User:Nuklear/SNDRI

This review will deal with SNDRI compounds although other aspects of depression will also be discussed as this is considered relevent due to the relative novelty of this group of compounds.

Introduction
Significant studies recently published are highlighting an un-met need to meet the demand for innovative new drugs, that confer multiple layers of activity (B. Roth, et al. 2004), and/or radically different mechanisms of action to the older medications (Berton & Nestler, 2006). The focus of this review is on compounds that inhibit the reuptake of endogenous monoamines since this is a well proven approach in the design of antidepressant therapies. The reader should however keep an open mind to the fact that there is a number of other ways that depression can be alleviated in experimental animals that do not rely on the direct targeting of monoamine transporters in order to demonstrate their effectiveness. Some of these will be discussed, although others will not be included if they are not considered relevent or if they are simply beyond the scope of this study.

Until very recently, SSRIs were the 'mainstay' in the treatment of depression. Although, SNRIs and NRIs have been recently introduced, they are not yet common place, although they are equally well tolerated, or even better, than SSRIs depending on the severity of the depression. This is due to an increased understanding of neuronal circuitry, realizing that serotonin is not the only biogenic monoamine involved in depression. Although it has been known since the early 60's that noradrenaline is also involved in the action of tricyclics, developing agents that do not promote hypertension has been a barrier to the successful introduction of newer agents, which do not possess the undesirable post synaptic receptor binding profile of the older compounds. Although dopamine is well known to be implicated in anhedonia and other core symptoms of depression, direct targeting of the DAT is not yet a widely practiced strategy, due to its direct link to drugs of abuse. However, in combination with NE and 5-HT, DA is well suited to novel antidepressant drug design protocols, as evidenced by a number of triple reuptake inhibitors being persued either in academia or active programs in the industry.

The role of catecholamines, and also GABA, in depression (DJ Nutt, et al. 2006).

Depression Theory
(Dranovsky and Hen, 2006), (Nestler and Carlezon, 2006), (Duman and Monteggia, 2006).

During the 1990's with the SSRI marketing boom, it was common knowledge that serotonin is implicated in depressive illness. In laymans terms depression has been ascribed to 'not enough serotonin' in the brain. This is an oversimplified picture although it is not without merit. For example, it has been demonstrated that since L-tryptophan is the biochemical precursor to endogenous serotonin, starving the diet of this amino acid can produce a depressive like state. The other two common monoamines are noradrenaline and dopamine. These are also part of the monoamine theory of depression, particularly where loss of motivational drive an anhedonia are prevalent, two cardinal symptoms of depression. While increasing the synaptic availability of monoamines by drugs is the target from a medicinal chemists perspective, there is still something to be said about the biological psychiatry of the illness.

The hippocampi are solidly established to play a critical role in learning, memory and cognitive function. The circuitry of this brain region is also closely linked up to the amygdala and prefrontal cortex, two other areas associated with similar functions. In addition the hippocampi have control over the release of and inhibition of (in a negative feedback loop) secretion of corticotropin releasing factor (CRF) from the hypothalamus. So, in a sense, it is believed that the hippocampi occupy a central position in this part of the brain circuitry, which is most strongly associated with mood disorders. As we will see in the next two subsections, both stress and depression decrease neurogenesis in the hippocampi, and chemical antidepressants and psychosocial stress management serve to counteract this negative effect. Furthermore, both a dysfunctional HPA axis and neurotrophic factors are believed to play an active role in the mechanism of how this occurs.

Also notable is the fact that 5-HT1A receptors should be stimulated to encourage neurogenesis. It was also found that in 5-HT1A knockout rodents, the actions of antidepressants did not reach manifest. This is an interesting finding in light of the fact that antagonizing the 5HT1A autoreceptor is a tactic that is being employed by a host of drug companies and considerable effort has gone into this domain as will become apparent in later subsections. It was also postulated that 5HT2C receptors should be antagonized although this was dependent to a degree on the brain region that was being examined. It should also be borne in mind that both 5-HT2C antagonists and 5-HT1A agonists have anxiolytic effects. This helps to explain why some SSRIs are used as a non-addictive alternative to GABAergic compounds, which has helped boost their sales due to the increased number of indications that they can be prescribed for. However, not all SSRIs are anxiolytic, and in certain tests that model anxiety like symptoms which are frequently employed when screening potential utility among antidepressants, benzodiazepams are believed to be more reliable than SSRIs. There is interaction between serotonergic neurons and GABAergic neurons. This reinforces a pattern that there is overlapping "cross talk" between neuronal circuitry and that these systems are not working in isolation. It also emphasizes that there are two distinct ways that neuronal pathways can be activated: indirectly in a subtle "milieu" type of interaction, or by initiating more direct contact with the appropriate receptors.

