arises through alterations in target neurons (specifically, the dendrites) in monoamine pathways.[119]

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.[120]

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.[121][122]

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.[118][122]

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.[122]

In 1965 Schildkraut formulated the catecholamine theory of depression.[123] This was subsequently the most widely cited article in the American Journal of Psychiatry.[124] 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.[122]

Inserting a chlorine atom into imipramine leads to clomipramine, a drug that is much more SERT selective than the parent compound.[118]

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.[125] 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.[126] Moreover, NRIs have the additional adverse safety risk of hypertension that is not seen for SSRIs.[127] Nevertheless, NRIs have still found uses.

Further support for the monoamine hypothesis came from monoamine depletion studies:

Dopaminergic

There appears to be a pattern of symptoms that are currently inadequately addressed by serotonergic antidepressants – loss of pleasure (anhedonia), reduced motivation, loss of interest, fatigue and loss of energy, motor retardation, apathy and hypersomnia. Addition of a pro-dopaminergic component into a serotonin based therapy would be expected to address some of these short-comings.[132][133][134]

Several lines of evidence suggest that an attenuated function of the dopaminergic system may play an important role in depression:

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,[139] although this remains to be demonstrated in humans.

The rate of clearance from the body is faster for ritalin than it is for regular amphetamine.

Noradrenergic

The decreased levels of NA proposed by Schildkraut, suggested that there would be a compensatory upregulation of β-adrenoceptors. Despite inconsistent findings supporting this, more consistent evidence demonstrates that chronic treatment with antidepressants and electroconvulsive therapy (ECT) decrease β-adrenoceptor density in the rat forebrain. This led to the theory that β-adrenoceptor downregulation was required for clinical antidepressant efficacy. However, some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density.[122]

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.

[140]

Serotonergic

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

Because serotonin and the related hormone melatonin are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. This is accounted for by the lethargic feel that some SSRIs can produce, although TCAs and antipsychotics can also cause lethargy albeit through different mechanisms.

Appetite suppression is related to 5-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. Systemic administration of a 5-HT1A agonist also induces growth hormone and adrenocorticotropic hormone (ACTH) release through actions in the hypothalamus.[141]

Current antidepressants

Most antidepressants on the market today target the monoaminergic system.

SSRIs

The most commonly prescribed class of antidepressants in the USA today are the 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.[142] 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.[143]

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.[127]

NRIs

Norepinephrine reuptake inhibitors (NRIs) such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. In addition, atomoxetine has found use in the treatment of ADHD as a non-addictive alternative to Ritalin. The chemical structure of atomoxetine is closely related to that of fluoxetine (an SSRI) and also duloxetine (SNRI).

NDRIs

Bupropion is a commonly prescribed antidepressant that acts as a Norepinephrine-dopamine reuptake inhibitor (NDRI). It prevents the reuptake of NA and DA (weakly) by blocking the corresponding transporters, leading to increased noradrenergic and dopaminergic neurotransmission. This drug does not cause sexual dysfunction or weight gain like the SSRIs but has a higher incidence of nausea. Methylphenidate is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Methylphenidate is used in the treatment of ADHD, its use in treating depression is not known to have been reported, it is presumed owing to its psychomotor activating effects and it functioning as a positive reinforcer. There are also reports of methylphenidate being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter.

SNRIs

Serotonin–norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine (Effexor), its active metabolite desvenlafaxine (Pristiq), and duloxetine (Cymbalta) prevent the reuptake of both serotonin and norepinephrine, however their efficacy appears to be only marginally greater than the SSRIs.[144]

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

Monoamine oxidase inhibitors (MAOIs) were the first antidepressants to be introduced. They were discovered entirely by serendipity.[118] Iproniazide (the first MAOI) was originally developed as an antitubercular agent but was then unexpectedly found to display antidepressant activity.

