User:Nuklear/SNDRI

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Contents 1 Introduction 1.1 SSRIs 1.2 Noradrenergics 1.3 Dopaminergics 2 Combination versus Conflation 2.1 Genuine versus Perceived Selectivity 2.2 Single Drugs versus Several Drugs 3 Multifarious versus Monotherapy 3.1 Dual Indications 3.2 Dirty Drugs 3.3 Effects on Cognition 4 Neurobiology of Depression 4.1 Adult hippocampal neurogenesis 4.2 CREB 4.3 Dynorphin 4.4 Neurotrophic Factors 4.5 Intracellular Signaling Pathways 4.6 Preclinical Depression Tests 5 Glucocorticoids 6 Glutamate 6.1 NMDA Antagonists 6.2 AMPA Potentiators 6.3 EAATs 6.4 Metabotropic Glu Receptors 7 A Pair of SNDRIs 7.1 DOV Pharmaceuticals 7.2 PRC Antidepressants 8 Conclusion 9 References 10 Patents

[edit] Introduction

Major depressive disorder (MDD) afflicts ~15% of the population at some point in their lives. A higher incidence of depression has been reported for woman than men, but this may just reflect the higher number of diagnoses and not the true incidence of the syndrome. Epidemiologic studies suggest 40-60% of the risk for depression is hereditary (i.e. genetics) and the remainder is from developmental and environmental abnormalities. Sometimes in cases where depression is relatively mild ("dysthemia") psychoactive drug intervention may not be necessary and various forms of psychotherapy can be enough to return to the patient to their unperturbed state. For more serious and persistant mood disorder subjects pharmacologic intervention or one of the alternative somatic forms of treatment are nearly always necessary. Out of these approaches, pharmacological agents (a.k.a. "drugs") represent the most affordable option for dealing with this.

Monoamines have been investigated extensively in the role of mood disorders. This has led to the consensus that their study may already have been exhausted, fueling the search for novel neurotherapeutics. The reader should consult the attached reference if they are predominantly interested in learning about drugs acting on non-monoaminergic targets of action: (Berton & Nestler, 2006).^[1] It needs to be borne in mind, however, that alot of these novel sites of action still interact with monoamines on some level. For other general reviews detailing recent advances in the field of treating depression see the further two documents: (Thomas Baghai, et al. 2006),^[2] (Holtzheimer & Nemeroff, 2006).^[3] The role of monoamines have nonetheless not been exhausted and while some of the non-monoaminergic avenues might provide the field with interesting novel insights, alot more work is necessary before any of these unproven approaches can become widely accepted. In the words of MJ Millan, it would actually be "fool-hardy" to abandon monoaminergic approaches in favor of compounds whose proof of validity is insufficiently proven. This is nevertheless not implying that they are without merit.

All of the currently available therapies for depression are the result of serendiptious discoveries made more than half a century ago. Iproniazid was originally developed for tuberculosis, and unexpectedly found to possess mood-elevating properties. This monoamine oxidase inhibitor (MAOI) was later found to irreversibly inhibit the enzymes responsible for the catabolism of mood-regulating monoamines in vivo. The tricyclic antidepressants (TCAs), e.g. imipramine, are also the result of chance discoveries, this time in the non-related area of antihistamines. TCAs likewise elevate synaptic levels of monoamines albeit their mechanism of action is slightly different; these compounds inhibit the monoamine pumps. For more detailed discussion, see the attached article: (L. Iversen, 2006) Thus although through distinct mechanisms, both tricyclics and MAOIs augment monoaminergic output. The compilation of these findings led to the monoamine theory of depression. This has stood the test of time remarkably well (Hirschfeld & Delgado, 2000).^[4]

[edit] SSRIs

Prozac® was the first FDA approved SSRI and since its introduction by Eli Lilly in 1976 it has made an estimated ~$22 billion world-wide with sales peaking in 1997 (D. Wong, et al. 2005).^[5] Five SSRIs are now available (sertraline, paroxetine, fluoxetine, escitalopram and fluvoxamine). Escitalopram is the most selective of these and is the preferred ligand for 5-HT transporter (SERT) research. Although the chemical structures of each of these agents are completely unique, pharmacologically they are all very similar at the dosages commonly administered. Now that SSRIs are becoming generic, biotech companies are keen to introduce newer agents that can be patented. The introduction of more SSRIs is unlikely but the prospect of add-on strategies is being explored.

Most of the financial gain from the SSRIs came first and foremost from the relatively benign side effects of these agents relative to the TCAs and MAOIs. This enabled their application to expand "off-label" to other indications particularly as non-addictive anxiolytics amongst other indications (D&G Spinks, 2002). Various of the less selective "traditional" ADs are still prescribed to this day, despite their track-record for producing potentially dangerous side effects. This highlights the inadequacies of SSRIs, particularly where refractory depression is an issue. Currently, the treatment option with the highest documented score of success is electroconvulsive therapy (ECT) – a non-chemical AD.

Collectively, the above inadequacies provide a convincing rationale that there remains an un-met need to make further advancements in this overcrowded field. In order for a novel AD to be a success, it is the authors personal conviction that it needs to be at least as effective as ECT.

Limitations of SSRIs include problems with efficacy, therapeutic lag, somnolence, nausea in the acute phase after initiating treatment, and decreased libido have all been reported (Moltzen and Bang-Andersen, 2006),^[6] (A. Adell, et al. 2005),^[7] (Skolnick and Basile, 2007).^[8]

[edit] Noradrenergics

It has been known since the early 1960's that noradrenaline (NA) is involved in the mechanism of action of TCAs, yet circumventing side effects such as hypertension has been a barrier to the successful introduction of newer agents, not possessing the undesirable anticholinergic and antihistaminergic side effects of the earlier agents. Duloxetine is a novel 5-HT/NA reuptake inhibitor (SNRI), FDA approved for the management of depression. A number of noradrenaline reuptake inhibitors (NARIs) are also available and reboxetine is used in the management of depression. NARIs are more well known for their applications in treating ADHD, although there is widespread acknowledgement of the overlap with respect to the treatment of mood disorders. Duloxetine has recently demonstrated excellent efficacy in the treatment of depression and and is also indicated for the management of pain as a further illustration of co-morbidity among systems biology/pharmacology. Furthermore, duloxetine does not promote hypertension successfully providing proof-of-concept for the idea that it is possible to dissociate NARI affinity from deleterious elevations in blood pressure.[cit]

The above considerations provide convincing evidence that: (a) with the erosion of the SSRI market over recent years, interest in the role of noradrenaline in the modulation of depression has undergone a renaissance, and (b) there has been a retrograde shift away from the highly selective agents in favor of drugs possessing a more balanced portfolio with regards to the in vivo modulation of endogenous pools of monoamines believed to be of importance in the regulation of mood (Boot, et al. 2006).^[9] Moreover, with the newer line of dual action SNRIs there is a diminution of the undesirable antihistaminergic, anticholinergic, and α1 adrenergic side-effects of the earlier TCA agents.