It has been hypothesized that although the actions of SSRIs work immediately the several weeks required reflect the changes in structural and cellular neuroplasticity. This only occurs after chronic treatment and is thought to reflect an upregulation in neurogenesis, cell survival, maturation and strengthening/rewiring of synaptic connectivity and the like. Thus these plastic changes only occur after a chronic period and are not representative of the actions that occur during the acute phase after initiating treatment. Thus it is very important that the patient continues to take their medication even if it does not seem like it is working.

VTA-NAc Circuitry
While the VTA-NAc circuit has been widely studied in the context of addiction, reward and schizophrenia, the role that it plays in depression is still in a developmental stage. In part this is to do with the fact that the hippocampus and prefrontal cortex have received much more attention in antidepressant programs. The monoamines 5-HT and NA have also received much more attention than dopamine and DA has been quite neglected with regard to its utility in the design of antidepressant agents. The marketed antidepressants nomifensine, bupropion and amineptine all have dopaminergic activity, although the latter was withdrawn due to its perceived abuse potential. However, selegiline has recently been approved for use in depression, which serves to further validify the input of dopamine in the design of antidepressant drugs.

CREB activity in the NAc is something that is worth discussing. Increased CREB activity in the NAc induces a depression like state and a dampening of response. For example, it increases the latency period in shock-escape procedures, and also makes rewarding stimuli less rewarding. On the contrary, decreased CREB activity in the NAc has antidepressant like effects and increases the sensitivity to rewarding stimuli. Although decreased CREB activity in the NAc such as is induced by social isolation increases emotional responsiveness, severe reductions in CREB activity are associated with anxiety like states.

HPA Axis
A dysfunctional hypothalamic pituitary adrenal axis is found in a high percentage of depressed patients. Both stress and depression cause the hippocampus to control the release of corticotropin releasing factor (CRF) from the hypothalamus. This then stimulates the anterior pituitary to secrete adrenocorticotopin hormone (ACTH), which then causes the adrenal glands to release glucocorticoids into the bloodstream. These have wide ranging effects on the body, although in the brain the effect of this is believed to be decreased neurogenesis and neuronal atrophy particularly in the subgranular and ventricular zones of the hippocampi. In humans it is believed that only the subgranular zone (SGZ) undergoes neurogenesis (birth of new neurons), although in rodents the subventricular zone (SVZ) is also involved. The fact that neurogenesis even occurs at all was strongly rejected by the scientific community for many years. In humans neurogenesis was proven when bromodeoxyuridine (BrdU) was administered to cancer patients to monitor tumor progression. Incorporation of this into specific brain regions of the hippocampi at postmortem thereby confirmed that new cells are continually added to this brain structures.

SSRIs can reverse this effect in the subgranular but not the subventricular zone. Furthermore SNRIs could also achieve this in SERT knockout mice, suggestive that noradrenaline can also achieve the same effect. Conversely DA could reverse this effect in the subventricular zone, respectively.

Neurotrophic Factors
Brain derived neurotrophic factor (BDNF) is known to play a postive role in the modulation of mood disorders. Whereas the HPA axis is endocrine based, neurotrophic factors are mediated by different systems to hormones. These are small protein molecules produced in vivo that cannot be directly administered to a patient because they have poor BBB penetration and in any event they are not easily synthesizable. Other factors of relevence include vascular endothelial growth factor (VEGF), insulin growth factor (IGF), nerve growth factor (NGF) etc.

BDNF is known to affect cell proliferation and survival positively. Depressed and stressed animal models have a decreased abundance of BDNF in the hippocampus that is consistent with neuronal atrophy. Likewise, antidepressant treatment, either chemically induced or environmentally based, stimulates BDNF production and has positive outcomes in the management of these disorders. Other growth factors also have similar effects that work in a different way but which correlates with the action of BDNF. For this reason it is difficult to single out BDNF as the only factor responsible for these changes.

Preclinical Depression Tests
There are four main tests that we will consider. The forced swim test (FST) involves placing a rodent in a beaker of water. Clinical experience has demonstrated that a depressed animal that is responding postively to an antidepressant will show increased activity in this test relative to an animal that was administered placebo. The next test involves hanging a rodent by its tail and is called the tail suspension test (TST). Although the outcomes of this test are very similar to the FST, apparently there is some differences in the results that are typically obtained. This means that both of these tests have clinical utility. The next major test is called learned helplessness (LH). In this test the rodent is placed in an inescapable cage and is then subjected to a series of unpleasant electric shocks. An escape route is then facilitated and the time it takes for the animal to escape from the cage is seen as a measure of the antidepressant efficacy. The fourth and last of the main tests is called 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.

