Serotonin–norepinephrine–dopamine reuptake inhibitors

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 neurotransmitters, 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 concentrations of these neurotransmitters and, therefore, an increase in serotonergic, noradrenergic or adrenergic, and dopaminergic neurotransmission.

Depression
Major depressive disorder (MDD) is the foremost reason supporting the need for development of an SNDRI. According to the World Health Organization, depression is the leading cause of disability and the 4th leading contributor to the global burden of disease in 2000. By the year 2020, depression is projected to reach 2nd place in the ranking of DALYs.

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.

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 (‘‘tachyphylaxis’’). 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 neurotransmitters 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 transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. The effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.

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 try and 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.

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 approved for marketing so far, although several of the newer agents are under active development and are currently in clinical trials. If they are successful, they could become available within the next few years.


 * In clinical trials:
 * DOV-102,677, DOV-21,947, DOV-216,303
 * Bicifadine
 * Tesofensine
 * RG7166
 * SEP-227162, SEP-225289


 * Research compounds:
 * Indatraline
 * JZ-IV-10 and, more recently (2010), JZAD-IV-22.
 * Methylnaphthidate
 * Naphyrone
 * PRC200-SS and PRC025
 * EXP-561
 * 3,3-Diphenylcyclobutanamine
 * Mazindol analogs
 * JNJ-7,925,476, although consider the simpler 4-aryl THIQ compounds including diclofensine.
 * GSK1360707F and related antidepressants (2010).


 * Further examples:
 * 3,4-disubstituted pyrrolidines
 * 3,3-disubstituted pyrrolidine
 * 2- and 3-ketopyrrolidines.
 * D-161
 * Naphthyl milnacipran analog (also NMDA receptor antagonist)
 * LR-5182
 * 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 (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: Some, if not all, depressions are associated with an absolute or relative deficiency of catecholamines, particularly noradrenaline (NA), at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines.

Shortly after Schildkraut’s catecholamine hypothesis was published, Coppen proposed that 5-HT, rather than NA, was the more important neurotransmitter in depression. This was based on similar evidence to that which produced the NA theory as reserpine, imipramine, and iproniazid affect the 5-HT system, in addition to the noradrenergic system. It was also supported by work demonstrating that if catecholamine levels were depleted by up to 20% but 5-HT neurotransmission remained unaltered there was no sedation in animals. Alongside this, the main observation promoting the 5-HT theory was that administration of a MAOI in conjunction with tryptophan (precursor of 5-HT) elevated mood in control patients and potentiated the antidepressant effect of MAOI. Set against this, combination of an MAOI with DOPA did not produce a therapeutic benefit.

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:


 * Alpha-methyl-p-tyrosine (AMPT) is a tyrosine hydroxylase enzyme inhibitor 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 fenclonine (para-chlorophenylalanine) is able able to bring about a depletion of 5-HT. The mechanism of action for this is via tryptophan hydroxylase inhibition. In the 1970s administration of parachlorophenylalanine produced a relapse in depressive symptoms of treated patients, but it is considered too toxic for use today.


 * Although depletion of tryptophan — the rate-limiting factor of serotonin synthesis — does not influence the mood of healthy volunteers and untreated patients with depression, it does produce a rapid relapse of depressive symptoms in about 50% of remitted patients who are being, or have recently been treated with serotonin selective antidepressants.

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 bromocriptine, pramipexole and ropinirole, exhibit antidepressant properties.
 * Amineptine, a TCA-derivative that predominantly inhibits DA re-uptake and has minimal noradrenergic and serotonergic activity has also been shown to possess antidepressant activity. A number of studies have suggested that amineptine has similar efficacy to the TCAs, MAOIs and SSRIs. However, amineptine is no longer available as a treatment for depression due to reports of an abuse potential.
 * The B-subtype selective MAOI selegiline (a drug which was developed for the treatment of PD) has now been approved for the treatment of depression in the form of a transdermal patch (Emsam). For some reason, there has been reports of users taking this drug in conjunction with beta-phenethylamine.
 * Taking psychostimulants for the alleviation of depression is well proven strategy, although in a clinical setting the use of such drugs is usually prohibited because of their strong addiction propensity.
 * 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 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.

Nordrenergic
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 amygdala. 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.

Neurotrophins and CREB
A SNDRI may also possibly be considered nootropic. 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.

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 dopamine, but other monoamines and acetylcholine may also participate. The anatomical core of the reward system are dopaminergic neurons of the ventral tegmentum that project to the nucleus accumbens, amygdala, prefrontal cortex and other forebrain structures.

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.

Relation to cocaine
Cocaine 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:

... 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-112 was not self-administered because at low doses the compound preferentially occupies the SERT and not the DAT.
 * Tesofensine was also not reliably self-administered by human stimulant addicts.
 * The nocaine analog JZAD-IV-22 only partly substituted for cocaine in animals, but produced none of the psychomotor activation of cocaine, which is a trait marker for stimulant addiction.

Current antidepressants
Most antidepressants on the market today target the monoaminergic system.

SSRIs
The most commonly prescribed class of antidepressants in the USA today are the SSRIs. These drugs inhibit the uptake of the neurotransmitter 5-HT by blocking the SERT, thus increasing its synaptic concentration, and have shown to be efficacious in the treatment of depression, however sexual dysfunction and weight gain are two very common side effects that result in discontinuation of treatment.

Although many patients benefit from SSRIs, it is estimated that approximately 50% of depressive individuals do not respond adequately to these agents. 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.

NRIs
NRIs such as reboxetine prevent the reuptake of norepinephrine, providing a different mechanism of action to treat depression. However reboxetine is no more effective than the SSRIs in treating depression. 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 NDRI. It prevents the reuptake of NA and DA (weakly) by blocking the corresponding transporters, leading to increased noradrenergic and dopaminergic neurotransmission. This drug does not cause sexual dysfunction or weight gain like the SSRIs but has a higher incidence of nausea. 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
SNRIs 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.

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 receptor can result in sedation, and the drug often causes significant weight gain.

Atypical
Agomelatine also targets various serotonin receptors and uniquely the melatonin receptors, another monoamine neurotransmitter.

Interestingly, tianeptine enhances the reuptake of serotonin, 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.

MAOIs
The first antidepressant agents were discovered entirely by serendipity. Iproniazide (the first MAOI) was originally developed as an antitubercular 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.

TCAs
The first TCA (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, which 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 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.