It is interesting to note that isoniazid also displayed activity as an antidepressant, even though it is not a MAOI.[145] This led some people to question whether it is some property of the hydrazine, which is responsible for mediating the antidepressant effect, even going as far as to state that the MAOI activity could be a secondary side-effect. However, with the discovery of tranylcypromine (the first non-hydrazine MAOI), it was shown that MAOI is thought to underlie the antidepressant bioactivity of these agents. Etryptamine is another example of a non-hydrazine MAOI that was introduced.

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

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

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

TCAs

The first tricyclic antidepressant (TCA), imipramine (Tofranil), was derived from the antipsychotic drug chlorpromazine, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative.[118] 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.[146]

Another example of an interesting TCA is amineptine which is the only one believed to function as a DRI. It is no longer available.

Failure of SNDRIs for depression

SNDRIs have been under investigation for the treatment of major depressive disorder for a number of years but, as of 2015, have failed to meet effectiveness expectations in clinical trials.[147] 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.[147] These occurrences have shed doubt on the potential benefit of dopaminergic augmentation of conventional serotonergic and noradrenergic antidepressant therapy.[147] As such, skepticism has been cast on the promise of the remaining SNDRIs that are still being trialed, such as ansofaxine (currently in phase I trials), in the treatment of depression.[147]