[edit] Dopaminergics

Agents geared towards increasing the synaptic availability of dopamine (DA) are also valid targets in the development of novel AD drugs. This can either be brought about directly (George Papakostas, 2006),^[10] or indirectly via for example 5-HT2 receptor mediated interactions (Ennio Esposito, 2006),^[11] and also e.g. α2 adrenergic antagonism (c.f. tetracyclics). Recently, a transdermal preparation of selegiline has been FDA approved showing proof-of-concept for dopaminergics in modern day management of depression. With regards to the direct blockade of the DA transporter (DAT), this strategy is widely employed in the addiction field since it is thought to underlie the mechanism of action of almost all drugs of abuse. Due to the fact that a hypo-dopaminergic state comprises most of the core symptoms of depression, the relevance of DA to this field is hardly something that can be neglected. Triple reuptake inhibitors (a.k.a. "SNDRIs") are now being persued both in academia and by active programs in the industry.

Amineptine was the predecessor to tianeptine introduced and developed by Servier. At one time this was used in the treatment of depression even though it has a dopaminergic (DARI) mode of activity. It was later pulled from the shelves though after it was judged to have unacceptable risk of abuse. Nomifensine was also useful in the treatment of depression, although this was pulled from the market after it emerged that it can cause hemolytic anemia which is a potentially dangerous side-effect.

The aim of this progress report is to summarise what is known about the neurobiology of depression. An overview of a range of some of the more recurrent exploratory novel treatment avenues will be covered. A pair of SNDRIs are also included at the bottom of this review for proof-of-concept. In the "drugging strategies" section useful information regarding the receptorial profiles of ADs and antipsychotics (APs) are presented. Some of these represent novel strategies whereas others are proven methods.

[edit] Combination versus Conflation

The complexity of mood disorders suggests that drugs with multifarious activities will likely be more efficacious than drugs such as the SSRIs, NARIs and DARIs that interact with only a single site of action (B. Roth, et al. 2004),^[12] (M. Millan, 2004),^[13] (D. Nutt). The quest to find selective agents at each of the 3 monoamine reuptake transporters has served to provide compelling pharmacological insights.

[edit] Genuine versus Perceived Selectivity

An agent that has been shown to possess selectivity for e.g. the SERT vs. the catecholamine transporters, will possess unknown activities at receptors that have not been screened. In addition, a drug such as venlafaxine, possesses a more marked elevation in noradrenaline in vivo than would be predicted on the basis of its affinity for the noradrenaline transporter in vitro.

Moreover, there are 15 identified subtypes of 5-HT receptor, 9 NA receptors, and 5 different DA receptors. Although some of these have high sequence homology and serve a similar function, others are more substantially different and their in/activation can lead to widely varying consequences. An SSRI that is selective for the serotonin transporter, increases the extracellular 5-HT concentrations in the synaptic cleft that will then interact with all of the 5-HT receptors. For this reason, it is a gross oversimplification to regard SSRIs within a one dimensional framework due to the large number of receptors that are activated by an SSRI. Similar arguments can be presented in the case of both NARIs and DARIs. It does however need to be emphasized that these drugs are activating their receptor manifold via an indirect mode of action.

Attempts have been made to try and discover which of the various 5-HT receptors have the most beneficial properties, and to discover their pharmacology more generally and not just trying to capitalize on the knowledge that can be garnered from studying this area. Recently, it was demonstrated that 5-HT4 agonists have profound antidepressant properties. Efforts will probably now be taken to screen a library of potential 5-HT4 agonists and to try and find a candidate ligand with a high potency and selectivity for this receptor. Inversely, recognizing which of the various 5-HT receptor subtypes are likely to be deleterious will probably be be exploited by finding antagonist ligands that can recognize these receptor subtypes. Both of these approaches are attempting to yield genuinely selective drugs, whereas in the case of SSRIs, it is much more open to controversy if these can be considered truly selective. That is dependent upon whether they are being considered within the context of a one dimensional- or a multidimensional-framework. The latter is the more accurate and realistic, but for the purposes of simplification this simple fact is sometimes overlooked/neglected.

It also has to be addressed that 5-HT receptors are distributed not only in the CNS, but also in peripheral tissues where they serve physiological roles that are unrelated to mood. In the event that this tid-bit of information is not taken into account, a drug might have unintentional side-effects on peripheral targets. In this regard, the dangerous combination of phentermine and fenfluoramine (phen-fen) originally developed for the indication of treating obesity was found to be toxic to cardiac valves. This side-effect was attributed to interaction of fenfluoramine with cardiac 5-HT2B receptors. Contrariwise, effects of drugs originally developed for CNS indications may actually have beneficial periphery effects. In this respect, a certain subtype of 5-HT receptor is involved in emesis.

The above considerations need not be limited to depression and mood disorders, or even the CNS. For example, cancer is often more robustly treated with drug cocktails, compared to administering a single drug alone.

[edit] Single Drugs versus Several Drugs

The purpose of this review though is dealing with drugs that have inbuilt activites at a multitude of receptors and not about which combinations of drugs yield good synergy. The reader should consult the file on combination strategies if they are more interested in learning about the latter. A combination therapy is a crude and unrefined approximation of a multi-target drug sets-out to achieve.

Caution needs to be exercized when considering mixing a pair of drugs together. A pair of agents may have demonstrated superior efficacy, when combined, versus the monotherapy of either agent used alone. Unsurprisingly though, the chances of incurring a dangerous drug-drug interaction is an obvious risk that needs to be properly managed to reduce the likelyhood of this occuring.

Similarly, the side effects of an intentionally non-selective SNDRI drug needs to be carefully assessed due to the risk of unintentional interactions with target sites other than the ones that are considered desirable. A drug with catecholaminergic activity for example can sometimes cause hypertension and would therefore not be suitable in instances where a subject is already suffering from elevated blood pressure. Also, consider the drug para-thiomethyl-amphetamine. This is a drug that was passed off as ecstasy in the late 1990's due to a loophole in drug legislation meaning that it was not actually illegal to do so. The auxiliary monoamine oxidase inhibitor actions of this drug meant that it was actually quite dangerous, even more so when taken in conjunction with MDMA.

If a drug posesses undesirable side effects, the likelyhood is that the chances of this being encountered is at greater risk for higher doses. In a similar vein, the chance of potentially dangerous side effects is more likely to become apparent when a cocktail of drugs are taken together. For this reason, the dose of a drug utilizing several pharmacological modes of action, ie. broadspectrum, would need to be less than those working on a single target. After taking a drug working on a single target, the target will become saturated after a certain amount has been taken, beyond which taking more will not have any further effect on this target. If a drug has two different mechanisms of action, it is often the case that one of the sites of action will show a correspondingly higher affinity than the other site of action. Cocaine is quite unique in that it shows approximately equal affinity at each of the 5-HT/NE/DA transporters. A drug such as RTI-112 shows roughly equal affinity for the SERT and the DAT in vitro. Upon in vivo administration however, it is not until the SERT becomes saturated, and hence correspondingly higher doses are achieved, that the DAT starts becoming occupied. This pharmacodynamic consideration is a good example of how a multireceptorial "broadspectrum" drug is fundamentally different from the low-tech approximation achieved through taking a drugs cocktail.

