User:Nuklear/Drugging Strategies
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[edit] Introduction
In contrast to the SNDRI document, which primarily is orientated at conflation, this document is instead directed at illustrating which combination strategies yield a particularly robust augmentation in the clinical response. While some people may argue against drug cocktails in favor of taking a single drug, drug cocktails are still widely practiced strategy with the goal of supplanting the inadequacies in the efficacy of the first medication. Moreover, they can provide proof-of-concept before embarking on a lengthy and costly campaign to elucidate the QSAR information of agents possessing a dual, or even a triple, mode of activity.
[edit] Serotonin Related
Given that with the introduction of the SSRIs, most antidepressants are either solely serotonergic or at least possess a 5-HTergic component in their mode of activity. For this reason, the combination strategies document starts by considering 5-HTergic based augmentation strategies.
[edit] 5HT1A/SSRI Augmentation
Following on from Artigas' original study with pindolol and the subsequent theory regarding presynaptic down-regulation of 5HT1A autoreceptors in accounting for the therapeutic lag of SSRIs, biotech companies have extensively tried to envelope these receptors into the target list of their drug design programs. Of particular mention is pharmacological conflation of SERT reuptake blockade and 5-HT1A antagonism into a single molecule. This strategy is proven to bolster extracellular 5-HT output, although it has not yet reached the market to date.
Inhibiting 5-HT1A receptors is also controversial inlight of the fact that these are reported to be needed to mediate neurogenesis. Although the importance of neurogenesis in antidepressant response is controversial, this is still a somewhat conflicting finding. 5-HT1A receptors are located both pre- and post-synaptically, however, finding an antagonist that can differentiate between the two, may prove unfeasible. Also note that buspirone is a 5-HT1A agonist, demonstrating that this receptor has anxiolytic properties. Gepirone is another partial 5-HT1A agonist that has demonstrated clinical efficacy.
The major metabolite of buspirone also contributes to its in vivo bioactivity; 1-pyrimidinyl-piperazine is a relatively potent α2 adrenergic antagonist. Selective 5-HT1A agonists may be able to potentiate cortical release of catecholamines in their own right, although their direct actions on 5-HT autoreceptors will abrogate SSRI induced elevations of endogenous 5-HT. None of the selective 5-HT1A agonists are used in monotherapy –they are always used in conjunction with another medicine.
5-HT1A agonists are anxiolytic.
[edit] SSRIs + Antipsychotics
The combination of fluoxetine/olanzapine (Symbiax) has been patented for treating refractory depression, particularly in bipolar patients. Although olazapine is an antipsychotic, it has known antagonist actions at the 5HT2 receptors which are thought to be inhibitory to mesocorticolimbic catecholaminergic neurotransmission. This effect is augmented via the concomitant administration of an SSRI.
In the case of fluoxetine, the (R)-isomer already has built-in 5-HT2 receptor antagonist affinty, however this effect is too light for it to be stastically important. Hence, augmentation is still necessary.
Mirtazapine is tetracyclic AD which can also be used combination with SSRIs if the selection choice is made appropriately. Mirtazapine has mixed 2A/2C receptor antagonist activity and is also known to block α2-adrenoreceptors, which is known to augment norepinephrine output. Since adrenergic receptors greatly outnumber dopaminergic receptors in mesocorticolimbic areas, enhanced DA output is also mediated via α2-adrenoreceptor blockade.
However, even the atypical antipsychotics are not without their side effects. Some of these combinations might be thought to offer a low-tech & dirty approximation for a mixed 5-HT/NA/DA therapy, providing proof-of-concept. Newer agents are needed that do not possess the undesirable antihistaminergic effects of mirtazapine.
Also, while these agents increase dopaminergic output in the frontal cortex as use in polytherapies, VTA-NAc dopamine overflow is not seen. VTA-NAc DA overflow is needed for producing the feeling of enjoyment.
Other antipsychotics where this effect is seen in conjunction with antidepressants include risperidal, quetiapine and sulpiride but not haloperidol. In the case of sulpiride, antagonist actions at presynaptic D2 autoreceptors are solely responsible since this agent does not have marked affinity for 5-HT2 receptors or α2-adrenergic autoreceptors. In the case of haloperidol –devoid of affinity for D2 autoreceptors– post-synaptic D2 receptor blockade is unlikely to improve affect and may even cause a worsening in symtomatology in non-psychotic patients, particularly at higher doses.
[edit] 5HT2C/SSRI Augmentation
(Ennio Esposito, 2006),[1] (Giuseppe Di Giovanni, et al. 2006)
Antagonists for the 5-HT2C receptor are believed to possess anxiolytic properties, whereas there is some evidence that 5-HT2C agonists can augment antidepressant activity. A number of compounds with potent SSRI/5-HT2C activity have been patented, indicating the importance of the 5-HT2C receptor.
