Serotonin-noradrenaline-dopamine reuptake inhibitor
Encyclopedia
A serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI), or triple reuptake inhibitor (TRI), is a drug
that acts simultaneously as a reuptake inhibitor
for the monoamine neurotransmitter
s, serotonin
(5-HT), norepinephrine
(noradrenaline, NA) and dopamine
(DA), by blocking the action of the serotonin transporter
(SERT), norepinephrine transporter
(NET), and dopamine transporter
(DAT), respectively. This, in turn, leads to increased extracellular
concentration
s of these neurotransmitter
s and, therefore, an increase in serotonergic
, noradrenergic or adrenergic
, and dopaminergic
neurotransmission
.
, 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.
About 16% and 1% of the population are estimated to be affected by major depression and bipolar disorder one or more times during their life time, respectively. The presence of the common symptoms of these disorders are collectively called ‘depressive syndrome’ and includes a long-lasting depressed mood, feelings of guilt, anxiety, and recurrent thoughts of death and suicide. 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. All this serves to underline the multifaceted and heterogeneous nature of depression.
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. Disturbingly, 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
.
The ability to work, familial relationships, social integration, and self-care are all severely disrupted.
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.
’’). It is, then, widely appreciated that there remains a need for more efficacious antidepressant agents in terms of: an increase in the proportion of patients responsive to treatment, a greater degree of remission in individual subjects, and more effective prevention of relapse. Ideally, novel agents should be divested of the distressing side effects of both first and second-generation antidepressants.
Although two-thirds of patients will ultimately respond to anti-depressant treatment, one-third of the patients respond to placebo.
A serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, one must generally reckon with a delay of 3–6 weeks before full efficacy is attained. This delay to onset of action is generally 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.
Depression has been associated with impaired neurotransmission
of serotonergic
, noradrenergic, and dopaminergic
pathways, although most pharmacologic treatment strategies directly enhance only 5HT and NE neurotransmission.
Preclinical and clinical research
indicates that drugs inhibiting the reuptake of all of these neurotransmitter
s can produce a more rapid onset of action and greater efficacy than traditional antidepressants.
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.
One must consider the dense connections that 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.
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).
In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably 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
.
To examine the role of monoamine transporter
s 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.
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, i.e., 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
"). Secondly, 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.
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.
Examples of "promiscuous" cancer drugs include: Sutent, Sorafenib
, Zactima, and AG-013736.
Additional indications
for which the use of a SNDRI may be justified is in the treatment of alcoholism
(c.f. DOV 102,677), cocaine addiction (e.g. indatraline
), obesity
(e.g. DOV-21,947), ADHD (c.f. NS-2359), chronic pain
(c.f. bicifadine
), PD
and AD
(c.f. tesofensine and brasofensine).
Finally the role of serendipity in drug discovery is worth considering. Several of the drugs that are used today in the field of neuropsychopharmacology are the result of "chance" discoveries.
for marketing
so far, although several of the newer agents are under active development
and are currently in clinical trial
s. If they are successful, they could become available within the next few years.
In clinical trials:
Research compounds:
Further examples:
The above-listed compounds constitute only a small percentage of the known triple-reuptake inhibitors that are available, and, in general, have been picked for use in research or possible clinical development because of their favourable pharmacodynamic and pharmacokinetic characteristics that made them stand out from the much larger pool of structurally diverse compounds that show similar high-binding affinity for the target monoamine transporter proteins in vitro.
Toxicological screening is also important to ensure safety of the drug molecules. In this regard, the 3,4-dichloro analog of venlafaxine was dropped from further development after its potential mutagenicity was called into question. More recently, the carcinogenicity of PRC200-SS was likewise reported.
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.
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.
Iproniazid
, an inhibitor of MAO, was fortuitously 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.
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. Similarly, 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.
In 1965 Schildkraut formulated the catecholamine
theory of depression. This was subsequently the most widely cited article in the American Journal of Psychiatry
. The theory stated that:
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.
Inserting a chlorine atom into imipramine leads to clomipramine
, a drug that is much more SERT selective than the parent compound.
Clomipramine was used as a springboard
to 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
. 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. Moreover, NRIs have the additional adverse safety risk of hypertension
that is not seen for SSRIs. Nevertheless NRIs have still found uses.
Further support for the monoamine hypothesis came from monoamine depletion studies:
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, 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.
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.
5-HT is known to cause hallucinations through activating the 5HT2A receptor.
In most cases serotonergic activation of receptors can result in a more lucid
state. It is dependent upon the exact therapeutic agent under discussion.
Appetite suppression is related to 5-HT2C receptor activation as for example was reported for PAL-287 recently.
Activation of the 5HT2C receptor has been described as "panicogen" by users of ligands for this receptor (e.g. mCPP
). Antagonism of the 5HT2C receptor is known to augment dopaminergic output. Although SSRIs with 5HT2C antagonist actions were recommended for the treatment of depression, 5HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless the 5HT2C 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 novel anxiolytic agents that are not associated with the dependence and side effect profile of the benzodiazepines. The hippocampal neurogenesis produced by various types of antidepressants similarly 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
.
some of the newly developed antidepressants do not alter, or even increase β-adrenoceptor density.
Another adrenoceptor implicated in depression is the presynaptic a2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of a2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of a2-adrenoceptor activity) although platelet studies proved inconsistent. This
supersensitivity of a2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression.
In addition to enhancing NA release, a2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of a2-adrenoceptors present on 5-HT nerve terminals.
. The amygdala receives noradrenergic innervation from the locus coeruleus and serotonergic projections from the midbrain raphe nuclei
. High levels of amygdala activation are associated with an increased prevalence of anxiety symptoms and dispositional negative affect. Electrical stimulation of the amygdala can evoke emotional experiences, especially fear and anxiety, and vivid recall of emotional life events.
. There is evidence linking the use of antidepressants to increased expression of neurotrophins (particularly BDNF). These are believed to be neuroprotective.
However, although tranylcypromine and ECS increase BDNF mRNA levels, the more selective antidepressants such as desipramine and fluoxetine have variable effects. Thus, because nonselective SNDRIs recruit a plurality of modes of activity, they are more likely to be effective at elevating BDNF RNA.