Pharmacokinetically, it is often the case that some of the chief metabolites of a drug are not merely inactive and also have complex pharamcology. The N-demethyl metabolites in the case of alkaloids often possess subtle differences to their parent compounds. For example, MDMA is metabolized to MDA in vivo, and for this reason the pharmacology of MDMA is correspondingly more sophisticated than MDA. Another common example of biologically active metabolites occurs after O-demethylation of anisole-based alkaloids. In the case of tramadol, it is not until O-demethylation has occured that the compound shows high in vitro affinity for μ-opioid receptors. This is one of the primary reasons why tramadol is often referred to as an analog of codeine and not morphine.

Due to the fact that a single drug may already display a complex pharmacology, this is a good ground to reason why it can sometimes be unwise to mix drugs together. In otherwords, an already sophisticated pharmacology, can mean that introduction of another separate agent can make for quite muddy interactions that arent easily accounted for.

This general rule of thumb is not without exception though. Taking harmaline in combination with mimosa rootbark provides an attractive illustration of synergy between compounds. Mimosa rootbark primarily contains dimethyltryptamine as the chief alkaloid. This is rapidly degraded to inactive metabolites upon ingestion by monoamine oxidase enzymes. Since harmaline contains harmine which is a monoamine oxidaze inhibitor, co-administering these two plants together has been used in the hallucinogenic ayahuasca potion for thousands of years.

[edit] Multifarious versus Monotherapy

The following review is excellent reading and thoroughly recommended: MJ Millan (2006).^[14]

Mood disorders are major maladies of our times and depression is just one in a list of mood disorders. Most of the treatment regimes still need fine-tuning, in some cases the theoretical foundations on which they are based may also require a conceptial revamping.

For example, the D2 antagonists used in the treatment of schizophrenia can also cause dyskinesia particularly at high doses (Cohen & Carlezon, 2007).^[15] D3 antagonists were recently reported – these may also be able to ameliorate cognitive function. Therefore it is conceivable that such agents might find application in the treatment of dementias. Such examples of this comorbidity are widespread, especially since difficulty in concentration is also among the symptomatology that constitutes the depressed mood state. Consider also the value of using fluvoxamine to treat compulsive behaviours, and the high prevalence of anhedonia in Parkinson's disease.

The list provided is not intended to be exhaustive, and comprises some of the more common symptoms that can accompany a depressed mood state. Since the list is longer than one item, drugs that have a 'rich pharmacology' may be better equipped to tackle a multifarious symtomatology, at least in principle, than monotherapies which would likely only correct a limited subset of the diagnostic criteria. In terms of an invention, it is clearly more profitable for a company to develop a product that can be used on as wide a cross-section of society as possible versus a product that has been designed to meet the requirements of a relatively narrower target audience. With this in mind, if a medication were theoretically developed that was able to not only treat depression, but also tackle the full battery of diagnostic criteria in the list provided, then the number of potential customers would be predicted to be enormous! Such optimism however may be misplaced in that this is obviously an incredibly tall order and the chances of finding such a product would be like trying to find a needle in a haystack (colloquially speaking).

• Sleeping disorders (insomnia, narcolepsy, perturbed diurnal rhythm).
• Anxiety (panic attacks).
• Low motivation (hopelessness).
• Lack of energy (somnolence).
• Restlessness (fidgety).
• Difficulty concentrating (easily distracted).
• Decreased threshold to painful stimuli (over-senstitive).
• Eating disorders (over-eating, bulimia, anorexia).
• Decreased memory retention (forgetfulness).

The mechanisms of action of a handful of recent drugs that have passed clinical trials are not clearly understood. The pharmacology of tianeptine, modafinil and pregabalin and even bupropion are illustrative. This underlines the element of surprise in drug discovery efforts in that in order for a drug to have a demonstrated clinical response, understanding of its mechanism of action is not prerequisite. In this regard, the pharmacological interactions of a relatively new agent does not have to be particularly well defined and may even be decidely 'fuzzy' in the earlier stages. The pharmacology of a novel agent can only be empirically proven and it is not possible to know beforehand based on theoretical conjecture alone.

An alternative strategy, based on a subjects diagnostic symptomatology, would be to administer medication that is most congruent with their individual requirements. One of the drawbacks of custom tailoring a treatment regime is that it is more expensive to do and requires more specialist knowledge than administering a medication that is palatable among a more general target audience.

[edit] Dual Indications

For example, agomelatine is a melatonin agonist but also a 5-HT2C antagonist. Such dual activity means that it is not only useful for treating depression but also in improving sleep architecture. Contrariwise, if a subject had depleted energy reserves, an SSRI can be augmented with bupropion. This is controversial in that it entails co-administering two different drugs. Thus a non-selective drug with built-in activities at a constellation of receptors will be preferable. The reasons why this is preferrable to co-administering two drugs together is clearly an important issue that has already been discussed. Ease of dosing is obvious, since only a single drug is being taken, the issue of titrating the doses of two different drugs together until the 'optimum' ratio is achieved is not even a factor that comes into play. Moreover, individual drugs may already have quite elegant pharmacology in terms of not only the parent drug, but also the delicate cocktail of pharmacologically active in vivo metabolites. Taking two separate drugs together might confuse an already intricate and balanced mode of activity. There are cases where it is actually beneficial to coadminister a pair of drugs and they may work together completely harmoniously and a perfect synergy is achieved. It must be understood that giving a second drug (bupropion) to patient already receiving a drug (venlafaxine) serves to supplant the inadequacies of the first drug. It is frequently the case that the two drugs will not be taken together initially due to the increased incidence of side effects among drug naïve subjects relative to those already having an appreciable tolerance. For drug combination to occur, the subject is usually refractory and shows only a partial remission from the first drug before augmentation is attempted.

It has been argued that it is somewhat unlikely that a panacea for the palliation of CNS diseases (esp. mood disorders) can be discovered. However, it should be stressed that drugs with multi-receptorial profiles possibly in concert with psychotherapy may ultimately lead to the best healthcare system for the alleviation of these syndromes/diseases. Thus, while it is not inconceivable that a monotherapy targeting a single receptor/gene will be effective (e.g. 5-HT4 agonists), it is increasingly likely that drugs that can act with a chosen constellation of receptors or intracellular signaling pathways will yield a stronger and more robust augmentation in the clinical response.