Paradoxically, both 5-HT2C agonists and antagonists can effect downregulation of this receptor. It is hypothesized that this might reflect an over-sensitization of this receptor in depressives.
5-HT2C receptor antagonists also augment serotonergic output as well as disinhibit dopaminergic transmission steming from VTA projections.
Due to the fact that 5-HT2A agonists disinhibit dopaminergic neurotransmission and 5-HT2C agonists have the reverse effect, the following hypothesis by Esposito may be feasible:
An SSRI in combination with a 5-HT2C antagonist is known to cause robust elevations in synaptic 5-HT. The VTA projections will not be inhibited if 5-HT2C receptors are blocked. Furthermore, the excess 5-HT can bind 5-HT2A receptors which will actually facilitate dopaminergic output. Such a dual effect is would be quite powerful although it has not yet been investigated at the clinical level.
[edit] 5-HT4 Agonists
(R. Duman, 2007),[2] (Lucas, et al. 2007).[3]
It has recently been shown that two 5-HT4 agonists are behaviorally similar to conventional SSRIs except for the fact that they by-pass the therapeutic lag. The two agonists are raclopride and RS6333. These agents were both effective in the FST except raclopride also produced LMA and was therefore censored from screening in the subsequent tests of this study.
RS6333 showed increases in phosphorylated CREB (pCREB), enhanced neurogenesis in the dentate gyrus, counteracted CMS reductions in sucrose consumption etc. And all this was evident after only three days! Thus, 5-HT4 agonists are close to 10 x more rapid in onset than SSRIs.
A possible explanation for the delay of conventional SSRIs is the inhbitory effect of presynaptically located 5-HT1A receptors which dampen 5-HT release. The downregulation of these receptors has been postulated to account for the lag that preceeds the mood elevating benefits of SSRIs.
ALthough SSRIs are selective in as far as their specificity for the 5-HT reuptake transporter, their mode of action serves to increase synaptic concentrations of 5-HT which then non-selectively bind to post-synaptic 5-HT receptor sites. Thus, understanding more about the role of each of the individual 5-HT receptors may go some way to 'decoding' which of the 5-HT receptors mediate the behavioral actions of SSRIs that are thought to be beneficial.
One potential drawback of 5-HT4 agonists is that the 5-HT4 receptor is also located periphially and is not specific to the CNS. Therefore the possiblity for unintended side effects is something that can not yet be ruled out.
[edit] Bupropion/SSRI Augmentation (Zisook, et al. 2006)[4]
Bupropion is an AD with novel neurotransmitter properties, that seems to augment SSRI or SNRI effectiveness and/or help relieve or reverse certain adverse events associated with these agents. The mechanism of action of bupropion has not been fully elucidated, although it appears to primarily block the reuptake of DA/NE. A dose of 150-300mg bupropion ≈ 5-10mg methyphenidate. Regardless of the exact mechanism, the overall effect of bupropion appears to be a dose dependent increase in brain extracellular DA/NE concentrations. Bupropion also appears to non-competitively inhibit the α3β2-, α3β4-, and α4β2 nicotinic acetylcholinergic receptors in vitro.
Bupropion is equally as effective in treating depressive symptoms regardless of the degree of anxiety and insomnia present at baseline. As a result, bupropion is often used as a first-line treatment for major depression, but also as an adjunct to the SSRIs in SSRI-resistent depression, or as an adjunct to alleviate SSRI-associated sexual dysfunction. In addition, due to its dual dopaminergic and noradrenergic activity, preliminary evidence suggests bupropion may be particularly effective in the treatment of certain symptoms of depression, including cognitive disturbance and fatigue.
A recent, pooled analysis of double-blind, randomized clincal trials comparing bupropion with an SSRI for MDD revealed a greater resolution of symptoms fatigue and sleepiness during bupropion- than SSRI-treatment. Other advantages of treatment with bupropion compared to the SSRIs is the lower risk of sexual dysfunction and GI side effects than the SSRIs. Furthermore, bupropion-treated MDD patients appear more likely to experience weight loss during the acute phase of treatment than placebo treated patients, while treatment of obesity with bupropion was reported to be more effective than placebo in two separate double blind studies.
In summary, bupropion/SSRI augmentation is relatively well tolerated without significant risk of increased side effects relative to monotherapy or placebo. Seizures with this drug combination are relatively rare but may occur at high dosages.
