User:Nuklear/Drugging Strategies

There is a growing awareness among physicians that 5-HT specific agents represent a far from an optimized approach to the treatment of depressive disorders (Zajecka and Albano, 2004). The fact that so many new drugs acting through non-SSRI mechanisms of action are surfacing into the mainstream is strong evidence for this important fact.

SSRIs provided a major improvement to treatments with TCAs and MAOIs. Although the SSRIs cannot be considered more efficious in severe depression than the TCAs, their much improved side effect profile warrents their widespread use (Sonawalla and Fava, 2001). SSRIs have been explored in a wide range of indications, such as panic disorder, GAD, PTSD, social phobia, OCD, eating disorders, premenstrual dysphoric disorder, and a further range of indications are still being explored (Spinks, 2002). The concept of combining 5-HT reuptake inhibition with other pharmacological activities within the treatment of depression has attracted much research attention during the past 15 years. Three different approaches have mainly been adopted: supplementing an SSRI with other pharmacological substances, e.g. bupropion, preparation of molecules with built-in activities at multiple targets, or a combination thereof.

Furthermore, ADs acting through non-monoaminergic pathways are beginning to get recognized. The AMPA receptors for example, as well as non-psychotomimetic NMDA antagonists, e.g. amantadine. Moreover, BDNF is central to a new hypothesis being used to explain antidepressant action (Ronald Duman, 2006). This can be thought to add a level of sophistication that extends beyond the MA theory of depression. For example, the hippocampus in chronically depressed patients is slightly smaller than in healthy volunteers. This etiology of depression is worth investigating further, because it can help account for the fact that different drugs acting on different cellular targets may still converge onto common biochemical pathways. Say for example, kappa antagonists increase DA availability in the NAc, by blocking an autoinhibitory mechanism that runs along the mesolimbic pathway. So while this is acting via a different mechanism to a DARI, the net effect is still more DA and thus can be useful in combatting anhedonia etc. However, this is still MA related, whereas BDNF and the like, are more radical diagnostic tests. This will be discussed in future sections. There is quite alot of talk about CREB activity in different brain regions, and the HPA axis is also important.

Dopamine and Depression
Because mesocorticolimbic DA pathways are involved in physiological functions regarding motivation and reward, this makes them a possible candidate as a neurobiological substrate of the depressive syndrome. A DA impairment in corticolimbic areas leads to anhedonia as well as loss of motivation: two symptoms usually present in depression. Thus a decreased DA turnover has been found in patients with depressive disorder. Particularly evident is the reduction of homovanillic acid concentrations. An additional mechanism causing DA hypofunctioning in major depression is a reduced DA release by dopaminergic nerve terminals, which is evident especially in the mesolimbic system. This reduction in DA release is accompanied by a decrease in the number of presynaptic DA transporters (Nestler and Carlezon, 2006).

Evidence for dopaminergic-system dysregulation in depression is supported by a variety of reports, ranging from 1) studiess of DA and DA metabolite levels, to 2) neuroimaging studies, 3) histopathological studies, and 4) neuroendocrine studies. Specifically, a number of reports suggest not only that depression may be linked to abnormally low DA levels, but also that the severity of depression is inversely correlated to CNS DA metabolite levels. A role for DA deficiency in the pathophysiology of depression is supported by studies demonstrating reduced levels of DA and its metabolite HVA in depressed and/or suicidal patients compared to normal individuals (Mitani, et al. 2006), and reduced DAT activity (Meyer, et al. 2001). receptor binding affinity (Willner, et al. 2005).

Studies of the DAT and DA receptors also suggest dopaminergic dysregulation in MDD. A number of neuroimaging studies suggest that depression is associated with increased D2/D3-receptor binding in the basal ganglia. Therefore, taken together, such preliminary reports of 1) lower or decreased DA or DA metabolite levels, 2) increased D2/D3 receptor binding/sensitivity, and 3) decreased DAT activity and/or suicide, suggest that depression may often be accompanied by a relative hypo-dopaminergic state, such that increased CNS D2/D3 receptor binding reflect a compensatory change secondary to primary low mesolimbic DA levels.

Chronic treatment with antidepressants potentiates the behavioural stimulant responses elicited by the stimulation of dopamine receptors, including reward-related behaviours. Moreover, antidepressants affect dopamine release in several brain areas (D’Aquala, et al. 2000). The relationship between depression and dopamine deficiency in the mesolimbic pathway has been hypothesized for many years. The experimental studies with animal models of depression and the human studies implicate the role of the dopamine system in depression (Dailly, et al. 2004). Therefore, developing effective antidepressant treatments with pro-dopaminergic properties, which also possess a relatively wide safety margin may further improve the standard of care for depression (Papakostas, et al. 2006).