See also

References

  1. ↑ Millan, MJ (2009). "Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: Novel concepts, new drugs". Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 6 (1): 53–77. doi:10.1016/j.nurt.2008.10.039. 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.
  3. 1 2 3 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. 1 2 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. 1 2 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.
  6. 1 2 3 4 5 6 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. 1 2 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. 1 2 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. PMC 2938284. PMID 20856599.
  10. 1 2 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. PMID 19501541.
  11. ↑ "Depression". World Health Organization. WHO. Archived from the original on 2010-07-21.
  12. 1 2 3 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): 800–806. doi:10.1177/2047487312444994. PMID 22496274.
  14. 1 2 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'Encephale 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.
  16. ↑ Li, M; Fitzgerald, P; Rodin, G (2012). "Evidence-based treatment of depression in patients with cancer". Journal of clinical oncology : official journal of the American Society 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.
  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'Encephale 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. PMID 18704023.
  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.
  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. 1 2 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.
  25. ↑ Buccafusco, JJ (2009). "Multifunctional receptor-directed drugs for disorders of the central nervous system". Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 6 (1): 4–13. doi:10.1016/j.nurt.2008.10.031. 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.
  27. ↑ Frantz, S (2005). "Drug discovery: Playing dirty". Nature 437 (7061): 942–3. Bibcode:2005Natur.437..942F. doi:10.1038/437942a. PMID 16222266.
  28. ↑ Hopkins, AL (2009). "Drug discovery: Predicting promiscuity". Nature 462 (7270): 167–8. Bibcode:2009Natur.462..167H. doi:10.1038/462167a. PMID 19907483.
  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. 1 2 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.
  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.
  36. ↑ http://clinicaltrials.gov/ct2/show/NCT00467428
  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.
  38. 1 2 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. ↑ 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): 511–518. doi:10.1038/clpt.2009.145. ISSN 0009-9236.
  40. ↑ Hofbauer, Karl (2004). Pharmacotherapy of obesity : options and alternatives. Boca Raton, Fla: CRC Press. ISBN 0-415-30321-4.
  41. ↑ 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.
  42. ↑ Wellington K, Perry CM (2001). "Venlafaxine extended-release: a review of its use in the management of major depression" (PDF). CNS Drugs 15 (8): 643–69. doi:10.2165/00023210-200115080-00007. PMID 11524036.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ ), David Healy (MRC Psych (January 2004). Let them eat Prozac: the unhealthy ... - Google Books. ISBN 978-0-8147-3669-2.
  48. ↑ Skolnick, P; Popik, P; Janowsky, A; Beer, B; Lippa, AS (2003). "Antidepressant-like actions of DOV 21,947: A "triple" reuptake inhibitor". European Journal of Pharmacology 461 (2–3): 99–104. doi:10.1016/S0014-2999(03)01310-4. PMID 12586204.
  49. ↑ Golembiowska, K; Kowalska, M; Bymaster, FP (2012). "Effects of the triple reuptake inhibitor amitifadine on extracellular levels of monoamines in rat brain regions and on locomotor activity". Synapse 66 (5): 435–44. doi:10.1002/syn.21531. PMID 22213370.
  50. ↑ Tran, P; Skolnick, P; Czobor, P; Huang, NY; Bradshaw, M; McKinney, A; Fava, M (2012). "Efficacy and tolerability of the novel triple reuptake inhibitor amitifadine in the treatment of patients with major depressive disorder: A randomized, double-blind, placebo-controlled trial". Journal of Psychiatric Research 46 (1): 64–71. doi:10.1016/j.jpsychires.2011.09.003. PMID 21925682.
  51. ↑ 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. doi:10.1371/journal.pone.0091775. PMID 24614602.
  52. ↑ Delorenzo, C; Lichenstein, S; Schaefer, K; Dunn, J; Marshall, R; Organisak, L; Kharidia, J; Robertson, B; et al. (2011). "SEP-225289 serotonin and dopamine transporter occupancy: A PET study". Journal of nuclear medicine : official publication, Society of Nuclear Medicine 52 (7): 1150–5. doi:10.2967/jnumed.110.084525. PMC 3856248. PMID 21680689.
  53. ↑ "Dasotraline Adult ADHD Study".
  54. ↑ "Development programme - Lundbeck".
  55. ↑ "Search of: Lu AA24530 - List Results - ClinicalTrials.gov".
  56. ↑ 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.
  57. ↑ 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.
  58. 1 2 EP 0756596
  59. ↑ 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.
  60. ↑ 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.
  61. ↑ 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.
  62. ↑ 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): 444–52. doi:10.1016/j.pbb.2010.10.001. PMID 20934452.
  63. ↑ U.S. Patent 3,308,160PHENYLBICYCLO[Z.Z.Z]OCTANE-L-AMINES AND SALTS THEREOF.