[edit] Duloxetine
Duloxetine is a potent SERT/NET inhibitor, that has recently entered the market as an antidepressant: Karpa, et al. (2002)
Generally, duloxetine is safe and well-tolerated across indications, with few reported serious side effects (Wernicke, et al. 2005).[5] The success of SERT/NET inhbitiors has initiated an increased activity to find new derivatives. The Lilly group has published further SAR efforts around duloxetine resulting in two related structures showing potent SERT/NET inhibition (J. Boot, et al.).[6][7]
The S stereochemistry represents an important pharmaceutical application of asymmetric synthesis. Unfortunately enantiopure fluoxetine never made it to market because of cardiovascular limitations.
[edit] Noradrenergic Strategies
The selective noradrenaline reuptake inhibitor (NERI) reboxetine is approved in many countries world-wide (although not by the FDA) for the management of depression. Additionally, atomoxetine is FDA approved for the treatment of ADHD, an indication for which for which methylphenidate is also prescribed. Both SSRIs and NERIs bind to their respective monoamine transporter pumps in a selective fashion. However, the resulting elevations in endogenous monoamines that ensues have the freedom to interact nonselectively with pre- and post-synaptic monoamine receptor subtypes. In the case of SSRIs, there are 14 subtypes of receptor that serotonin (5-HT) can bind to, whereas there are 9 subtypes of noradrenaline receptor in the case of NERIs.
Moreover, in some areas of the brain such as the prefrontal cortex where DATs are low in number, DA is instead reabsorbed into presynaptic neurons via NA transporters. There are further examples of these non-specific types of interaction. In summary, on the molecular, cellular and systems level, there is high connectivity and interaction within CNS circuitry. It is correct to compartmentalize the individual components into discrete packages, but it is still naїve to regard them as working in isolation. Recently, an analogy was made between the CNS and the world-wide web.
Venlafaxine is a marketed SNRI although in vitro its NET affinity is not particularly marked relative to the SERT. However, in vivo (particularly at higher doses), venlafaxine appreciably increases synaptic noradrenaline output, as monitored by microdialysis. The reasons for this could be manifold or alternatively there may be a simple explanation. In any case, this observation serves to underscore the point made in the above paragraph.
Stimulating β-adrenergic receptors increases cognitive function whereas α-adrenergic receptors have the opposite effect. For example, propranolol is a β-adrenergic antagonist being explored for use in the treatment of post traumatic stress disorder (PTSD) because it disrupts mnemonic function. [MDMA was also being considered for treatment of PTSD but thats immaterial here.] Likewise, the α-adrenergic agonist clonidine, whilst useful in counteracting the physical aspects of opioid withdrawal, is also known to worsen cognitive function. The utility of β-adrenergic agonists in ameliorating cognitive deficits is cautioned on by their propensity to cause hypertension. Note that β- and α-adrenergic receptors are postively/negatively coupled though G-protein coupled receptors (GPCRs) to adenylyl cyclase (AC) and hence the cAMP cascade.
[edit] α2 Autoreceptors
Out of all of the adrenergic receptors, the α2 autoreceptor is perhaps most interesting. Autoreceptors are usually located presynaptically where they are tonically activated to function as a molecular rheostat preventing the unabated release of monoamines into the synapse. It is also possible that they might upregulate transporter clearance of endogenous monoamines. Whatever the case, it can be seen that their activation decreases neurotransmission. It is like with a thermostat, once the desired temperature is reached, further application of heat is temporarily halted. Hence, autoreceptors provide a compensatory form of homeostasis. It can thus be argued that autoreceptors in mood disorder subjects are pathologically oversensitive. Proof of validity for this comes from the finding that autoreceptors are downregulated –and hence desensitized– upon chronic application of various classes of antidepressant.
In a manner similar to what has already been discussed for 5-HT1A autoreceptors, the inactivation of autoreceptors is more directly accomplished via application of an exogenous antagonist. Consonantly, the effects of autoreceptor blockade are much more pronounced if they are co-administered with an appropriate choice of monoamine transporter inhibitor. It is even more desirable if the conflation of all these phamacologic properties can be condensed into a single molecule.
In contrast to 5-HT1A autoreceptors, α2 autoreceptors are particularly interesting in that antagonizing their negative feedback not only augments noradrenergic output — extracellular DA, 5-HT, histamine and acetylcholine concentrations are also elevated.
Yohimbine is a natural α2 adrenergic antagonist. Such agents in polytherapy with various classes of monoamine reuptake inhibitors can augment frontocortical release of NA, DA and acetylcholine, respectively. These agents therefore possess the ability to ameliorate cognitive performance found in certain dementias. In that a difficulty in concentrating is known to contrive one of the key symptoms involved in depression, a relatively clean SNRI also comrpsising an α2 adrenergic antagonist profile was recently reported by Servier.
[edit] Dopamine and Depression
(Papakostas, et al. 2006)[8] (Ari Gershon, et al. 2007)[9]
Agents targeting dopaminergic transmission has largely been overlooked in the treatment of depression, although they have been employed with some success in other neurological disorders such as Parkinsons, ADHD and substance abuse treatments.