The hippocampus
is one of several limbic brain structures implicated in the pathophysiology and treatment of mood disorders. Preclinical and clinical studies demonstrate that stress and depression lead to reductions of the total volume of this structure and atrophy
and loss of neurons in the adult hippocampus. One of the cellular mechanisms that might account for alterations in hippocampal structure as well as function is the regulation of adult neurogenesis
. Stress exerts a profound effect on neurogenesis, leading to a rapid and prolonged decrease in the rate of cell proliferation in the adult hippocampus. In contrast, chronic antidepressant treatment up-regulates hippocampal neurogenesis, and could thereby block or reverse the atrophy and damage caused by stress. Recent studies show that neurogenesis is also requisite for the actions of antidepressants in behavioral models of depression.
, 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.
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.
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.
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.
WIN 35428, RTI-31
, RTI-51
and RTI-55 were all compared and it was found that the rate of self-administration decreased from left to right across the series. 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, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.
The rate of onset of the drug must be as rapid as possible to ensure immediate therapeutic effect, however the compounds duration must be sufficiently long to prevent it from being repeatedly self-administered, which would tend to indicate a high propensity for abuse (e.g. nicotine).
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, and also the fact that the NRI atomoxetine was not reinforcing. However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC
.
is an extremely 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
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. Arguably, 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:
However, not all SNDRIs are reliably self administered by animals. Examples include:
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. Even in remitters, a relapse is often observed following drug discontinuation. Finally, the major limitation of SSRIs concerns their delay of action. It appears that the clinical efficacy of SSRIs only becomes evident after a few weeks.
SSRIs can be combined with a host of other drugs including bupropion, alpha-2 adrenergic antagonists (e.g. yohimbine) as well as some of the atypical antipsychotics. The augmentation agents are said to behave synergistically with the SSRI although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. It is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. In addition, single compounds are more likely to be approved by the FDA than are drugs that contain greater than one pharmaceutical ingredient (polytherapies).
A number of SRIs were under development that had auxiliary interactions with other receptors. Particularly notable were agents behaving as co-joint SSRIs with additional antagonist activity at 5-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 (c.f. 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.
s such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. Additionally, 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).
. 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. Ritalin is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Ritalin is used in the treatment of ADHD, its use in treating depression is not known to have been reported, probably owing to its psychomotor activating effects and it functioning as a positive reinforcer. There are also reports of Ritalin being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter.
s such as venlafaxine
(trade name "Effexor"), its active metabolite desvenlafaxine
("Pristiq"), and duloxetine
("Cymbalta") prevent the reuptake of both serotonin and norepinephrine, however their efficacy only appears to be marginally greater than the SSRIs.
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. Importantly, at high doses both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA re-uptake is unlikely to be relevant at clinically approved doses.
These drugs all feel markedly different, although the fact that they are all branded as SNRIs might lead some people into believing that they are similar. One must consider structure-activity-relationships in accounting for this. It is likely that duloxetine is antihistaminergic whereas sibutramine causes hypertension.
A number of analogs of sibutramine are known that behave as SNDRIs, changing the aromatic substituent in venlafaxine can also affect the degree of noradrenergic activation, although it is unclear to what extent the dopaminergic pathways can also be affected.
D Wong was unaware of any analogs of fluoxetine/atomoxetine/nisoxetine/duloxetine based on the same structural motifs that displayed dopaminergic activity.
Milnacipran
is a further example of an SNRI.
can result in sedation, and the drug often causes significant weight gain
.
Interestingly, tianeptine
enhances the reuptake of serotonin (according to earlier studies but disputed later), yet has comparable efficacy to the other antidepressants and an excellent side effect profile.
Consider also nefazodone
and trazodone
.
Atypical antipsychotics are also being explored within the context of treating bipolar disorder
and related conditions.
agent but was then unexpectedly found to display antidepressant activity.
Interestingly, isoniazid
also displayed activity as an antidepressant, even though it is not a MAOI. 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
.
(imipramine
) was derived from the antipsychotic
drug chlorpromazine
, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative. 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 (α-1) blockade that is responsible for the side-effects of TCAs. These include somnolence and lethargy, anticholinergic side effects, and hypotension. Due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the TCAs could be lethal. TCAs were, for 25 years, the leading cause of death from overdoses in many countries. Patients being treated with antidepressants
are prone to attempt suicide and one method they use is to take an overdose of their medications.
Cocaine also has auxiliary actions on other receptors: it has muscarinic activity, is a sigma agonist and has sodium channel blocking activity.
Ketamine is antidepressant and behaves as a NMDA antagonist.
Both the glutamate (c.f. ketamine) and GABA neurotransmitters are involved in depression.
Opiates are known to exhibit antidepressant activities.
Lots of new targets for depression are emerging.
It is hoped that these new therapeutic targets will be helpful for neurological as well as for behavioral disorders.
For example, drugs that augment cholinergic neurotransmission, such as galanthamine, have found use in the treatment of neurodegenerative diseases such as Alzheimer's disease
and cerebrovascular disease
. Nonetheless, it would be interesting to know if such agents can find a place in the market for treating persons that are not already brain damaged.
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
that acts simultaneously as a reuptake inhibitor
Reuptake inhibitor
A reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
for the monoamine neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s, serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
(5-HT), norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
(noradrenaline, NA) and dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
(DA), by blocking the action of the serotonin transporter
Serotonin transporter
The serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
(SERT), norepinephrine transporter
Norepinephrine transporter
The norepinephrine transporter , also known as solute carrier family 6 member 2 , is a protein that in humans is encoded by the SLC6A2 gene....
(NET), and dopamine transporter
Dopamine transporter
The dopamine transporter is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synapse back into cytosol, from which other transporters sequester DA and NE into vesicles for later storage and release...
(DAT), respectively. This, in turn, leads to increased extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
s of these neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s and, therefore, an increase in serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
, noradrenergic or adrenergic
Adrenergic
An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
, and dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
.
Depression
Major depressive disorder (MDD) is the foremost reason supporting the need for development of an SNDRI. According to the World Health OrganizationWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
, depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...
is the leading cause of disability
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...
and the 4th leading contributor to the global burden of disease
Global burden of disease
The global burden of disease is a comprehensive regional and global assessment of mortality and disability from 107 diseases and injuries and ten risk factors. The GBD is assessed using the GBD study by the World Health Organization , and is an example of an evidence-based input to public health...
in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of DALYs.