Serotonin Receptors
The 5-HT neurotransmitter system is situated to exert fundamental modulatory influence upon DA neurotransmission within the reward pathway, as 5-HT neurons provide a dense innervation of terminals to the VTA, NAc and PFC. Application of 5-HT or stimulation of the raphe nuclei elicits a heterogenous change in firing rates of VTA DA neurons. The involvement of 5-HT2A and 5-HT2C receptors in the control of mesocorticolimbic and nigrostriatal DA neuron activity is now well established, and evidence has been provided that they exert opposite effects on DA release. (Ennio Esposito, 2006), (Bubar and Cunningham, 2006), (Cremers, et al. 2004).

Several recent studies have focused on the role of 5HT2 receptors in the regulation of forebrain DA function and highlight their potential as a target for improved treatments of neuropsychiatric disorders related to central DA neuron dysfunction. Systematic administration of 5-HT2CR antagonists increased basal firing rates of VTA DA neurons, and increased DA release in the NAc. These results suggest that the 5-HT2CR tonically inhibits DA mesocorticoaccumbens output. Although the 5-HT2AR does not exert tonic influence upon DA neuronal firing or DA release, stimulation of this receptor with an exogenous agonist reveals an enhancement of DA neuronal output.

In view of the hypothesis that disinhibition of the mesolimbic DA system underlies the mechanism of action of several antidepressant drugs, 5HT2C receptor antagonists might exert antidepressant activity. Acute administration of amitriptyline and mianserin, two antidepressants with high affinity for 5-HT2C receptors, enhances DA release in the rat NAc by blocking these receptor subtypes.

Selegiline
Selegiline is now a clinically accepted AD, not just Parkinson's approved. In other words, pure dopamine positively reinforces "executive function", and is endorsed for this purpose (Nestler & Carlezon, 2005). It is important not to confuse it with amphetamine, e.g. rasagiline is an even stronger MAOB incinerator. A cheap drug, its low price is likely to attract potential customers. By disposing of MAOB enzymes, DA is allowed to accumulate in the synapse. Irreversible MAOI inhibitors do have certain drawbacks, although in the absence of a better option, they still have 'something to offer' and can be recommended. It also deserves mention that physical exercise can mediate antidepressant activity. The mild stimulatory properties may therefore exert desirable outcomes, on provision that it does not express unreasonable hypertension etc.

Duloxetine
Duloxetine is a potent SERT/NET inhibitor, that has recently entered the market as an antidepressant (Karpa, et al. 2002), (Bymaster, et al. 2003). Generally, duloxetine is safe and well-tolerated across indications, with few reported serious side effects (Wernicke, et al. 2005). 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.). The S stereochemistry represents an important pharmaceutical application of asymmetric synthesis. Unfortunately enantiopure fluoxetine never made it to market because of cardiovascular limitations.

NESRI Drugs
atomoxetine and reboxetine are the two main NESRI drugs. Reboxetine has been approved for depression whereas atomoxetine is only handed out for ADHD.

NESRI = Noradrenaline selective apparently, not noradrenaline + serotonin

NARI might be more to the point

NET reuptake inhibition was very much part of the profile of the TCAs, and the antidepressant effect of elevating NE levels in the brain has long been realized (Brunello, et al. 2002). The NET effect is mainly associated with improvement in the anhedonic and melancholic features of depression as well as higher remission rates. The antidepressant effect of selective NET uptake inhibition is supported by the NET selective Reboxetine which is on the market and displays clinical efficacy, particularly in MDD (Lambert and Bourin, 2002).

Bupropion
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 (Zisook, et al. 2006).

5HT1A/SSRI Augmentation
After Artigas' original study with pindolol and the subsequent theory regarding presynaptic down-regulation of 5HT1A autoreceptors in accounting for the therapeutic lag of SSRIs, it has subsequently been popular strategy to target the 5-HT1A receptor in drug design programs. Particularly notable, is getting candidate drug molecules with SSRI and 5-HT1A antagonist activity both into the same molecule. This has been proven to boost 5-HT extracellular output although none of these approaches have reached the market to date.

5HT2/SSRI Augmentation
Fluoxetine/olanzapine has been patented (Symbiax) for treating refractory depression, particularly in bipolar patients. Although olazapine is an antipsychotic, the augmentation part comes from antagonism at the 5HT2 receptors. In particular, it is known to have antagonist action at the 5HT2A receptor, which is believed to raise extracellular DA levels when taken in conjunction with an SSRI. The R isomer of fluoxetine already has 5HT2 receptor activity, although fluoxetine used alone is not as effective as when used in combination therapy.

Mirtazepine is a good example, although it is important that the combination choice is made appropriately. Mirtazapine has mixed 2A/2C antagonism and is also known to block the α2 adreno-receptor, which is known to augment norepinephrine output.

5HT2C/SSRI Augmentation
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.

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 strategies of such strategies are needed.