  64. ↑ 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 (Oxford, England) 26 (5): 653–62. doi:10.1177/0269881111424931. PMID 22048884.
  65. 1 2 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.
  66. 1 2 Alan Travis, home affairs editor (2010-04-01). "NRG-1 may be next legal high to face ban by ministers | Politics". The Guardian. Retrieved 2010-04-03.
  67. ↑ 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: 18–38. Bibcode:2012NYASA1248...18C. doi:10.1111/j.1749-6632.2011.06199.x. PMID 22092008.
  68. ↑ Carnmalm, B; Rämsby, S; Renyi, AL; Ross, SB; Ogren, SO; Stjernstrom, Nils E. (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.
  69. ↑ U.S. Patent 4,556,676
  70. ↑ 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.
  71. ↑ 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): 411–41. doi:10.1016/0024-3205(95)00209-o. PMID 7623609.
  72. 1 2 Tamiz, AP; Zhang, J; Flippen-Anderson, JL; Zhang, M; Johnson, KM; Deschaux, O; Tella, S; Kozikowski, AP (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.
  73. ↑ 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.
  74. ↑ 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.
  75. ↑ Bøgesø, KP; Christensen, AV; Hyttel, J; Liljefors, T (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.
  76. ↑ 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.
  77. ↑ WO 2005041875
  78. 1 2 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): 762–70. doi:10.1124/jpet.110.174011. PMC 2993553. PMID 20864506.
  79. ↑ Wong, DT; Bymaster, FP (1978). "An inhibitor of dopamine uptake, LR5182, cis-3-(3,4-dichlorophenyl)-2-n,n-dimethylaminomethyl-bicyclo-2,2,2-octane, hydrochloride". Life Sciences 23 (10): 1041–7. doi:10.1016/0024-3205(78)90664-1. PMID 713683.
  80. ↑ Fuller, RW; Perry, KW; Snoddy, HD (1979). "In vivo effects of LR5182, cis-3-(3,4-dichlorophenyl)-2-n,n-dimethylaminomethyl- bicyclo-2,2,2-octane hydrochloride, an inhibitor of uptake into dopamine and norepinephrine neurons". Neuropharmacology 18 (5): 497–501. doi:10.1016/0028-3908(79)90076-5. PMID 460546.
  81. ↑ Wong, DT; Bymaster, FP; Reid, LR (1980). "Competitive inhibition of catecholamine uptake in synaptosomes of rat brain by rigid bicyclo-octanes". Journal of Neurochemistry 34 (6): 1453–8. doi:10.1111/j.1471-4159.1980.tb11225.x. PMID 7381469.
  82. ↑ 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): 356–66. doi:10.1124/jpet.103.049825. PMID 12954808.
  83. ↑ Criado, Elisa (2 May 2014). "A fast-acting antidepressant could be on the horizon". The Independent. Retrieved 22 June 2014.
  84. ↑ http://www.fasebj.org/content/28/1_Supplement/1144.1.short
  85. 1 2 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): 573–83. doi:10.1124/jpet.108.143610. PMID 18689611.
  86. ↑ Fang, X.; Guo, L.; Jia, J.; Jin, G. Z.; Zhao, B.; Zheng, Y. Y.; Li, J. Q.; Zhang, A.; Zhen, X. C. (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. PMID 23892272.
  87. ↑ 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: 124–30. doi:10.1016/j.neuroscience.2011.08.064. PMID 21925241.
  88. 1 2 3 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.
  89. ↑ 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.
  90. ↑ 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.
  91. ↑ 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.
  92. ↑ 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 : an official journal of the Society of Toxicology 120 (2): 269–83. doi:10.1093/toxsci/kfr013. PMID 21258088.
  93. ↑ 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.
  94. 1 2 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.
  95. ↑ U.S. Patent 6,395,748
  96. ↑ U.S. Patent 6,376,673
  97. ↑ WO 2004039778
  98. ↑ U.S. Patent 7,560,562
  99. ↑ http://www.youtube.com/watch?v=1ZCNaQFVkhs
  100. ↑ 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.
  101. ↑ Abuse, National Institute on Drug. "Drug-Related Hospital Emergency Room Visits". www.drugabuse.gov. Retrieved 2016-04-04.
  102. 1 2 3 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.
  103. 1 2 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.
  104. 1 2 Vetulani, J (2001). "Drug addiction. Part II. Neurobiology of addiction". Polish journal of pharmacology 53 (4): 303–17. PMID 11990077.
  105. ↑ 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.
  106. ↑ Koob, GF; Volkow, ND (2010). "Neurocircuitry of addiction". Neuropsychopharmacology 35 (1): 217–38. doi:10.1038/npp.2009.110. PMC 2805560. PMID 19710631.
  107. ↑ 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.
  108. ↑ 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.
  109. ↑ 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.
  110. ↑ 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.
  111. ↑ 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: 59–74. Bibcode:1998NYASA.844...59R. doi:10.1111/j.1749-6632.1998.tb08222.x. PMID 9668665.
  112. ↑ 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.
  113. ↑ 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.
  114. ↑ 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:10.2165/00129784-200909030-00005 (inactive 2015-02-01). PMID 19463023.
  115. ↑ 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.
  116. ↑ 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.
  117. ↑ 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.
  118. 1 2 3 4 5 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.