About 16% and 1% of the population are estimated to be affected by major depression and bipolar disorder one or more times during their life time, respectively. The presence of the common symptoms of these disorders are collectively called ‘depressive syndrome’ and includes a long-lasting depressed mood, feelings of guilt, anxiety, and recurrent thoughts of death and suicide. 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. All this serves to underline the multifaceted and heterogeneous nature of depression.
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. Disturbingly, 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
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
.
The ability to work, familial relationships, social integration, and self-care are all severely disrupted.
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.
Pharmacotherapy
Currently available antidepressants are effective in many patients. However, all elicit undesirable side effects. Further, remission is frequently sub-maximal (‘‘residual’’ symptoms), and 30% of patients remain refractory to pharmacotherapy. In addition to post-treatment relapse, depressive symptoms can even recur in the course of long-term therapy (‘‘tachyphylaxisTachyphylaxis
Tachyphylaxis is a medical term describing a decrease in the response to a drug due to previous exposure to that drug. Increasing the dose of the drug may be able to restore the original response. In this context tachyphylaxis is a synonym for drug tolerance...
’’). It is, then, widely appreciated that there remains a need for more efficacious antidepressant agents in terms of: an increase in the proportion of patients responsive to treatment, a greater degree of remission in individual subjects, and more effective prevention of relapse. Ideally, novel agents should be divested of the distressing side effects of both first and second-generation antidepressants.
Although two-thirds of patients will ultimately respond to anti-depressant treatment, one-third of the patients respond to placebo.
A serious drawback of all antidepressants is the requirement for long-term administration prior to maximal therapeutic efficacy. Although some patients show a partial response within 1–2 weeks, one must generally reckon with a delay of 3–6 weeks before full efficacy is attained. This delay to onset of action is generally attributed to a spectrum of long-term adaptive changes. These include receptor desensitization, alterations in intracellular transduction cascades
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
and gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
, the induction of neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
, and modifications in synaptic architecture and signaling.
Depression has been associated with impaired neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
of serotonergic
Serotonergic
Serotonergic or serotoninergic means "related to the neurotransmitter serotonin". A synapse is serotonergic if it uses serotonin as its neurotransmitter...
, noradrenergic, and dopaminergic
Dopaminergic
Dopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
pathways, although most pharmacologic treatment strategies directly enhance only 5HT and NE neurotransmission.
Preclinical and clinical research
Clinical research
Clinical research is a branch of medical science that determines the safety and effectiveness of medications, devices, diagnostic products and treatment regimens intended for human use...
indicates that drugs inhibiting the reuptake of all of these neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
s can produce a more rapid onset of action and greater efficacy than traditional antidepressants.
DA may promote neurotrophic processes in the adult hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, 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.
One must consider the dense connections that 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.
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
Plasma membrane monoamine transporter
The plasma membrane monoamine transporter is a low-affinity monoamine transporter protein. It is also known as human equilibrative nucleoside transporter-4...
(PMAT).
In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably 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
Motivation
Motivation is the driving force by which humans achieve their goals. Motivation is said to be intrinsic or extrinsic. The term is generally used for humans but it can also be used to describe the causes for animal behavior as well. This article refers to human motivation...
, concentration
Concentration
In chemistry, concentration is defined as the abundance of a constituent divided by the total volume of a mixture. Four types can be distinguished: mass concentration, molar concentration, number concentration, and volume concentration...
, and pleasure
Pleasure
Pleasure describes the broad class of mental states that humans and other animals experience as positive, enjoyable, or worth seeking. It includes more specific mental states such as happiness, entertainment, enjoyment, ecstasy, and euphoria...
.
To examine the role of monoamine transporter
Monoamine transporter
Monoamine transporters are protein structures that function as integral plasma membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. Three major classes of MATs are responsible for the reuptake of their associated amine neurotransmitters...
s in models of depression DAT, NET, and SERT knockout
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
(KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test
Tail suspension test
The tail suspension test is an experiment used to assay mood levels in rodents in scientific research. Changes in immobility time indicate changes in mood. It is widely used to detect potential antidepressant effects of drugs....
, 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.
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
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
state.
Most common CNS disorders are highly polygenic in nature, i.e., 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
Magic bullet
Magic bullet may refer to:* In the German folk legend Freischütz, an enchanted bullet obtained by a marksman through a contract with the devil....
"). Secondly, 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.
Clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
and dimebon
Dimebon
Latrepirdine , is an antihistamine drug which has been used clinically in Russia since 1983....
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.
Examples of "promiscuous" cancer drugs include: Sutent, Sorafenib
Sorafenib
Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
, Zactima, and AG-013736.
Additional indications
Indication (medicine)
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. The opposite of indication is contraindication.-Drugs:...
for which the use of a SNDRI may be justified is in the treatment of alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
(c.f. DOV 102,677), cocaine addiction (e.g. indatraline
Indatraline
Indatraline is a non-selective monoamine transporter inhibitor that has been shown to block the reuptake of dopamine, norepinephrine, and serotonin with effects similar to those of cocaine...
), obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
(e.g. DOV-21,947), ADHD (c.f. NS-2359), chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
(c.f. bicifadine
Bicifadine
Bicifadine is a serotonin-norepinephrine reuptake inhibitor developed by DOV Pharmaceutical. It has been developed as an analgesic and is currently under development for the treatment of various pain conditions...
), PD
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
and AD
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(c.f. tesofensine and brasofensine).
Finally the role of serendipity in drug discovery is worth considering. Several of the drugs that are used today in the field of neuropsychopharmacology are the result of "chance" discoveries.
Examples
SNDRIs are not new drugs. Many of them first came to light in the 1980's and 1990's. In fact, EXP-561 first appears in the literature as far back as 1967. However, none have been approvedApproved drug
In the United States, the FDA approves drugs. Before a drug can be prescribed, it must undergo an extensive FDA approval process. This process involves first testing the drug on animals or in medical labs. If found to be safe by the FDA and approved for the next phase of study, the drug is then...
for marketing
Pharmaceutical marketing
Pharmaceutical marketing , sometimes called medico-marketing, is the business of advertising or otherwise promoting the sale of pharmaceuticals or drugs. There is some evidence that marketing practices can negatively affect both patients and the health care profession...
so far, although several of the newer agents are under active development
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
and are currently in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s. If they are successful, they could become available within the next few years.
