Antidepressants serotonin activity

Mirtazapine (Remeron). Mirtazapine is the newest of the atypical antidepressants. It mainly works by blocking the alpha-2 negative feedback receptor and thus increases norepinephrine and serotonin activity. In addition, mirtazapine blocks serotonin-2 and serotonin-3 receptors to produce a specific serotonin action like nefazodone. Mirtazapine is approved for the treatment of depression. Its use in the anxiety disorders is being studied. 

Buspirone (Buspar). Buspirone is an anxiety-relieving medication that alters serotonin activity. When added to an antidepressant, buspirone may help treat the depression. It will also relieve anxiety and may reverse sexual side effects of a SSRl. Please refer to Chapter 5 Anxiety Disorders for more information regarding buspirone. 

Pindolol (Visken). Pindolol is a blood pressure medicine that also alters serotonin activity. Some believe that it helps speed the response to antidepressants, but more study is needed. It is generally well tolerated. 

When switching between a MAOl and other antidepressants that affects serotonin activity, the first medication must be allowed to wash out of the patient s system before the new antidepressant is started. The duration of this washout period is determined by the half-life of the antidepressant that is being discontinued. If a washout is neglected, then a potentially dangerous serotonin syndrome may result. 

Serotonin-Boosting Antidepressants. Antidepressants that enhance serotonin activity in the brain have also been studied in ADHD. In particular, fluoxetine (Prozac) and the serotonin-selective TCA clomipramine (Anafranil) have been the most extensively evaluated, with mixed success. They provide some benefit for aggression and impulsivity but don t significantly improve the poor attention of ADHD. As a result, the SSRls and other serotonin-boosting antidepressants do not appear to be effective first-line treatments for ADHD. Conversely, depressed patients without ADHD often show improvements in symptoms of concentration and attention when treated with a SSRI. Although SSRls are not widely used in the treatment of ADHD, they may be worthy of consideration in ADHD patients whose impulsivity is not controlled by stimulants alone. Those with comorbid conduct disorder or ODD who are prone to agitation and at times violent outbursts may be helped by the addition of a SSRI. 

Antidepressants. The most widely used psychiatric medicines with the broadest range of application in TBI patients are undoubtedly the SSRI antidepressants. They are well tolerated, unlikely to worsen any of the preexisting deficits associated with TBI, and offer relief from not only depression but also impulsivity and virtually all variants of anxiety in these patients. As such, SSRIs are the preferred first-line treatment for all anxiety disorders after TBI. Other newer antidepressants that also work (at least in part) by boosting serotonin activity, namely, mirtazapine (Remeron), nefazodone (Serzone), venlafaxine (Effexor XR), and duloxetine (Cymbalta) can also be considered, but they have not been well studied in patients with TBI. In... 

Antidepressants that increase serotonin activity can also indirectly decrease dopamine activity by inhibiting the activity of dopamine-secreting nerve cells. This effect on dopamine nerve cells is generally not of sufficient magnitude to treat psychosis, but it may explain why patients taking these antidepressants on rare occasions experience akathisia and other extrapyramidal side effects. 

Probably the greatest advances in psychiatric medications of the last 15 years have involved the neurotransmitter serotonin. First was the arrival of serotonin-specific antidepressants with fewer side effects and greater safety than their predecessors. More recently, atypical antipsychotics have highlighted the importance of serotonin-dopamine interactions in the optimal treatment of schizophrenia and other psychotic disorders. While these are indeed significant advances, medications that alter serotonin activity are not without their own side effect burden. 

When we talk about serotonin-blocking medications, a point of clarification must be made. In most cases, medications do not block overall serotonin activity but instead block the activity at one of the many serotonin receptor types. For example, the antidepressants trazodone, nefazodone, and mirtazapine increase total serotonin activity yet they block certain of the serotonin receptors. Mirtazapine increases both serotonin and norepinephrine activity by interfering with the alpha-2 receptor. By also blocking the serotonin-2 and serotonin-3 receptors, mirtazapine avoids the sexual dysfunction and GI side effects commonly experienced with other serotoninboosting medications. We cannot truly call these serotonin-blocking medications, because they are serotonin-boosting medications that selectively block certain serotonin receptors. 

Chenu F, Guiard BP, Bourin M, Gardier AM. Antidepressant-like activity of selective serotonin reuptake inhibitors combined with 87. a NKl receptor antagonist in the mouse forced swimming test. 

Because 25% of patients will stop SSRIs due to side effects and an additional 30% to 40% will fail to achieve a therapeutic response, other antidepressant alternatives are of great importance. Venlafaxine is a dual-action antidepressant that enhances serotonin activity at low doses and norepinephrine at higher doses. Preliminary evidence suggests that these multiple actions on neurotransmitters may confer therapeutic superiority over SSRIs for the management of severe or melancholic depression, but the risk of HTN with high-dose venlafaxine should not be overlooked. 

The risk of serotonin syndrome may be increased shortly after dosage increases of SSRIs or when drug interactions increase serotonin activity. Concomitant or proximal use of SSRIs, tricyclic antidepressants, or monoamine oxidase inhibitors may cause serotonin syndrome. Further, the addition of certain drugs, such as tryptophan, dextromethorphan, cocaine, or sympathomimetics, to SSRI therapy may increase the risk of developing serotonin syndrome." ... 

The contribution of serotonin toxicity to deaths has been explored in an epidemiological study [34 ]. Of 1123 deaths over 7 years in which serotonin-active drugs were detected, seven deaths were thought to have had serotonin toxicity as a contributory mechanism. Three cases involved tramadol co-administered with serotonergic antidepressants. 

Napamezole (68) is a dihydroimidazole derivative with antidepressant activity probably as a result of its combined a 2 adrenergic receptor blockuig and serotonin uptake blocking proper ties It can be synthesized by Wittig olefination of p-tetralone (65) with diethyl (cyanomethyl) phosphonate (66) and base to give nitnle 67 Imidazoline construction on the latter was smoothly... 

Cusin, C., Serretti, A., Zanardi, R. etal. (2002). Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. Int.. Neuropsychopharmacol, 5, 27-35. 

I suppose that some ingenious minds will be able to find a way of accommodating the chemical-balance hypothesis to these data, but I suspect that the accommodation will require convoluted circumventions, like those used by the Flat Earth Society in their efforts to maintain their defunct theory in the face of photographic evidence from space. If depression can be equally affected by drugs that increase serotonin, drugs that decrease it and drugs that do not affect it at all, then the benefits of these drugs cannot be due to their specific chemical activity. And if the therapeutic benefits of antidepressants are not due to their chemical composition, then the widely proffered chemical-imbalance theory of depression is without foundation. It is an accident of history produced serendipitously by the placebo effect. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

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