Antidepressants mechanisms of action

The catecholamine hypothesis was then modified to include 5-HT in the etiology of depression (9,10). It should be noted, however, that not all Inhibitors of monoamine reuptake are antidepressants, because cocaine, a potent inhibitor of NE and dopamine reuptake, is not an antidepressant but, rather, an addictive stimulant. Subsequent studies with inhibitors of monoamine biosynthesis appear to confirm Kielholz s opinion and Schiidkraut s modified theory that clinical depression is the result of a deficiency in both 5-HT and NE and that the antidepressive mechanism of action most likely affects levels of both. 

Maprotiline exhibits the highest affinity and selectivity for the NE transporter (Fig. 21.6). Its antidepressant mechanism of action is similar to that of desipramine, with an onset of action of up to 2 to 3 weeks. 

Of these, the low level of SERTs in depressed patients has received the most attention in the development and synthesis of the SSRIs. The precise antidepressant mechanism of action for the SSRIs eludes neuroscientists, but the SSRIs have been shown to alleviate depression and are the most commonly used drugs in the therapy for depression. Claims of decreased adverse effects (adverse drug reactions) and less toxicity in overdose than both the MAOIs and the TCAs, together with increased safety, have led to their extensive use, and several are ranked in the Top 50 prescription drugs dispensed in the United States during the year 2005. 

Clomipramine is different from the other TCAs, exhibiting preferential selectivity for inhibiting the reuptake of 5-HT at the presynaptic neuronal membrane. Its antidepressant mechanism of action as an inhibitor of the 5-HT transporter is reduced in vivo, however, because of the formation of its active metabolite, N-desmethylclomipramine, which inhibits the reuptake of NE. As a result of its common structure with the other TCAs, clomipramine shares the pharmacological and adverse-effect profile of the other TCAs. 

The search for antidepressant test methods, unrelated to the monoamine hypothesis, has become more and more important. In order to find new antidepressant mechanisms of action, new experiments are being devised which either demonstrate the effectiveness of known antidepressants or suggests a relation to the human depressed state. 

Atypical Antidepressants. StmcturaHy diverse dmgs such as the tetracyclic mianserin (46) and various bicyclic and tricyclic compounds such as trazodone (47), venlafaxine (48), nefazodone (49), and amfebutamone (50) are atypical antidepressants. The exact mechanism of action is unclear but probably... 

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

The original monoamine hypothesis of depression states that depressions are associated with a deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines. The hypothesis was articulated in 1966 only after the mechanism of action of the tricyclic antidepressant desipramine and of the psychostimulants... 

The mechanism of action of most of the miscellaneous antidepressants is not clearly understood. Examples of this group of drugs include fluoxetine (Prozac) and bupropion (Wellbutrin). 

Nortriptyline. Nortriptyhne, a tricychc antidepressant, has been shown in double-blind, placebo-controlled randomized trials to be superior to placebo for smoking cessation (Prochazka et al. 1998). Nortriptyline appears to have efficacy comparable to that of bupropion for smoking cessation (Hall et al. 2002). The efficacy of this agent may be improved with more intensive behavioral therapies (Hall et al. 1998). Nortriptyline s mechanism of action is thought to relate to its noradrenergic and serotonergic reuptake blockade, because these two neurotransmitters have been implicated in the neurobiology of nicotine dependence. Side effects of nortiptyline are typical of tricyclic antidepressants and include dry mouth, blurred vision, constipation, and orthostatic hypotension. Nortriptyline appears to have some utility for smokers with a past history of major depression, and it can be recommended as a second-... 

A logical conclusion from this work was that depression is caused by hyperresponsive )S-adrenoceptors. At first, this might seem to undermine Schildkraut s suggestion that depression is caused by a deficit in noradrenergic transmission. However, proliferation of receptors is the normal response to a deficit in transmitter release and so the opposite change, dowmegulation of jS-adrenoceptors by antidepressants, would follow an increase in the concentration of synaptic noradrenaline. This would be consistent with both their proposed mechanism of action and the monoamine theory for depression. 

Vetulani, J, Stawarz, RJ, Dingell, JV and Sulser, F (1976) A possible common mechanism of action of antidepressant treatments. Naunyn-Schmiedeberg s Arch. Pharmacol. 293 109-114. 

Each antidepressant has a response rate of approximately 60% to 80%, and no antidepressant medication or class has been reliably shown to be more efficacious than another 22 MAOIs may be the most effective therapy for atypical depression, but MAOI use continues to wane because of problematic adverse effects, dietary restrictions, and possibility of fatal drug interactions.22,28 There is some evidence that dual-action antidepressants, such as TCAs and SNRIs, may be more effective for inpatients with severe depression than are the single-action drugs such as SSRIs,22,28 but the more general assertion that multiple mechanisms of action confer efficacy advantages is quite controversial.33... 

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. 