In clinical trials:
- DOV-102,677DOV-102,677DOV 102,677 is a psychoactive drug being developed by Merck as an antidepressant and is currently in clinical trials. It is a so-called triple uptake inhibitor , or serotonin-norepinephrine-dopamine reuptake inhibitor ....
, DOV-21,947, DOV-216,303 - BicifadineBicifadineBicifadine is a serotonin-norepinephrine reuptake inhibitor developed by DOV Pharmaceutical. It has been developed as an analgesic and is currently under development for the treatment of various pain conditions...
- TesofensineTesofensineTesofensine is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity...
- RG7166
- SEP-227162SEP-227162SEP-227,162 is an antidepressant being developed by Sepracor which is currently in clinical trials. It acts as a serotonin-norepinephrine reuptake inhibitor. As of 1st July 2009, the compound has not shown sufficient efficacy, and its future development is unknown.- References :...
, SEP-225289SEP-225289SEP-225,289 is an antidepressant drug derived from the active enantiomer of sibutramine, which was being developed by Sepracor. It is a so-called triple reuptake inhibitor .-Further reading:Original Sibutramine patentsLiming Shao Patent... - Tedatioxetine
- IndatralineIndatralineIndatraline is a non-selective monoamine transporter inhibitor that has been shown to block the reuptake of dopamine, norepinephrine, and serotonin with effects similar to those of cocaine...
- JZ-IV-10JZ-IV-10JZ-IV-10 is a piperidine derivative related to nocaine which is a highly potent triple reuptake inhibitor . The eugeroic modafinil, was used as a lead to fuel these compounds' discovery . Although it turns out that the QSAR of the pharmacophoric elements do not appear to be strongly similar...
and, more recently (2010), JZAD-IV-22. - Methylnaphthidate
- Naphyrone
- PRC200-SS and PRC025
- EXP-561EXP-561EXP-561 is a drug which acts as a inhibitor of the reuptake of serotonin, dopamine, and norepinephrine. It was developed in the 1960s by Du Pont and was suggested as a potential antidepressant but was never marketed.-Synthesis:...
- 3,3-Diphenylcyclobutanamine3,3-Diphenylcyclobutanamine3,3,-Diphenylcyclobutanamine is a psychostimulant drug which was originally prepared as an antidepressant in the late 1970s. It appears to inhibit the reuptake of serotonin, norepinephrine, and dopamine, and may also induce their release as well. The N-methyl and N,N-dimethyl analogues of the...
- MazindolMazindolMazindol is a stimulant drug of the tetracyclic chemical class which is used as an anorectic. It was developed by Sandoz-Wander in the 1960s- Indications :...
analogs - JNJ-7,925,476, although consider the simpler 4-aryl THIQTetrahydroisoquinolineTetrahydroisoquinoline is a secondary amine with the chemical formula C9H11N.-Reactions:Like other secondary amines, tetrahydroisoquinoline can be oxidized to the corresponding nitrone using hydrogen peroxide, catalyzed by selenium dioxide....
compounds including diclofensineDiclofensineDiclofensine is a stimulant drug which acts as a triple monoamine reuptake inhibitor, primarily inhibiting the reuptake of dopamine and noradrenaline...
. - GSK1360707FGSK1360707FGSK1360707F is a new and potent selective triple reuptake inhibitor.This research chemical is still relatively new so no details are available for it as of yet.-Synthesis:#BOC Protecting group.#Enolization and trapping with triflate group....
and related antidepressants (2010).
Further examples:
- 3,4-disubstituted pyrrolidines
- 3,3-disubstituted pyrrolidine
- 2- and 3-ketopyrrolidines.
- D-161D-161D-161 is a chemical known in research circles as a triple reuptake inhibitor. Although this compound has lent support to the inclusion of dopamine in the monoamine hypothesis of depression, D-161 has not been tested in clinical trials.-References:...
- Naphthyl milnacipranMilnacipranMilnacipran is a serotonin–norepinephrine reuptake inhibitor used in the clinical treatment of fibromyalgia...
analog (also NMDA receptor antagonist) - LR-5182LR-5182LR-5182 is a stimulant drug which acts as a norepinephrine-dopamine reuptake inhibitor, structurally related to the better known drug fencamfamine. It was developed by the pharmaceutical company Eli Lilly in the 1970s, and researched for potential use as an antidepressant, although never marketed...
- A host of phenyltropanes including WF-23, dichloropane and RTI-55.
- 3-aryl-3-azolylpropan-1-amines (2010)
- 2-Substituted N-aryl piperazines (2010)
The above-listed compounds constitute only a small percentage of the known triple-reuptake inhibitors that are available, and, in general, have been picked for use in research or possible clinical development because of their favourable pharmacodynamic and pharmacokinetic characteristics that made them stand out from the much larger pool of structurally diverse compounds that show similar high-binding affinity for the target monoamine transporter proteins in vitro.
Toxicological screening is also important to ensure safety of the drug molecules. In this regard, the 3,4-dichloro analog of venlafaxine was dropped from further development after its potential mutagenicity was called into question. More recently, the carcinogenicity of PRC200-SS was likewise reported.
Monoamine Hypothesis
The 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.When reserpine
Reserpine
Reserpine is an indole alkaloid antipsychotic and antihypertensive drug that has been used for the control of high blood pressure and for the relief of psychotic symptoms, although because of the development of better drugs for these purposes and because of its numerous side-effects, it is rarely...
(an alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
with uses in the treatment of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
and psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
) was first introduced to the West
Western world
The Western world, also known as the West and the Occident , is a term referring to the countries of Western Europe , the countries of the Americas, as well all countries of Northern and Central Europe, Australia and New Zealand...
from India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
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
Vesicular monoamine transporter
The vesicular monoamine transporter is a transport protein integrated into the membrane of intracellular vesicles of presynaptic neurons. It acts to transport monoamines into the synaptic vesicles.-Monoamines:...
, leading to their increased catabolism by monoamine oxidase. However, not everyone has been convinced by claims that reserpine is depressogenic, some authors (David Healy
David Healy
David Healy may refer to:*David Healy , Northern Irish footballer*David Healy , Irish psychiatrist*David Healy , Irish politician...
in particular) have even claimed that it is antidepressant.