Therapeutic Lag
(Moltzen and Bang-Andersen, 2006), (A. Adell, et al. 2005), (Skolnick and Basile, 2007).

The slow onset of SSRIs is viewed as an unacceptable aspect of these compounds. This waiting period has been reported to be in the time frame of several weeks delay following the start of the treatment regimen. It is hypothesized that while SERT inhibition starts immediately after a single dose of an SSRI presynaptic 5HT1A and terminal dendritic 5HT1B autoreceptors respond to this by inhibiting the firing rate of serotonergic neurons, and reducing synthesis and terminal release of serotonin. Support for this hypothesis comes from the fact that selective 5HT1A receptor antagonists serve to raise extracellular 5-HT in the synaptic cleft. Results with pindolol have left something to be desired, although this strategy has been used to make add-on molecules. This concept entails hybridizing known SSRIs and 5-HT1A antagonists together into a single molecule. Such compounds show 4-6 x basal levels of extracellular 5-HT after only a single treatment and have the desired immediate onset of action. This is in view of the belief that the several weeks usually required reflects the time taken for these autoreceptors to desensitize.

5-HT 2A/2C receptors are also the target of improving upon the shortcomings of conventional SSRIs. Because these receptors are reasonably homologous, compounds displaying activity at one sub-type are likely to also display activity at the other, and vice versa. This has meant that antipsychotics such as olanzapine and the atypical antidepressant compound mirtazepine which have antagonist activity at these receptors, have been shown to augment SSRI monotherapy.

There is also various evidence that seems to acknowledge that the so-called dual reuptake inhibitors or SNRIs have a more rapid onset of action than SSRIs. With drugs that have a norepinephrine component, α2 adrenoreceptor antagonism can influence the therapeutic lag in a similar fashion as has already been mentioned above for SSRIs.

One last theory worth mentioning is that the time lag might reflect adaptive reconnections in neuronal circuitry that indirectly modulate mesocorticoaccumbens DA release. While this is indeed a possiblity, this theory is not wide-spread.

Efficacy
(George Papakostas, 2006), (Ennio Esposito, 2006), (Bubar and Cunningham, 2006),

Tricyclics and MAOIs were both serendiptiously discovered to possess antidepressant activity when they were introduced in the 1950's. These drugs possess several limiting side effects that curtail their usage. Importantly, it was found that they inhibit the reuptake of monoamines, leading to the monoamine theory of depression, which still occupies a central position of drug design in this area. Although this theory does not necessarily account for the neurobiological basis of depression, which is still an evolving research avenue, it still adequately armours chemists with the knowledge needed to design novel drug molecules effectively. The fact that these drugs are still prescribed despite their inherent safety limitations dictates that the SSRIs are not an optimized treatment method. Evidence has also suggested that SNRIs and NESRIs can also be used, and may even be superior to SSRIs. All this serves to highlight the need for introduction of antidepressants with a less biased, more balanced mode of action, to optimize patient response rates. Quantitatively, only 50% of patients experience full remission with SSRIs and several of these will still incur rebound depression afterwards. Chronic and/or treatment resistant patients are also less likely to respond to SSRIs than the drug naive.

Recent work has suggested that DARIs have antidepressant properties in their own right, and need not be combined with 5-HT and NE components in order to demonstrate efficacy. However, it can be argued that a drug combining all three of these factors together is the most balanced way to treat depression, in general, as oppose to targetting specific sub populations. This is not yet completely proven, although several lines of evidence have suggested that this is the direction in which the "monoamine theory of depression" is heading. Thus, introduction of a novel agent that can fulfil this criteria will benefit an unmet need in this important field.

Actions with more selective ligands has shown that 5-HT2 A/C receptors have "oppositional" effects on DA release, and rates of firing, in the VTA/NAc/PFC. 5-HT2A receptors should be agonised, while 5-HT2C receptors should be antagonised. In this sense, it is possible to modulate DA release indirectly, through serotonergic pathways. The role that these receptors play in mediating anxiety/anxiolytic properties must also be clarified. For example, compounds displaying 5-HT2C agonism tend to function as panicogens, whereas GABAergic compounds are well known anxiolytics.