  119. ↑ Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 14:Neuropharmacology of Neural Systems and Disorders". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 355–360. ISBN 9780071481274. Pharmacologic observations such as these led to a simple hypothesis: depression is the result of inadequate monoamine neurotransmission, and clinically effective antidepressants work by increasing the availability of monoamines. Yet this hypothesis has failed to explain the observation that weeks of treatment with antidepressants are required before clinical efficacy becomes apparent, despite the fact that the inhibitory actions of these agents—whether in relation to reuptake or monoamine oxidase—are immediate. This delay in therapeutic effect eventually led investigators to theorize that long-term adaptations in brain function, rather than increases in synaptic norepinephrine and serotonin per se, most likely underlie the therapeutic effects of antidepressant drugs. Consequently, the focus of research on antidepressants has shifted from the study of their immediate effects to the investigation of effects that develop more slowly. The anatomic focus of research on antidepressants also has shifted. Although monoamine synapses are believed to be the immediate targets of antidepressant drugs, more attention is given to the target neurons of monoamines, where chronic alterations in monoaminergic inputs caused by antidepressant drugs presumably lead to long-lasting adaptations that underlie effective treatment of depression. The identification of molecular and cellular adaptations that occur in response to antidepressants, and the location of the cells and circuits in which they occur, are the chief goals that guide current research. The work described toward the beginning of the chapter on mood-regulating circuits that involve the subgenual cingulate gyrus, for instance, represent a significant advance over a narrow focus on monoamine neuron function. ...
    The several weeks latency in onset of the therapeutic actions of antidepressants contributes to distress and clinical risk for those with severe depression. In the search for treatments of more rapid onset, great effort has gone into trying to understand the delay in efficacy of current antidepressants. All current ideas posit that antidepressant-induced increases in synaptic monoamine concentrations cause slowly accumulating adaptive changes in target neurons. Two broad classes of theories have emerged: (1) Changes in protein phosphorylation, gene expression, and protein translation occur in target neurons that ultimately alter synaptic structure or function in a way that relieves symptoms; and (2) antidepressant-induced neurogenesis in the hippocampus and the incorporation of those new neurons into functional circuits is a required step in the therapeutic response. Before considering specific hypotheses, however, it is important to discuss obstacles in relating research in animal models to human depression.
  120. ↑ 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.
  121. ↑ 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.
  122. 1 2 3 4 5 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.
  123. ↑ 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 (inactive 2015-02-01). PMID 5319766.
  124. ↑ http://www.fa.hms.harvard.edu/about-our-faculty/memorial-minutes/s/joseph-j-schildkraut/
  125. ↑ 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.
  126. ↑ http://www.healyprozac.com/Book/Introduction.pdf
  127. 1 2 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.
  128. ↑ 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.
  129. ↑ 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.
  130. 1 2 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.
  131. ↑ Castrén, E (2005). "Is mood chemistry?". Nature Reviews Neuroscience 6 (3): 241–6. doi:10.1038/nrn1629. PMID 15738959.
  132. ↑ 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 (Oxford, England) 21 (5): 461–71. doi:10.1177/0269881106069938. PMID 17050654.
  133. ↑ 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.
  134. ↑ 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.
  135. ↑ 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.
  136. ↑ 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.
  137. ↑ 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.
  138. ↑ 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.
  139. ↑ 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.
  140. ↑ 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. PMID 21155988.
  141. ↑ Nichols, DE; Nichols, CD (2008). "Serotonin receptors". Chemical Reviews 108 (5): 1614–41. doi:10.1021/cr078224o. PMID 18476671.
  142. ↑ 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.
  143. ↑ Blier, P (2003). "The pharmacology of putative early-onset antidepressant strategies". European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 13 (2): 57–66. doi:10.1016/S0924-977X(02)00173-6. PMID 12650947.
  144. ↑ 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.
  145. ↑ Ban, TA (2001). "Pharmacotherapy of depression: A historical analysis". Journal of neural transmission (Vienna, Austria : 1996) 108 (6): 707–16. doi:10.1007/s007020170047. PMID 11478422.
  146. ↑ 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.
  147. 1 2 3 4 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.
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