The nigrostriatal dopaminergic system has been studied extensively because its degeneration is strongly correlated with the symptomatology and etiology of movement disorders and hence Parkinson's disease. On the other hand, the mesolimbic and mesocortical dopaminergic pathways are strongly correlated with affective syndromes. More specifically the dopaminergic projections that extend from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and the prefrontal cortex (PFC) have received most attention in this regard.
Given the role of dopamine in modulating hedonic function and its importance to motivation, attention and reward mediated behavior it would be foolish not to give its study serious consideration in the treatment of affective disorders. Drugs like bromocriptine, pramipexole and pergolide are DAR agonists.
The marketed antidepressants nomifensine, bupropion and amineptine all have dopaminergic activity. Nomifensine was withdrawn because it causes hemolytic anemia, only amineptine was perceived to have abuse potential, although this also caused side effects such as severe acne at higher dosags. Selegiline has recently been approved for use in depression, which serves to further validify the input of dopamine in the design of antidepressant drugs.
Evidence has indicated that dopaminergic agents are useful in alleviating depressive behaviors in their own right and do not need 5-HT/NA input in order to demonstrate clinical efficacy.
Patients with depression have been shown in neuroimaging studies to have decreased concentrations of homovanillic acid (HVA), the main endogenous metabolite of DA.
D2 receptors are actually downregulated in depressed subjects. This is actually the opposite of what would be expected, in that if there is decreased dopaminergic neurotransmission in depressed subjects then a corresponding upregulation of D2 receptors would be expected as a compensatory type of measure. Treatment with various classes of antidepressant increases the sensitization of D2 receptors. This effect is not observed the in acute actions of antidepressant drugs and only manifests itself after a chronic period of treatment. Inasmuch as all currently marketed antidepressants require an induction period of several weeks, a drug directly modulating dopaminergic activity might therefore yield a more rapid relief of the depressed symptomatology.
Further evidence comes from the finding that drugs which either block dopamine receptors (DRs) or drugs that interfere with the synthesis of dopamine, are also known to induce depression. In addition, a hypodopaminergic state occurs upon withdrawal of amphetamine (a drug of abuse), which also induces depression. Combined this is provides further proof of validity for the role of dopamine in depression.
[edit] Conclusions
In summary, depression is a highly prevalent, serious, and often chronic and/or recurring illness. The goals of treatment are to bring the person to full symptomatic and functional recovery and also to keep the recovered person from developing another episode. To do this, clinicians often need treatment strategies that go beyond monotherapy, both to maximize the chances of remission and to minimize the burden of persistent side effects. The combination of bupropion and SSRIs or SNRIs is one such strategy. The combination often seems to improve efficacy, reduce AD-associated sexual side effects, and is generally well tolerated. Additional randomized, controlled trials studying the safety, effectiveness, and optimal dosing of such strategies are needed.
[edit] References
- ^ [1]Esposito, et al. (2006) Serotonin-Dopamine Interaction as a Focus of Novel Antidepressant Drugs. Current Drug Targets, Volume 7, Number 2, pp. 177-185(9).
- ^ [2]Duman RS. A silver bullet for the treatment of depression? Neuron. 2007 Sep 6;55(5):679-81.
- ^ [3]Lucas, et al. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron. 2007 Sep 6;55(5):712-25.
- ^ [4]Zisook, et al. (2006) Use of Bupropion in Combination with Serotonin Reuptake Inhibitors. Biological Psychiatry, Volume 59, Issue 3, 1 February 2006, Pages 203-210.
- ^ [5]Wernicke, et al. (2005) Safety and adverse event profile of duloxetine. Expert Opinion on Drug Safety, Vol. 4, No. 6, Pages 987-993.
- ^ [6]Boot, et al. (2004) Benzothienyloxy phenylpropanamines, novel dual inhibitors of serotonin and norepinephrine reuptake. Bioorganic & Medicinal Chemistry Letters, Volume 14, Issue 21, Pages 5395-5399.
- ^ [7]Boot, et al. (2006) N-Alkyl-N-arylmethylpiperidin-4-amines: Novel dual inhibitors of serotonin and norepinephrine reuptake. Bioorganic & Medicinal Chemistry Letters, Volume 16, Issue 10, Pages 2714-2718.
- ^ [8]Papakostas, George (2006) Dopaminergic-based pharmacotherapies for depression. European Neuropsychopharmacology, Volume 16, Issue 6, Pages 391-402.
- ^ [9]Dopamine D2-Like Receptors and the Antidepressant Response. Biological Psychiatry, Volume 61, Issue 2, 15 January 2007, Pages 145-153. Ari A. Gershon, Tali Vishne and Leon Grunhaus