[edit] Dirty Drugs

The derogatory nick-name of "dirty drugs" refers to multi-receptorial drugs in general, but is more specifically exemplified by the deleterious outcomes of pharmacological non-selectivity rather than the outcomes that might be viewed as being beneficial. The tricyclic antidepressants are a specimen example of drugs that are said to have a "dirty phamacology". Taking TCAs causes histamine (H1), α1 adrenergic and cholinergic receptor blockade, consequentially leading to: somnolence, hypotension and even cardiotoxicity. The piperazine based antidepressants, trazodone and nefazodone likewise display a similar side effect profile.

All of the above drugs also antagonize 5-HT2 receptors. On the other hand, this is believed to be a beneficial, and hence, desirable pharmacolgical interaction. In the specific case of the two piperazines though, N-dealkylation occuring in vivo leads to the formation of 1-(3-chlorophenyl)piperazine (mCPP) which is an active metabolite. This is a well-known 5-HT2C receptor agonist. At least upon acute administration 5-HT2C agonists are "panicogen" and inhibit dopaminergic neurotransmission.

β-Naphthyl-isopropylamine also elicits 5-HT2C agonism as one of its principle modes of activity.[cit] This compound was discovered as part of a recent effort by Rothman and co-workers to explore analogs of amphetamine with the express intent of finding cures for psychostimulant abuse. However, the consequential anorexic side-effects that 5-HT2C agonism causes has meant that this compound is unlikely to be useful in the context of treating the indication for which it had been originally designed.

Conversely, a 5-HT2C agonist would be worth considering in the context of treating obesity. Although 5-HT2C ant/agonists have contrasting acute mechanisms of action –i.e. dis/inhibition of dopaminergic neurotransmission– both lead to a downregulation of this receptor subtype after chronic exposure.

[edit] Effects on Cognition

The anticholinergic actions of TCAs and even paroxetine can actually worsen cognitive function. In contrast, the dopaminergic secondary effect of sertraline has been speculated to slightly improve cognitive performance. With regards to dopaminergic agents, D1(D5) agonists ameliorate cognitive function, whereas in the case of D3 and possibly D4 subtypes, antagonists are beneficial.

D2 agonists may possess antidepressant potential, however their usefulness clashes with the antagonist actions of antipsychotics on this receptor. A more cogent recent theory of schizophrenia is that this derangement is a consequence of decreased NMDA receptor function. The limitation of this hypothesis is that drugs causing an increased glutamatergic tone may also be neurotoxic. The reader is referred to any of the several articles cited in later sections more specifically delineating glutamateric function, if they are interested in learning about this. This document is only intended as a general review, and is therefore limited in scope for in-depth consideration of recent glutamatergic hypotheses.

[edit] Neurobiology of Depression

For a useful primer to the molecular neurobiology of depression, the reader is referred to the following review which, though oversimplified is highly readible and easily accessible: (Nestler, et al. 2002)

[edit] Adult hippocampal neurogenesis

(Vollmayr, et al. 2007),^[16] (Sahay & Hen, 2007).^[17]

The finding that neurogenesis occurs in adult mammals has had important consequences in the neurosciences field. Specifically it occurs in the dentate gyrus of the hippocampus. Depression and antidepressants decrease and increase, respectively, neurogenesis in the dentate gyrus region of the hippocampus in humans. Santarelli et al. 2003 reported that X-ray destruction of proliferating neurons impaired responses to antidepressant drugs. Likewise, in the same study, knockout of 5-HT1A receptors (which are necessary for neurogenesis), also blocked behavioral responses to AD drugs. Based on these findings, at first sight it would appear likley that that a drug specifically aiming to increase neurogenesis in the dentate gyrus would be able to provide relief in depressive symptomatology.

In another study, there were however some findings inconsistent (or incongruent) with this belief. Conti, et al. (2002) reported that antidepressant responses can be mediated even in the absence of neurogenesis.

The compilation of these findings provided the rationale that decreased neurogenesis and cellular proliferation in the dentate gyrus is not the cause (etiology) of depression but is part of the symptomatology (or consequence) of chronic depression and a maladaptive mood state.

Hence, decreased cellular proliferation and neurogenesis, decreased dendritic arborization and complexity of spine growths, and decreased glial cell counts and volume, are all linked to mood disorders and can be corrected or remedied by the chronic yet not the acute actions of antidepressants. The finding by Conti et al. (2002), simply shows that depression does not hinge on decreased neurogenesis per se, rather that depression is a complex multifactorial disorder and decreased neurogenesis is just one of the trait markers for this syndrome. Decreased neurogensis is a consequence of depression but is efferent to (downstream of) the cause (etiology), and is certainly not the sole trait marker for a depressed mood state.

The role of increased glutamatergic tone and overactive secretion of cortisol are more congruent with the depressed etiology. In other words these are acting afferent to (ie upstream of) the changes in neurological 'architecture' or, more specficially, the cellular/structural and systems morphology that analytical studies have shown to be adversely or pathologically disrupted/impaired after a subject has suffered from several depressive episodes (ie a chronic sufferer). Although this section was titled "neurogenesis" there is clearly an overlap between this and "neuroplasticity" in general. "Synaptic plasticity" is another subject for which I have a recent review.

The above morphological derangements would thus be a consequence of pathologically elevated concentrations of cortisol and glutamate, both of which can become neurotoxic if their concentrations exceed certain threshold values. Elevations that exceed the 'threshold value' are commonly brought on by stressful episodes. Stress is more congruent with post-traumatic stress disorder (PTSD) than depression, although stress is still commonly used to model depression in laboratory animals.

It is still unclear how a drug able to enhance synaptic concentrations of 5-HT would be able to correct this. Whatever the exact mechanism of action, it would clearly be correcting these deficits in CNS structural achitecture via an indirect pathway. 5-HT is well known to interact with post synaptic G-protein coupled receptors. There are 15 different 5-HT receptors although the 5-HT4 receptor recently has shown very interesting pharmacology. As should be further elaborated, G-protein coupled receptors are both positively and negatively coupled to intracellular signaling pathways on the post synaptic neuron. Via CREB and other nuclear proteins, these regulate the transcription of messenger RNA, which can upregulate the expression of various proteins/biomolecules. The nucleus of a cell is like a factory that manufactures AMPA receptor subunits, other receptors, and BDNF among other neurotrophic/growth factors.

Another theory is that whereas glutamate is the major excitatory neurotransmitter in the CNS, GABA is the major inhibitory neurotransmitter in the CNS. Serotonergic fibres orginating in the raphe nucleus and innervating several target regions within the brain could be colocalized with GABAergic neurons. These cell bodies would provide a tonic and compensatory counterbalancing effect in response to the overactive Glu transmission, and somehow offer relieved symptomatology, thereby mediating partial recovery.

Recent studies have suggested that new neurons may help with the encoding of time into newly formulated memories.

New neurons, after a period of growth, survival and maturation, are transported to the relevant brain areas where they offer trophic support.