Side Effects
SSRI drugs occupy an abnormally high SERT occupancy relative to the other transporters. Such a clean drug might be thought to possess relatively few side-effects. It must be conceeded that SSRIs are relatively safe drugs, in that overdoses do not usually result in death, and drug interactions are reasonably well tolerated. However, SSRIs do have a number of non-dangerous side effects that limit their desirability and therapeutic potential. Common side effects include acute anxiety, jitteryness, nausea, and sexual dysfunction is also frequently reported with this class of medication. In fact, a very common side effect of SSRIs that does not necessarily resolve with time is drowsyness, fatigue, sleepyness and the like. This may not necessarily be seen as a problematic feature when treating severly anxious or distressed patients, however it can be argued that a sedative is better suited to this type of condition than an antidepressant, at least in the short-term until the patient has been stabilized. The fact that a number of these side effects can be corrected with bupropion or mitazapine augmentation further presses the case for inclusion of a catecholamine component into antidepressant based therapies. Upon incorporating the catecholamine component, it is necessary to ensure that the medicine does not exert hypertension from elevated BP. This is an obvious concern with these types of drugs, although it is more of an issue with psychostimulants than drugs that fit into the 'antidepressant' bracket, even though such a distinction is not always clear-cut. Clearly, since all mood altering drugs can affect appetite, appropriate selections need to be made when considering the BMI of the depressed patient. It may also be pertinent to assess the likelyhood that a given drug is probable to induce self-harming and/or homo-/sui-cidal tendancies relative to placebo controls. Many antidepressants have been used as a scapegoat for this type of behavior in the past, and has even resulted in costly law suits resulting in company losses etc.

Serotonin promotes release of prolactin, while DA inhibits release of this hormone. Thus, elevation of prolactin levels can be seen with drugs which potently block the serotonin transporter (Amsterdam, et al. 1997), (Egberts et al. 1997).

Interactions with the Cyp450 liver enzymes, are a problem with some of the SSRIs. In particular, Cyp450 2D6 enzyme inhibitions reported with prozac and paroxetine. To minimize the effects of drug-drug interactions calls for careful management, to avoid serotonin syndrome. Sexual dysfunction,<> insomnia and nausea are also reported to be adverse effects of SSRI therapy.<>

Socioeconomic Factors
The economic cost of depression in Europe was estimated at €118 billion in 2004, or €253 per inhabitant (Soboki, et al. 2006).

Depression costs the US economy $80 billion / year, mostly due to lost workplace productivity (Greenberg, et al. 2003). Public Health Burden of Depression Risk of death from unnatural causes is especially high for the functional disorders, particularly schizophrenia and major depression (Harris and Barraclough, 1998). Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated in patients with CVD. This is of particular importance because several studies have shown depression and its associated symptoms to be a major risk factor for both the development of CVD and death after an index myocardial infarction (Musselman, et al. 1998). Depression has long had a popular link to CVD and death. However, only during the last 15 years has scientific evidence supporting this common wisdom been available (Glassman, 2007). The persistent activation of the hypothalamic-pituitary-adrenal (HPA) axis in the chronic stress response and in depression probably impairs the immune response and contributes to the development and progression of some types of cancer (Reiche, et al. 1998). Major depression and depressive symptoms, although commonly encountered in patients with medical illnesses, are frequently underdiagnosed and undertreated in women with breast cancer. Depression and its associated symptoms diminish quality of life, adversely affect compliance with medical therapies, and reduce survival. Treatment of depression in women with breast cancer improves their dysphoria and other depressive symptoms, enhances quality of life, and may increase longevity (Somerset, et al. 2004). Persons with major depression are more likely to smoke and to have difficulty when they try to stop. When they manage to succeed in stopping, such persons are at increased risk of experiencing mild to severe states of depression, including full blown major depression (Covey, et al. 1998).

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.).

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.

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). Infact, this was the group that first coined the name "SNDRI" when referring to these compounds (P. Carlier, et al. 1998).

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 Rx MA reuptake inhibitors, e.g. duloxetine, paroxetine, fluoxetine, atomoxetine, & reboxetine.



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.

Conclusion
Thus, the 'medication' should occupy all three of the monoamine transporters ≈ equally, so that the full-spectrum of mood elevating effects can reach manifest, without causing unwanted side effects. If an artist were planning a painting, the likelyhood is that they would find the experience more enriching/rewarding, if they were equipped with the full range of colors, comparing to just sketching in charcoal. The picture shown is illustrative of such a painting. The gray color is supposed to convey a mixture of all three monoamines working in combination; heliotrope is representative of a catecholamine selective drug; orange is for an SNRI, and bogey green is for SDRIs (unreported). http://www.ingentaconnect.com/content/ben/cnsnddt/2007/00000006/00000002/

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.