Tetrabenazine
Tetrabenazine
Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorder and is marketed under the trade names Nitoman in Canada and Xenazine in New Zealand and some parts of Europe, and is also available in the USA as an orphan drug. On August 15, 2008 the U.S...
, 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.
Iproniazid
Iproniazid
Iproniazid is a hydrazine drug used as an antidepressant. It acts as an irreversible and nonselective monoamine oxidase inhibitor . Though it has been widely discontinued in most of the world, it is still used in France.- History :Iproniazid was the first antidepressant ever marketed...
, an inhibitor of MAO, was fortuitously 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.
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. Similarly, administration of DOPA
Dopa
Dopa or DOPA can refer to:* L-DOPA , used in the treatment of Parkinson's disease* D-DOPA, a chemical compound related to L-DOPA* Dopa, an angel in Enochian* Deleting Online Predators Act of 2006...
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.
In 1965 Schildkraut formulated the catecholamine
Catecholamine
Catecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
theory of depression. This was subsequently the most widely cited article in the American Journal of Psychiatry
American Journal of Psychiatry
The American Journal of Psychiatry is a monthly peer-reviewed medical journal covering all aspects of psychiatry and the official journal of the American Psychiatric Association. The first volume was issued in 1844, at which time it was known as the American Journal of Insanity...
. The theory stated that:
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.
Inserting a chlorine atom into imipramine leads to clomipramine
Clomipramine
Clomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
, a drug that is much more SERT selective than the parent compound.
Clomipramine was used as a springboard
Springboard
A springboard or diving board is used for diving and is a board that is itself a spring, i.e. a linear flex-spring, of the cantilever type....
to 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
Talopram
Talopram , also known as phthalapromine, is a selective norepinephrine reuptake inhibitor which was researched for the management of depression in the 1960s and 1970s but was never commercialized. Along with talsupram, talopram is structurally related to the selective serotonin reuptake inhibitor ...
and melitracen
Melitracen
Melitracen is a tricyclic antidepressant marketed in Europe and Japan by Lundbeck and Takeda, respectively, for the treatment of depression and anxiety...
). In fact, it is also believed that the selective NRI nisoxetine
Nisoxetine
Nisoxetine is a drug which inhibits the reuptake of norepinephrine . It is a racemic compound with two isomers...
was discovered prior to the invention of fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
. 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. Moreover, NRIs have the additional adverse safety risk of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
that is not seen for SSRIs. Nevertheless NRIs have still found uses.
Further support for the monoamine hypothesis came from monoamine depletion studies:
- Alpha-methyl-p-tyrosine (AMPTAMPTAlpha-methyl-p-tyrosine is a tyrosine hydroxylase enzyme inhibitor. It has been used in the treatment of pheochromocytoma. It has been demonstrated to inhibit the production of melanin.-Side-effects:...
) is a tyrosine hydroxylaseTyrosine hydroxylaseTyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dihydroxyphenylalanine . It does so using tetrahydrobiopterin as a coenzyme. DOPA is a precursor for dopamine, which, in turn, is a precursor for norepinephrine ...
enzyme inhibitorEnzyme inhibitorAn enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
that serves to inhibit catecholamine synthesis. AMPT produced a resurgence of depressive symptoms in patients improved by the NE reuptake inhibitor (NRI) desipramine, but not by the SSRI fluoxetine. 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.
- Administration of fenclonineFenclonineFenclonine, also known as para-chlorophenylalanine , is a synthetic amino acid which acts as a selective and irreversible inhibitor of tryptophan hydroxylase, which is a rate-limiting enzyme in the biosynthesis of serotonin. Fenclonine consequently depletes serotonin in the body and reduces its...
(para-chlorophenylalanine) is able able to bring about a depletion of 5-HT. The mechanism of action for this is via tryptophan hydroxylaseTryptophan hydroxylaseTryptophan hydroxylase is an enzyme involved in the synthesis of the neurotransmitter serotonin. TPH catalyzes the following chemical reactionIt employs one cofactor, iron.- Function :...
inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients, but it is considered too toxic for use today.
- Although depletion of tryptophanTryptophanTryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
— 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.
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.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). For example, the prevalence of depression can reach up to 50% of individuals suffering from PD.
- Patients taking strong dopaminergic antagonists such as those used in the treatment of psychosis are more likely than the general population to suffer from symptoms of depression.
- Data from clinical studies have shown that DA agonists, such as bromocriptineBromocriptineBromocriptine , an ergoline derivative, is a dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease , hyperprolactinaemia, neuroleptic malignant syndrome, and type 2 diabetes.- Indications :Amenorrhea, female infertility, galactorrhea, hypogonadism, and acromegaly...
, pramipexolePramipexolePramipexole is a non-ergoline dopamine agonist indicated for treating early-stage Parkinson's disease and restless legs syndrome...
and ropiniroleRopiniroleRopinirole is a non-ergoline dopamine agonist. It is manufactured by GlaxoSmithKline , Cipla and Sun Pharmaceutical. It is used in the treatment of Parkinson's disease...
, exhibit antidepressant properties. - AmineptineAmineptineAmineptine was developed by the French Society of Medical research in the 1960s. Under the trade-names is used as an atypical tricyclic antidepressant that selectively inhibits the reuptake of dopamine and to a lesser extent norepinephrine, thus exerting a powerful and fast-acting...
, 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 selegilineSelegilineSelegiline is a drug used for the treatment of early-stage Parkinson's disease, depression and senile dementia. In normal clinical doses it is a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A...
(a drug which was developed for the treatment of PD) has now been approved for the treatment of depression in the form of a transdermalTransdermalTransdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery, and transdermal implants used for medical or aesthetic purposes....
patch (EmsamEmsamEmsam is the trade name of an antidepressant of the monoamine oxidase inhibitor class. Emsam is a transdermal patch containing the MAOI selegiline. Selegiline, in small doses, is most commonly used in the treatment of Parkinson's disease. It is also effective in higher doses for the treatment...
). For some reason, there has been reports of users taking this drug in conjunction with beta-phenethylaminePhenethylaminePhenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
. - 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.
- When users withdraw from psychostimulant drugs of abuse (particularly 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, although this remains to be demonstrated in humans.
The rate of clearance from the body is faster for ritalin than it is for regular amphetamine.