[edit] CREB

(Carlezon, et al. 2005),^[18] (Nestler and Carlezon, 2006).^[19]

cAMP regulated element binding protein (CREB) is found in the nucleus of all CNS cells and regulates nuclear transcription of important biomolecules. Upon phosphorylation of CREB at Ser-133, CREB dimerizes and then binds to CRE sites that regulate gene transcription. mCREB is a mutant strain of CREB that can still dimerize with wild-type CREB and bind to CRE sites. However this genetic point mutation in mCREB has the consequence that the Ser-133 site can no longer be phosphorylated. This in turn means that gene transcription is no longer possible. Viral transfection of mCREB into various brain regions, in addition to simple CREB transfusion, therefore also offers a useful means for investigating the effects of increased/decreased CREB expression in the CNS.

As will be further discussed in the section on signaling transduction pathways, CREB is intimately linked to the actions of G-protein coupled receptors, which in-turn, are modulated either postively or negatively by neurotransmitters in the synaptic cleft. Neurotransmitters are well known to be involved in the mode of action of numerous psychoactive drugs working through diverse/varying mechanisms and sites of action. Thus, there is a plethora of CNS signaling pathways that ultimately converge upon CREB in the post-synaptic neuron to regulate/mediate nuclear gene transcription, repectively.

CREB is most well-known for its affect on memory and learning although upregulation of CREB is not always beneficial. In the hippocampus upregulation of CREB is nearly always beneficial, whereas in the NAc the opposite effect is observed. Overexpression of CREB in the NAc causes prodepressant effects and dampens response to both rewarding and aversive stimuli. On the contrary, decreased CREB in the NAc, is antidepressant and in extreme cases such as that seen in social isolation, causes an anxiety like state.

There is evidence that antidepressants work to upregulate CREB in the hippocampus and this can improve cognitive function – an ability often impaired in mood disorder subjects. For this reason, it has been argued that molecules able to increase CREB function in regions that subserve beneficial effects on memory and learning may be desirable even in persons not suffering from depressive syndrome. Mind steroids, performance enhancing drugs for the brain.

Ethical difficulties hamper the administration of ADs to patients not thought to be suffering from depressive illness. However, other important considerations attend such a treatment; Not all memories are desirable. This point is elaborated by the beta-blocker propranolol which disrupts memory. As such, it is being investigated for its clinical application in the treatment of PTSD.

Also relevant to cognitive function, while antidepressants may be useful in this regard it should also be borne in mind that the anticholinergic effects of tricyclic and tetracyclic ADs may offset the hippocampal increase in CREB expression.

[edit] Dynorphin

Dynorphin (Dyn) is an endogenous opioid peptide localized in the NAc. It binds to kappa opioid receptors (KORs) expressed on GABAergic cell bodies and terminals that project from the NAc and innervate the VTA. KOR agonists such as endogenous Dyn cause dysphoria and other aversive effects. This is because activation of KORs block dopaminergic neurotransmission along the ventral striatum. Dyn expression is upregulated by the cAMP-PKA-CREB cascade as well as by influx of extracellular Ca++ and activation of TrkB receptors.

The hippocampus has historically been the central target of antidepressant research whereas the mesolimbic dopaminergic pathway has received treatment in drug addiction. This is clearly an artificial distinction in that the decreased motivation, energy, and anhedonic behavioral traits are core symptoms of depression that also constitute the hypodopaminergic phenotype. In the field of addiction, CREB expression is upregulated during withdrawal from drugs of abuse such as cocaine and opioids. KOR antagonists are therefore of utility in the treatment of drug withdrawal although there is also hope that these agents might be useful in the treatment of depression.

Several lines of evidence have shown that dopaminergic transmission is profoundly altered, either postively or adversely, by life experiences. I.e. non-drug reinforcers also affect the mesolimbic pathway as documented by Wolfram Schulz.

In conclusion, while blocking KORs is a useful indirect strategy to enhance dopaminergic neurotransmission, more generally it helps account for one of the possible reasons why BDNF and CREB expression in the NAc are prodepressant. In addition, all this research helps to consolidate on the fact that incorporation of a dopaminergic tone into standard ADs can be beneficial because of its mood elevating properties.

[edit] Neurotrophic Factors

(Duman and Monteggia, 2006)^[20] (Pittenger and Duman, 2007)^[21]

Brain derived neurotrophic factor (BDNF) is known to play a postive role in the modulation of mood disorders. It is a nuclear protein, as its name suggests it is most prevailent in the brain. BDNF binds to tyrosine kinase receptors TrkB receptors, whereby it can influence intracellular signaling cascades via the MAPK-ERK pathway.

While BDNF postively modulates cell survival, it has no effect on cell proliferation. Rather, vascular endothelial growth factor (VEGF) controls this process. BDNF has regional effects on the hippocampus and NAc neurons that are similar to that already outlined for CREB above. Neurotrophins are some of the transcription factors that are mediated at the genetic level by CREB. So it can be seen that their induction is not intrinsically postive or negative, rather this depends on their localization within the brain regions that are being examined.

As is probably already apparent, depression decreases the expression of BDNF in the hippocampus, whereas AD drugs have the opposite effect. BDNF plays a positive role in restorative processes and can reverse neuronal atrophy.

The ADs with the highest scores for clinical success (i.e. ECT and MAOIs) had the most profound effect on BDNF expression.

A potential drawback of the direct targeting of neurotrophic/growth factors is that conversely inhibitors of these are investigatory agents for the treatment of cancer where cells are known to profilerate uncontrollably. It is therefore a genuine concern that agents that attempt to upregulate neurogenesis through direct mechanisms may be carcinogenic. As is delineated in other sections of this review, monoaminergic drugs and AMPA potentiators go about this indirectly.

[edit] Intracellular Signaling Pathways

(Tanis & Duman, 2007),^[22] (Tanis, et al. 2007).^[23]

Intracellular signaling pathways work upstream of CREB and downstream of postsynaptic receptor sites. There are four main pathways which we will consider.

• Cyclic adenosine monophosphate (cAMP): Postsynaptic monoamine receptors are coupled to intracellular adenylyl cyclase (AC). This enzyme catalyzes the conversion of adenosine triphosphate (ATP) to cAMP. cAMP in turn activates protein kinase A (PKA) which can translocate to the cells nucleus and phosphorylate CREB. PKA also indirectly phosphorylates CREB via activating the DA and cAMP regulated phosphoprotein of 32 kDa (DARPP-32). This in turn phosphorylates the AMPA Glu-1A subunit stimulating influx of Ca++ ions. Increased intracellular Ca++ ions activate calcium calmodulin dependant kinase (CAMK) and also protein kinase 3 (PKC).

• cAMP accumulation is prevented by phosphodiesterase (PDE) dependent degradation to adenosine monophosphate AMP. Rolipram for example is a PDEIV inhibitor that has AD effects although it causes emesis and nausea, presumably due to its lack of specificity. However, all this serves to consolidate on the importance of increased cAMP and has fueled an interest in more selective PDE inhibitors (c.f. cilomilast).