Two rather broad structural classes account for the large majority of drugs that have proven useful in the clinic for treating depression. Each of these has associated with it some clearly recognized side effects the monoamine oxidase inhibitors, most commonly derivatives of hydrazine, tend to have undesirable effects on blood pressure the tricyclic compounds on the other hand may cause undesirable changes in the heart. Considerable effort has thus been expended toward the development of antidepressants that fall outside those structural classes. An unstated assumption in this work is the belief that very different structures will be associated with a novel mechanism of action and a different set of ancillary activities. One such compound, trazodone... 

Blier P., Abbott F. V. (2001). Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. J. Psychiatry Neurosci. 26, 37-43. 

The role of DA. Several reviews suggest that increased DA neurotransmission in the mesolimbic pathway may be related to the mechanism of action of antidepressants. 

After more than a decade of use, bupropion (24) is considered a safe and effective antidepressant, suitable for use as first-line treatment. In addition, it is approved for smoking cessation and seasonal affective disorder. It is also prescribed off-label to treat the sexual dysfunction induced by SSRIs. Bupropion is often referred to as an atypical antidepressant and has much lower affinity for the monoamine transporters compared with other monoamine reuptake inhibitors. The mechanism of action of bupropion is still uncertain but may be related to inhibition of dopamine and norepinephrine reuptake transporters as a result of active metabolites [71,72]. In a recently reported clinical trial, bupropion extended release (XL) had a sexual tolerability profile significantly better than that of escitalopram with similar re-... 

Stahl, S.M., Kaiser, L., Roeschen, J., Keppel Hesselink, J.M. and Orazem, J. (1998) Effectiveness of ipsapirone, a 5-HT-1A partial agonist, in major depressive disorder support for the role of 5-HT-1A receptors in the mechanism of action of serotonergic antidepressants. International Journal of Neuropsychopharmacology, 1, 11-18. 

Bonhomme N, Esposito E. (1998). Involvement of serotonin and dopamine in the mechanism of action of novel antidepressant drugs a review. J Clin Psychopharmacol. 18(6) 447-54. 

Stahl SM. (1998). Basic psychopharmacology of antidepressants, part 1 antidepressants have seven distinct mechanisms of action. J Clin Psychiatry. 59(suppl 4) 5-14. 

Bupropion is an atypical antidepressant drug that is the only nonnicotine-based prescription medicine approved for smoking cessation by the FDA. Its mechanism of action is presumed to be mediated by its capacity to block neuronal reuptake of dopamine and/or norepinephrine (Fiore et al. 2000). Relative to other antidepressants, bupropion has a relatively high affinity for the dopamine transporter (Baldessarini 2001). There is also evidence that bupropion acts as a functional nicotine antagonist, suggesting another potential mechanism by which bupropion could reduce smoking rates (Slemmer et al. 2000). 

First, you will learn about the human nervous system and how it works when it is healthy. This will include an introduction to the structure (anatomy) of the nervous system and the function (physiology) of the nervous system. Next, we ll describe the things that can go wrong. We ll look at how the system breaks down and malfunctions. Then we ll show you how these breakdowns can result in psychiatric illness. Finally, we ll introduce you to the medications used to treat psychiatric illness. You will learn where these medications work and our best guess of how they work. The presumed mechanism of action of many medications is just that, presumed. In contrast to antibiotics, in which we know quite a lot about the ways that they kill bacteria or stop them from reproducing and how these mechanisms ultimately effect a cure for an infectious disease, less is known about how psychotropic medicines work. Oh, we pretty well understand what psychotropic medicines do when they reach the nerve cell. For example, most of the antidepressants used today block the reuptake of serotonin at the nerve cell, but we re still not sure why blocking serotonin reuptake gradually improves mood in someone with depression. This will lead to a tour, if you will, of what happens to a medication from the time the pill is swallowed, until it exerts its therapeutic effect. 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

Listing of antidepressants grouped by principal mechanism of action in the synapse. Abbreviations MAOI—irreversible = irreversible monoamine oxidase inhibitor MAOI—reversible = reversible monoamine oxidase inhibitor NDRl = norepinephrine/ dopamine reuptake inhibitor NRI = norepinephrine reuptake inhibitor NSRl = norepinephrine/serotonin reuptake inhibitor NSSA = norepinephrine/specific serotonin agonist SRI = serotonin reuptake inhibitor SRl/serotonin-2 blocker = serotonin reuptake inhibitor and serotonin-2 receptor antagonist. 

Bupropion (Weiibutrin, Zyban). Bupropion is an antidepressant that is also FDA approved as a treatment for smoking cessation. It is marketed as an antidepressant as Weiibutrin and for the treatment of nicotine dependence as Zyban. Its mechanism of action in this regard is obscure, but it may act on dopamine and/or norepinephrine systems. 

Table 7.1. Changes in brain and tissue amine neurotransmitters in depressed patients which may be indicative of the mechanism of action of antidepressants...

Theories of the mechanisms of action of antidepressants is there a common mechanism of action ... 

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