Serotonergic
5-Hydroxytryptamine (5-HT or serotonin) is an important cell-to-cell signaling molecule found in all animal phyla. In mammals, substantial concentrations of 5-HT are present in the central and peripheral nervous systems, gastrointestinal tract and cardiovascular system. 5-HT is capable of exerting a wide variety of biological effects by interacting with specific membrane-bound receptors, and at least 13 distinct 5-HT receptor subtypes have been cloned and characterized. With the exception of the 5-HT3 receptor subtype, which is a transmitter-gated ion channel, 5-HT receptors are members of the 7-transmembrane G protein-coupled receptor superfamily. In humans, the serotonergic system is implicated in various physiological processes such as sleep-wake cycles, maintenance of mood, control of food intake and regulation of blood pressure. Accordingly, 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
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
are involved in promoting sleep, they counterbalance the wake-promoting action of increased catecholaminergic neurotransmission. This is accounted for by the lethargic feel that some SSRIs can produce, although TCAs and antipsychotics can also cause lethargy albeit through different mechanisms.
5-HT is known to cause hallucinations through activating the 5HT2A receptor.
In most cases serotonergic activation of receptors can result in a more lucid
Lucid
Lucid is a dataflow programming language. It is designed to experiment with non-von Neumann programming models. It was designed by Bill Wadge and Ed Ashcroft and described in the book Lucid, the Dataflow Programming Language.-Model:...
state. It is dependent upon the exact therapeutic agent under discussion.
Appetite suppression is related to 5-HT2C receptor activation as for example was reported for PAL-287 recently.
Activation of the 5HT2C receptor has been described as "panicogen" by users of ligands for this receptor (e.g. mCPP
MCPP
MCPP may stand for:* meta-Chlorophenylpiperazine – a recreational drug and stimulant of the piperazine class* Methylchlorophenoxypropionic acid – a herbicide* Microsoft Communications Protocol Program – a set of IT documentation...
). Antagonism of the 5HT2C receptor is known to augment dopaminergic output. Although SSRIs with 5HT2C antagonist actions were recommended for the treatment of depression, 5HT2C receptor agonists were suggested for treating cocaine addiction since this would be anti-addictive. Nevertheless the 5HT2C is known to be rapidly downregulated upon repeated administration of an agonist agent, and is actually antagonized.
Azapirone-type drugs (e.g., buspirone
Buspirone
Buspirone is an anxiolytic psychoactive drug of the azapirone chemical class, and is primarily used to treat generalized anxiety disorder Bristol-Myers Squibb gained FDA approval of buspirone in 1986 for treatment of GAD...
), which act as 5-HT1A receptor agonists and partial agonists have been developed as novel anxiolytic agents that are not associated with the dependence and side effect profile of the benzodiazepines. The hippocampal neurogenesis produced by various types of antidepressants similarly is thought to be mediated by 5-HT1A receptors. Systemic administration of a 5-HT1A agonist also induces growth hormone
Growth hormone
Growth hormone is a peptide hormone that stimulates growth, cell reproduction and regeneration in humans and other animals. Growth hormone is a 191-amino acid, single-chain polypeptide that is synthesized, stored, and secreted by the somatotroph cells within the lateral wings of the anterior...
and adrenocorticotropic hormone
Adrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH) release through actions in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
.
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.
Another adrenoceptor implicated in depression is the presynaptic a2-adrenoceptor. Chronic desipramine treatment in rats decreased the sensitivity of a2-adrenoceptors, a finding supported by the fact that clonidine administration caused a significant increase in growth hormone (an indirect measure of a2-adrenoceptor activity) although platelet studies proved inconsistent. This
supersensitivity of a2-adrenoceptor was postulated to decrease locus coeruleus (the main projection site of NA in the central nervous system, CNS) NA activity leading to depression.
In addition to enhancing NA release, a2-adrenoceptor antagonism also increases serotonergic neurotransmission due to blockade of a2-adrenoceptors present on 5-HT nerve terminals.
Anxiety
The neurocircuitry of fear appears to focus on the amygdalaAmygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
. The amygdala receives noradrenergic innervation from the locus coeruleus and serotonergic projections from the midbrain raphe nuclei
Raphe nuclei
The raphe nuclei are a moderate-size cluster of nuclei found in the brain stem. Their main function is to release serotonin to the rest of the brain...
. High levels of amygdala activation are associated with an increased prevalence of anxiety symptoms and dispositional negative affect. Electrical stimulation of the amygdala can evoke emotional experiences, especially fear and anxiety, and vivid recall of emotional life events.
Neurotrophins and CREB
A SNDRI may also possibly be considered nootropicNootropic
Nootropics , also referred to as smart drugs, brain steroids, memory enhancers, cognitive enhancers, and intelligence enhancers, are drugs, supplements, nutraceuticals, and functional foods that improve mental functions such as cognition, memory, intelligence, motivation, attention, and concentration...
. There is evidence linking the use of antidepressants to increased expression of neurotrophins (particularly BDNF). These are believed to be neuroprotective.
However, although tranylcypromine and ECS increase BDNF mRNA levels, the more selective antidepressants such as desipramine and fluoxetine have variable effects. Thus, because nonselective SNDRIs recruit a plurality of modes of activity, they are more likely to be effective at elevating BDNF RNA.
The hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
is one of several limbic brain structures implicated in the pathophysiology and treatment of mood disorders. Preclinical and clinical studies demonstrate that stress and depression lead to reductions of the total volume of this structure and atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
and loss of neurons in the adult hippocampus. One of the cellular mechanisms that might account for alterations in hippocampal structure as well as function is the regulation of adult neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
. Stress exerts a profound effect on neurogenesis, leading to a rapid and prolonged decrease in the rate of cell proliferation in the adult hippocampus. In contrast, chronic antidepressant treatment up-regulates hippocampal neurogenesis, and could thereby block or reverse the atrophy and damage caused by stress. Recent studies show that neurogenesis is also requisite for the actions of antidepressants in behavioral models of depression.
Addiction
Drug addiction may be regarded as the 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 location from which electrical self-stimulation is readily evoked. The main neurotransmitter involved in the reward is dopamineDopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, but other monoamines and acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum
Ventral tegmentum
The ventral tegmentum , better known as the ventral tegmental area , is a group of neurons located close to the midline on the floor of the midbrain...
that project to the nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
, amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
and other forebrain structures.
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.