• A downregulated cAMP pathway was observed in MDD subjects who comitted suicide, and it is upregulated by chronic AD treatment. In bipolar disorder the sitation is more complicated than this and some evidence is suggestive that the cAMP pathway may be hyperactive. In part, this deduction was formed on the observation that various of the mood stabilizing drugs reduced AC activity. Certain of the monoamine receptors upregulate AC activity whereas others have an inhibitory effect on this enzyme. It is tempting to speculate that cAMP production should thus be 'normalized' or regulated in that excessive cAMP could possibly induce mania, whereas the converse scenario is prodepressive.

• Mitogen activated protein kinase (MAPK) / extracellular signal regulatedkinase (ERC): This pathway is postively upregulated by neurotrophin/growth factors. BDNF, VEGF, IGF, NT-3 and activin are examples of this. As was already discussed in the previous paragraph, intracellular Ca++ ions also activate the MAPK-ERC pathway via recruitment of PKC. Through a highly intricate and ill-understood web of signaling cascades, CREB phosphorylation is upregulated mediating postive outcomes.

• Phosphoinositol pathway: The mechanisms of mood stablizing drugs including lithium, carbemazepine and valproate appear to inhibit this pathway. However, the significance of this pathway in the actions of commonly prescribed AD drugs is not known.

• GSK-3 pathway: Activation of GSK-3 promotes cell apoptosis. ADs can help phosphorylate GSK-3 which inactivates it. Conversely, amphetamines can activate GSK-3.

[edit] Preclinical Depression Tests

• Forced swim test (FST): A rodent is placed in a beaker of water and the immobility time is measured. Typically administration of an effective AD prior to testing increases the latency to immoblity relative to placebo.

• Tail suspension test (TST): A rodent is suspended by its tail and similarly latency times to immoblity are measured. Although this test is very similar to the FST, apparently there is some differences in the results typically obtained. This means that both of these tests have utility.

Note: The above two tests can show positives with psychostimulants. For this reason, it is necessary to also screen for locomotor activity (LMA). A likely novel AD in preclinical tests should be able to effect positive FST and TST results without stimulating basal LMA.

• Learned helplessness (LH): In this test the rodent is placed in an inescapable cage and is then subjected to a series of aversive stimuli (e.g. electric foot-shocks). An escape route is then facilitated. Treatment with an effective AD should result in a decreased escape latency relative to placebo controls.

The first 3 tests provide measures of behavioral despair or "giving up" and are representative of depression apathy.

• Novely suppressed feeding (NSF): The basis of this test works around the concept that depression typically involves anxiety and anorexia as some of the symptoms in diagnostic models of the disease. A rodent is deprived of food for a period of time and a source of food is then supplied in a brightly lit box separate to the area in which the rodent is housed. The time it takes for the rodent to take the bait is seen as a measure of the effectiveness of the antidepressant relative to placebo. The concept for this is that if an animal were in its wild habitat, a brightly lit room would present genuine survival hazards such as risk of attack from predators etc. However severe fear in this test would be associated with a pathological illness that may even be detrimental to the animals survival. One of the drawbacks of this test is that it responds positively to anxiolytic drugs such as GABAergic benzodiazepams and is therefore not treatment specific. The main plus of this last method derives from the fact that it responds more positively to chronic rather than the acute actions of antidepressants, whereas the earlier tests show efficacy in the pre-chronic, or acute actions of the antidepressant therapy.

Also note that ADs screened in rodent behavioral models can give false positives and also the reverse scenario where clinically effective ADs can give false negatives.

NSF is more of a test for anxiolytic effects that may attend AD therapy rather than a precise measure of AD efficacy. Indeed, in order to assess the effectiveness of a given AD at alleviating the depressive syndrome, chronic mild stress (CMS) is perhaps the best model. This test involves basically mal-treating the rodents over a period of several weeks. During this time the rodents consume less of a sucrose solution when it is made available to them relative to controls. An effective AD treatment should help to reverse this effect.

[edit] Glucocorticoids

(Dranovsky and Hen, 2006)^[24]

The hippocampus plays a critical role in learning, memory and cognitive function. The circuitry of this brain region is also closely connected to the amygdala and prefrontal cortex, two other areas associated with similar functions.

A prominent mechanism by which the brain reacts to acute or chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis. Neurons in the paraventricular nucleus (PVN) of the hypothalamus secrete corticotropin releasing factor (CRF), which stimulates the synthesis and release of adrenocorticotopin hormone (ACTH) from the anterior pituitary. ACTH then stimulates the synthesis and release of glucocorticoids (cortisol in humans, corticosterone in rodents) from the adrenal cortex. Glucocorticoids exert profound effects on general metabolism and also dramatically affect behavior via direct actions on numerous brain regions.

Mineraolcortoid receptors (MRs; type 1) have a higher affinity for corticoids are the first receptors to become activated. It has been speculated that these receptors are actually neuroprotective and may represent one of the normal physiological coping mechanisms in response to stressful stimuli. Upon more sustained elevations in circulating levels of corticosteroids, glucocorticoid receptors (GRs; type 2) are activated. This may be maladaptive and coordinated to the pathological actions of stressful stimuli.

These have wide ranging effects on the body, although in the brain the effect of this is believed to be decreased neurogenesis & dentritic arborization, and neuronal atrophy particularly in the subgranular and ventricular zones of the hippocampi. Decreased hippocampal volumes are also reported in chronically depressed subjects although not all studies have reported this. In addition chronically depressed subjects have a decreased number of glial cells and glial number is also reduced.

At least 50% of depressed subjects are believed to have an overactive HPA axis. Increased cortisol secretion causes changes in metabolism leading to visceral lipid accumulation and hence obesity. Further, obesity can result in type 2 diabetes if left untreated and also cardiovascular disease. This again serves to underscore the link between affective disorders and physiological medical diseases.

Current strategies can involve administering compounds that interfere with the synthesis of cortisol (ketoconazole or mifepristone, repectively). Alternatively, antagonists recognizing either CRF or glucocorticoid receptors are also being persued. Mifepristone is more benign than ketoconozole because of its increased adrenal/gonadal ratio. In combination with SSRIs lower doses are possible, leading to a further diminution of side-effects. In further contrast to ketoconazole, mifepristone also penetrates the CNS leading to further complexity of its pharmacolgic intercourse. Upon pharmacological intervention with mifepristone, circulating levels of precursors to cortisol and hence neurosteroids, are increased. These can positvely modulate affect. Finally, MRs are upregulated and an increased denisty of postsynaptic 5-HT1A receptors are also reported, which are important to mediating the antidepressive response. Upon discontinuation of mifepristone, there is a corresponding rise in the circulating level of corticosteroids, and then the HPA axis feedback control is reinstated.

Glucocorticoid receptor (GR) antagonists have recently demonstrated activity in rodent models of depression. In humans, cortisol binds to CRF receptors in the hippocampus. This then inhibits the release of further CRF, and therefore acts as a homeostatic regulatory mechanism, preventing further stimulation of the HPA system.

It is hypothesized that depressed patients might have damaged this part of the brain circuitry and have therefore impaired this negative feedback loop. Interestingly stress and depression are not perfectly synonymous in that persons who have suffered numerous stressful life experiences do not necessarily display the exact same diagnostic criteria as those thought to be suffering from depression. Post traumatic stress disorder (PTSD) more closely parallels this.

Importantly, currently prescribed antidepressants seem to be able to normalize an overactive HPA axis. Although it has been demonstrated that cortisol is an important endogenous steroid that may even facilitate neurogenesis at normal physiological levels, hypersecretion of cortisol —such as that seen in Cushings syndrome— may cause neuronal atrophy, particularly in CA3 pyramidal neurons in the hippocampus. This would clearly be detrimental and may account for the learning and memory cognitive deficits seen in certain sub-sections of depressives.

Whilst acute mild stress and normal physiological levels of glucocorticoids improve cognitive function, chronic stress and associated hypercortisolaemia are clearly detrimental causing hippocampal atrophy, decreases in neurogenesis and impairment of cognitive function.

[edit] Glutamate

[edit] NMDA Antagonists

(Pittenger, et al. 2007)^[25]

Of the different types of glutamatergic receptor, it is probably the NMDA receptor which is the best characterized in terms of its pharmacology. Not least, this is because of the fact that interesting drugs including phencyclidine (PCP a.k.a. "angel dust") and ketamine (a.k.a. "special K") derive their principle mechanism of action via blockade of NMDA receptors. Both of these are potent drugs of abuse with limited medicinal application, although the latter is also used in veterinary medicine as a dissociative anethesic. Another research agent, dizocilpine (MK-801), is probably the most potent NMDA antagonist known and is active at <1mg doses.

The above agents are potent and noncompetitive NMDA receptor ion-channel blockers. All of them cause potent pro-psychotic effects resembling schizophrenia which has limited their medical usefulness. Conversely, amantadine and memantine are weaker competitive antagonists for the glycine subunit of the NMDA receptor. These are less likely to cause profound dissociations from reality. Amantadine is useful in treating Parkinsons disease because of its auxiliary effect of dopamine receptors.

In at least two separate studies, it has been reported that ketamine is profoundly antidepressant. A single dose of ketamine has been reported to lead to an antidepressant effect that lasts at least seven days! This has led to some speculation that NMDA receptor blockers may have utility in the treatment of depression.

Although there may be some truth in the above claim, efforts have been made that attempt to dissociate the antidepressant actions of ketamine from its ability to precipitate psychosis. While the psychotic side effects of ketamine are not necessarily limiting within the context of its recreational user base, clearly this would be an unacceptable property for an antidepressant agent to gain wide-spread approval.

Tricyclic antidepressants are also believed to have micro-molar affinites for NMDA receptors and endogenous zinc is another weak NMDA ion-channel blocker.

Various synthetic opioids such as ketobemidone and methadone are also reported to cause auxiliary NMDA receptor blockade, thought useful counteracting opiate tolerance and dependance.

Somewhat disappointingly, it remains to be seen if it is possible to separate the psychotic recreational aspects of NMDA antagonists from agents not eliciting psychosis that are more likely to be acceptable in a clinical setting for the management of depression.

While pure NMDA receptor blockers might not be good canidate molecules for treating depression, it is still conceivale that they are of use in treating Alzheimers disease. Furthermore NMDA receptor antagonism is a useful auxiliary activity which can counteract opioid tolerance and dependence. The importance of these agents to CNS drug discovery efforts therefore should not be discredited.

[edit] AMPA Potentiators

(Alt, et al. 2006)^[26]

[edit] EAATs

(Dunlop & Butera, 2006)^[27]

[edit] Metabotropic Glu Receptors

Glutamate is the major excitatory neurotransmitter in the CNS. There are two types of glumamate receptor, ionotropic (voltage gated) and metabotropic (G-protein coupled receptors). The ionotropic receptors can be further broken down to include NMDA, kainate and AMPA.

Glutamatergic neurotransmission is ubiquitous to long term potentiation (LTP) and its role in learning and memory. During epileptic seizures are chronic stress, extrasynaptic 'spill-over' of glutamate can occur when it is not cleared from the synaptic cleft rapidly enough – this is neurotoxic. In depth discussion of these processes will not be covered in detail, but glutamate is cleared from the synaptic cleft by excitatory aminoacid transporters (EAATs) located mainly on astrocytes but also postsynaptically. A survey of drugs that were designed with the deliberation of blocking EAATs was recently reported with applications in the management of schizophrenia. The glutamate hypothesis of schizophrenia is based on the observation that non-competitive NMDA antagonists give a more reliable drug-induced behavioral model of the disorder than drugs that enhance dopaminergic neurotransmission. There is a rich resource of mechanisms through which glutamatergic activity can be modulated. Efforts directed at small molecules capable of inhibiting the EAATs have been hesistant due to the fact that pathologically increased glutamatergic tone is well established to be neurotoxic. However, even here agents with sub-type specificity for the five classes of EAAT are being invented.

It has long been known that NMDA antagonists can be antidepressant, recently sub-anesthetic doses of ketamine have been proven to have profound AD utility. Importantly the antidepressant response to ketamine began immediately after a single dose and lasted for at least three days. The psychotomimetic properties of ketamine limits its widespread application. Instead, investigative efforts were attempting to dissociate mood elevating effects from the propensity to induce psychosis. In this light, agents that act on the glycine binding site were being considered instead of non-competitive ion channel blockers. Two such agents, memantine and amantadine are partial agonists for the glycine site on the NR1 subunit. Results were not that encouraging but the latter agent, possibly co-administered with Zn++ which is also an NMDA antagonist are an interesting second option.

NMDA receptors are located post synaptically and extrasynaptically. In contrast to AMPA receptors, NMDARs require the simulatenous presence of enough ligand (glutamate) and depolarisation in order to open. Upon opening, NMDA receptors allow the influx of Ca++ across the cell membrane. For this reason a cell membrane containing only NMDA receptors is called a silent synapse. Insertion of AMPARs into the membrane unsilences the silent synapses and this is thought to lead to a strengthening of synaptic connectivity.

Fluoxetine is known to cause AMPA potentiation, probably through recruitment DARRP-32 in the cAMP cascade. Influx of Ca++ upregulates MAPK-ERC which activates CREB via serine-133 phosphorylation. Eli Lilly and other biotech companies are currently developing selective AMPAkines for the treatment of mood disorders, in part, because of the BDNF hypothesis of depression. Preliminary studies for AMPAkines have been encouraging with one agent showing a result in the FST similar to imipramine.