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.
RTI-112
RTI-112
RTI-112 is a synthetic stimulant drug from the phenyltropane family. In contrast to RTI-113 which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor....
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.
WIN 35428, RTI-31
RTI-31
-2β-Carbomethoxy-3β-tropane is a synthetic analog of cocaine that acts as a stimulant. Semi-synthesis of this compound is dependent upon the availability of cocaine starting material. According to the article, RTI-31 is 64 x the strength of cocaine in terms of its potency to elicit...
, RTI-51
RTI-51
-2β-Carbomethoxy-3β-tropane is a semi-synthetic alkaloid in the phenyltropane group of psychostimulant compounds. First publicized in the 1990s, it has not been used enough to have gained a fully established profile. RTI-51 can be expected to have properties lying somewhere in between RTI-31 and...
and RTI-55 were all compared and it was found that the rate of self-administration decreased from left to right across the series. 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, and the phen/fen combination was also shown to have limited abuse potential relative to administration of phentermine only.
The rate of onset of the drug must be as rapid as possible to ensure immediate therapeutic effect, however the compounds duration must be sufficiently long to prevent it from being repeatedly self-administered, which would tend to indicate a high propensity for abuse (e.g. nicotine).
NET blockade is unlikely to play a major role in mediating addictive behavior. This finding is based on the premise that desipramine
Desipramine
Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
is not self-administered, and also the fact that the NRI atomoxetine was not reinforcing. However, it was still shown to facilitate dopaminergic neurotransmission in certain brain regions such as in the core of the PFC
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
.
Relation to cocaine
CocaineCocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
is an extremely 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
Cardiotoxicity
Cardiotoxicity is the occurrence of heart electrophysiology dysfunction or/and muscle damage. The heart becomes weaker and is not as efficient in pumping and therefore circulating blood...
due to its local anesthetic
Local anesthetic
A local anesthetic is a drug that causes reversible local anesthesia, generally for the aim of having local analgesic effect, that is, inducing absence of pain sensation, although other local senses are often affected as well...
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
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
. There has been speculation over whether the new SNDRIs will have an abuse potential like cocaine does. Arguably, 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.
However, not all SNDRIs are reliably self administered by animals. Examples include:
- PRC200-SS was not reliably self-administered.
- RTI-112RTI-112RTI-112 is a synthetic stimulant drug from the phenyltropane family. In contrast to RTI-113 which is DAT selective, RTI-112 is a nonselective triple reuptake inhibitor....
was not self-administered because at low doses the compound preferentially occupies the SERT and not the DAT. - TesofensineTesofensineTesofensine is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being developed for the treatment of obesity...
was also not reliably self-administered by humanHumanHumans are the only living species in the Homo genus...
stimulantStimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
addicts. - The nocaineNocaine-CPCA is a stimulant drug similar in structure to RTI-31, but lacking the two-carbon bridge of the tropane skeleton This compound was first developed as a substitute agent for cocaine.Since this time a large number of substituted phenylpiperidine derivatives have been discovered, hybridizing the...
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.
SSRIs
The most commonly prescribed class of antidepressants in the USA today are the 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 dysfunctionSexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
and weight gain
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
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. Even in remitters, a relapse is often observed following drug discontinuation. Finally, the major limitation of SSRIs concerns their delay of action. It appears that the clinical efficacy of SSRIs only becomes evident after a few weeks.
SSRIs can be combined with a host of other drugs including bupropion, alpha-2 adrenergic antagonists (e.g. yohimbine) as well as some of the atypical antipsychotics. The augmentation agents are said to behave synergistically with the SSRI although these are clearly of less value than taking a single compound that contains all of the necessary pharmacophoric elements relative to the consumption of a mixture of different compounds. It is not entirely known what the reason for this is, although ease of dosing is likely to be a considerable factor. In addition, single compounds are more likely to be approved by the FDA than are drugs that contain greater than one pharmaceutical ingredient (polytherapies).
A number of SRIs were under development that had auxiliary interactions with other receptors. Particularly notable were agents behaving as co-joint SSRIs with additional antagonist activity at 5-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 (c.f. studies done with pindolol
Pindolol
Pindolol is a beta blocker....
). 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.
NRIs
NRINorepinephrine reuptake inhibitor
A norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
s such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. Additionally, 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 an NDRINDRI
NDRI may refer to:* Norepinephrine-dopamine reuptake inhibitor.* National Dairy Research Institute* National Defense Research Institute* National Development and Research Institute* National Disease Research Interchange* National Drug Research Institute...
. 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. Ritalin is a much more reliable example of an NDRI (the action that it displays on the DAT usually getting preferential treatment). Ritalin is used in the treatment of ADHD, its use in treating depression is not known to have been reported, probably owing to its psychomotor activating effects and it functioning as a positive reinforcer. There are also reports of Ritalin being used in the treatment of psychostimulant addiction, in particular cocaine addiction, since the addictive actions of this drug are believed to be mediated by the dopamine neurotransmitter.
SNRI
SNRISNRI
SNRI may refer to:* Serotonin–norepinephrine reuptake inhibitor* Strategic Naval Research Institute...
s such as venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(trade name "Effexor"), its active metabolite desvenlafaxine
Desvenlafaxine
Desvenlafaxine , also known as O-desmethylvenlafaxine, is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth . Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine...
("Pristiq"), and duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
("Cymbalta") prevent the reuptake of both serotonin and norepinephrine, however their efficacy only appears to be marginally greater than the SSRIs.
Sibutramine
Sibutramine
Sibutramine is an oral anorexiant. Until 2010 it was marketed and prescribed as an adjunct in the treatment of exogenous obesity along with diet and exercise...
is the name of an SNRI based appetite suppressant with use in the treatment of obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. This was explored in the treatment of depression, but was shown not to be effective.
Both sibutramine and venlafaxine are phenethylamine
Phenethylamine
Phenylethylamine or phenethylamine is a natural monoamine alkaloid, trace amine, and also the name of a class of chemicals with many members well known for psychoactive drug and stimulant effects. Studies suggest that phenylethylamine functions as a neuromodulator or neurotransmitter in the...
based. Importantly, at high doses both venlafaxine and sibutramine will start producing dopaminergic effects. The inhibition of DA re-uptake is unlikely to be relevant at clinically approved doses.
These drugs all feel markedly different, although the fact that they are all branded as SNRIs might lead some people into believing that they are similar. One must consider structure-activity-relationships in accounting for this. It is likely that duloxetine is antihistaminergic whereas sibutramine causes hypertension.
A number of analogs of sibutramine are known that behave as SNDRIs, changing the aromatic substituent in venlafaxine can also affect the degree of noradrenergic activation, although it is unclear to what extent the dopaminergic pathways can also be affected.
D Wong was unaware of any analogs of fluoxetine/atomoxetine/nisoxetine/duloxetine based on the same structural motifs that displayed dopaminergic activity.
Milnacipran
Milnacipran
Milnacipran is a serotonin–norepinephrine reuptake inhibitor used in the clinical treatment of fibromyalgia...
is a further example of an SNRI.
NaSSAs
The tetracyclic antidepressants (TeCAs), or more specifically, the noradrenergic and specific serotonergic antidepressants (NaSSAs), such as mirtazapine, antagonise various serotonergic and noradrenergic receptors leading to a greater outflow of these neurotransmitters. However mirtazapine's strong antagonism of the histamine receptorHistamine receptor
The histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...
can result in sedation, and the drug often causes significant weight gain
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
.
Atypical
Agomelatine also targets various serotonin receptors and uniquely the melatonin receptors, another monoamine neurotransmitter.Interestingly, tianeptine
Tianeptine
Tianeptine was discovered by The French Society of Medical Research in the 1960s. Under the trade-names it is a drug used for treating major depressive episodes ....
enhances the reuptake of serotonin (according to earlier studies but disputed later), yet has comparable efficacy to the other antidepressants and an excellent side effect profile.
Consider also nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
and trazodone
Trazodone
Trazodone is an antidepressant of the serotonin antagonist and reuptake inhibitor class. It is a phenylpiperazine compound...
.
Atypical antipsychotics are also being explored within the context of treating bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
and related conditions.
MAOIs
The first antidepressant agents were discovered entirely by serendipity. Iproniazide (the first MAOI) was originally developed as an antitubercularTuberculosis treatment
Tuberculosis treatment refers to the medical treatment of the infectious disease tuberculosis .The standard "short" course treatment for TB is isoniazid, rifampicin , pyrazinamide, and ethambutol for two months, then isoniazid and rifampicin alone for a further four months...
agent but was then unexpectedly found to display antidepressant activity.
Interestingly, isoniazid
Isoniazid
Isoniazid , also known as isonicotinylhydrazine , is an organic compound that is the first-line antituberculosis medication in prevention and treatment. It was first discovered in 1912, and later in 1951 it was found to be effective against tuberculosis by inhibiting its mycolic acid...
also displayed activity as an antidepressant, even though it is not a MAOI. 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
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
.
TCAs
The first TCATCA
TCA may refer to:In economics:* True cost accounting, a method of accounting which seeks to calculate the social, environmental, and economic costs and benefits of a product over its lifespan instead of focusing solely on the cost of its initial purchase.In chemistry:* Trichloroethane , one of two...
(imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
) was derived from the antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
drug chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...
, which was developed as a useful antihistaminergic agent with possible use as a hypnotic sedative. Imipramine is an iminodibenzyl (dibenzazepine
Dibenzazepine
Dibenzazepine is a chemical compound with two benzene rings fused to an azepine group.Dibenzazepine is used as an intermediate for the synthesis of specific analgesic and antipsychotic agents....
).
The TCAs such as imipramine and amitriptyline typically prevent the reuptake of serotonin or norepinephine.
It is the histaminiergic (H1), muscarinic acetylcholinergic (M1), and alpha adrenergic (α-1) blockade that is responsible for the side-effects of TCAs. These include somnolence and lethargy, anticholinergic side effects, and hypotension. Due to the narrow gap between their ability to block the biogenic amine uptake pumps versus the inhibition of fast sodium channels, even a modest overdose of one of the TCAs could be lethal. TCAs were, for 25 years, the leading cause of death from overdoses in many countries. Patients being treated with antidepressants
are prone to attempt suicide and one method they use is to take an overdose of their medications.
Beyond Monoamines
Certain studies have suggested the inclusion of other neurotransmitters and molecular targets than just the monoamines in the treatment of depression.Cocaine also has auxiliary actions on other receptors: it has muscarinic activity, is a sigma agonist and has sodium channel blocking activity.
Ketamine is antidepressant and behaves as a NMDA antagonist.
Both the glutamate (c.f. ketamine) and GABA neurotransmitters are involved in depression.
Opiates are known to exhibit antidepressant activities.
Lots of new targets for depression are emerging.
It is hoped that these new therapeutic targets will be helpful for neurological as well as for behavioral disorders.
For example, drugs that augment cholinergic neurotransmission, such as galanthamine, have found use in the treatment of neurodegenerative diseases such as Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and cerebrovascular disease
Cerebrovascular disease
Cerebrovascular disease is a group of brain dysfunctions related to disease of the blood vessels supplying the brain. Hypertension is the most important cause; it damages the blood vessel lining, endothelium, exposing the underlying collagen where platelets aggregate to initiate a repairing process...
. Nonetheless, it would be interesting to know if such agents can find a place in the market for treating persons that are not already brain damaged.
See also
- Reuptake inhibitorReuptake inhibitorA reuptake inhibitor , also known as a transporter blocker, is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron, leading to an increase in the extracellular concentrations of the neurotransmitter and therefore an...
- Serotonin reuptake inhibitor (SRI)
- Selective serotonin reuptake inhibitorSelective serotonin reuptake inhibitorSelective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
(SSRI) - Norepinephrine reuptake inhibitorNorepinephrine reuptake inhibitorA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
(NRI) - Serotonin-norepinephrine reuptake inhibitorSerotonin-norepinephrine reuptake inhibitorSerotonin–norepinephrine reuptake inhibitors are a class of antidepressant drugs used in the treatment of major depression and other mood disorders...
(SNRI) - Dopamine reuptake inhibitorDopamine reuptake inhibitorA dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
(DRI) - Norepinephrine-dopamine reuptake inhibitorNorepinephrine-dopamine reuptake inhibitorA norepinephrine-dopamine reuptake inhibitor is a drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and dopamine by blocking the action of the norepinephrine transporter and the dopamine transporter , respectively...
(NDRI)