Glutamate is rapidly cleared from the synaptic cleft by astrocyte glial cells. The excitatory amino acid transporters (EAATs) facilitate this transport. Glutamate is metabolized to glutamine, and once it has been transported back into presynaptic vesicles it can then be reconverted to glutamate and the cellular cycle is repeated.

As cited above, Ca++ influx upregulates MAPK-ERC signaling and also activates PKC which can phosphorylate CREB directly. In view of this, it seems paradoxical at first glance that NMDA antagonists might have potential uses in the management of mood disorders. The rationale for this comes from the finding that chronic stress causes excessive glutamatergic neurotransmission. In a manner similar to and colocalized with what has already been discussed for glucocortiocids, this is excitotoxic and can impair neurogenesis, decrease numbers of glial cells and hippocampal volume shrinkage. [I am not a biologically minded individual, but from a medicinal chemists stand-point the effects of stress on neuro/synaptic plasticity are clearly detrimental and are linked to excessive glutamate and glucocorticoid release]

There are two types of NMDA receptors: synaptic and extrasynaptic. Because glutamate concentrations are less in the extrasynaptic space, an NMDA antagonist is expected to preferentially bind to these. This helps block the neurotoxic consequences of excess Ca++ in the synaptic neuron. At higher doses, blockade of synaptic NMDA receptors may occur and there is evidence that this may also be toxic (c.f. Olney's Lesions).

In summary, the agent should work to 'normalize' permeability of Ca++ into the post synaptic neuron – too little causes depression, whereas too much is toxic.

Also worthy of mention is the fact that phencyclidine/ketamine paradoxically cause increased glutamate in the prefrontal cortex (PFC). This is in good concordance with the role of AMPAkines despite the fact that it is a little unexpected.

Efforts have been made to try and dissociate the mood elevating effects of NMDA antagonists from their pro-psychotic liability. Such efforts have not been very promising and it seems disconcerting that pure NMDA antagonists will find use as monotherapy in managing depression. Agents like lamotrigine are actually clinically useful antiepileptics.

There is still a good chance that drugs modulating glutaminergic transmission will have important applications in CNS medicinal chemistry. On this basis, it seems necessary that efforts are made to try and better understand the pharmacology.

[edit] A Pair of SNDRIs

[edit] DOV Pharmaceuticals

DOV pharmaceuticals have conducted lengthy clinical trials on one such compound, and have thus, assumed a lead in development, in the arena of "Triple Reuptake Inhibitor" (TRI) based antidepressants (Phil Skolnick, et al.).^{[28][29][30][31][32][33][34]}

The DOV compound employs the 'catecholaminergic' p,m-dichlorophenyl ring. The heterocyclic part of the molecule is bicyclic. One half employs pyrrolidine, cf. nicotine; the other is cyclopropane based, cf. milnacipran.

Certain properties are worth pointing out such as: the compounds are not ultra potent and doses of up to 100mg per day are well tolerated with only nausea, and GI disturbances reported as side effects. The effects are not long-lasting meaning that an XR version of this drug is needed if repeat dosing is unacceptable. This compound does not cause notable shifts in LMA, and is not pyschostimulant. All this, is in contrast to Indatraline, showing how small changes in molecular structure, frequently embark marked changes in pharmacological activity.

[edit] PRC Antidepressants

The PRC group have also been developing mixed antidepressants over the past decade, their in vivo activities were recently reported (Shaw, et al. 2007).^[35] Infact, this was the group that first coined the name "SNDRI" when referring to these compounds (P. Carlier, et al. 1998).^[36]

These are chemically related to, yet far more advanced and stronger in effects than the older drug venlafaxine [1990]. The fossilized synthetic chemistry of these compounds involves what is called a "nitrile aldol" rxn, there is a racemic pair of diastereoisomers. The dia/stereochemistry can be manipulated to get some level of selectivity.

The PRC compounds employ the γ–amino-alcohol pharmacophore, found in venlafaxine, although, more generally, the γ-amino-ether 'linker' exists in a wide variety of R_x MA reuptake inhibitors, e.g. duloxetine, paroxetine, fluoxetine, atomoxetine, & reboxetine.

PRC Antidepressant Triple QSAR (nM)

Compound	[3H]5-HT Uptake	[3H]NE Uptake	[3H]DA Uptake	Ki ÷ Kd			Uptake Ratio
Compound	hSERT Kd (Ki)	hNET Kd (Ki)	hDAT Kd (Ki)	5-HT	NE	DA	NE ÷ 5-HT	DA ÷ 5-HT	DA ÷ NE
PRC025	6.0 ± .8 (6.0 ± .8)	19 ± 2 (10 ± .5)	100 ± 10 (53 ± 1)	1.000	.5263	.5300	3.167 (1.667)	16.67 (8.833)	5.263 (5.3)
PRC050	6.0 ± .3 (12 ± 2)	.40 ± .05 (1.2 ± .1)	120 ± 10 (43 ± 7)	2.000	3.000	.358	.0667 (.1)	20 (3.583)	300 (38.83)
Venlafaxine	9.0 ± 0.3 (39 ± 3)	1060 ± 40 (210 ± 20)	9.3K ± 50 (5.3K ± 6h)	4.333	.1981	.5700	5.385 (117.8)	1033 (135.9)	8.774 (25.24)
Values Represent the geometric mean of at least 3 different experiments for PRC025 and PRC50.

Increased BP may actually be a desirable property of the PRC compounds, since they are based around the psychostimulant β-PEA skeletal backbone, and not γ-PPA based. Carlier's compounds are actually naphthyl, not phenyl derived.

[edit] Conclusion

Thus, a medication that serves to occupy all three of the monoamine transporters ≈ equally, is more likely to facilitate in the manifestation of the full-spectrum of mood elevating effects, without precipitating unwanted side effects.

The above image was drawn by me. The secondary colors were customized in paint to be exactly half of each on the primary colors. For the center, I could have used brown but preferred the look of gray (grey).

In addition, learning how to draw circles was important not only for this image but also for sketching aromatic rings in molecular structures:

[edit] References

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[edit] Patents

United States Patent 6,069,177 Carlier, et al. May 30, 2000
United States Patent 6,700,018 Richelson, et al. March 2, 2004
United States Patent 6,914,080 Richelson, et al. July 5, 2005
United States Patent 6,569,887 Lippa, et al. May 27, 2003
United States Patent 6,716,868 Lippa, et al. April 6, 2004
United States Patent 7,041,835 Lippa, et al. May 9, 2006
United States Patent 7,081,471 Lippa, et al. July 25, 2006
United States Patent 7,098,230 Lippa, et al. August 29, 2006
WO2004052858 Publication date: 2004-06-24 Inventor: CLARK BARRY PETER, et al. (GB)
WO2005092885 Publication date: 2005-10-06 Inventor: BOULET SERGE LOUIS, et al. (US)
WO2006020049 Publication date: 2006-02-23 Inventor: MOLINO BRUCE F, et al.
WO2006058016 Publication date: 2006-06-01 Inventor: MOLINO BRUCE F, et al.