Serotonin and noradrenaline

Molecular target Gastrointestinal lipases Serotonin and noradrenaline transporter Cannabinoid-1 receptor... 

Sibntramine (Meridia ) - Serotonin and Noradrenaline Renptake Inhibitor... 

Acute treatment with nonselective MAO inhibitors (iproniazid, tranylcypromine, phenelzine), as a consequence of inhibiting both forms of the enzyme, increase, brain levels of all monoamines (phenylethylamine, tryptamine, methylhistamine aminergic neurotransmitters (dopamine, noradr enaline, adrenaline and serotonin). By contrast MAO-A inhibitors (clorgyline) increase serotonin and noradrenaline, while MAO-B inhibitors (selegiline, rasagiline) increase brain levels... 

Antidepressive agents which increase synaptic availability of serotonin and noradrenaline have been empirically found to be efficacious against chronic pain, particularly that of neuropathic origin. 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

Explain how imipramine and iproniazid affect the synaptic concentrations of serotonin and noradrenaline. 

Venlafaxine An atypical antidepressant that inhibits the reuptake of both serotonin and noradrenaline. 

Yaksh, T. L. (1979) Direct evidence that spinal serotonin and noradrenaline terminals mediate the spinal antinociceptive effects of morphine in the central periaqueductal gray. Brain Res.. 160 180-185. 

Kehr J, Yoshitake T, Wang FH, Wynick D, Holmberg K, et al. 2001. Microdialysis in freely moving mice Determination of acetylcholine, serotonin and noradrenaline release in galanin transgenic mice. J Neuro Sci Method 109 71-80. 

Selective serotonin and noradrenaline reuptake inhibitors (SNRIs)... 

Venlafaxine is a serotonin and noradrenaline re-uptake inhibitor indicated in depression and may be used in generalised anxiety disorder. Venlafaxine can cause diarrhoea and headache as side-effects. It does not cause blurred vision. 

Imipramine is a tricyclic antidepressant (TCA), which acts by blocking the reuptake of serotonin and noradrenaline. TCAs may cause cardiovascular... 

Due to the frequent unwanted effects and, in case of tranylcypromine, the numerous and dangerous interactions MAO-inhibitors are more and more replaced by the much less problematic SSRIs. Compounds belonging to this group are citalopram, escitalopram, fluoxetine, paroxetine and sertraline. They are used clinically in the therapy of depression, bulimia and obsessive-compulsive disorders. All SSRIs show a slow onset of action (1-2 weeks). They may induce insomnia and weight loss. The antidepressant ven-lafaxine inhibits both, serotonin and noradrenaline re-uptake and might therefore additionally induce hypertension. 

Moclobemide increases concentrations of serotonin and noradrenaline by means of reversible inhibition of MAO-A. Although moclobemide has an elimination half-life of only 1 hours its duration of action is considerably longer. 

Venlafaxine is a serotonin and noradrenaline reuptake inhibitor (SNRI). It shares these properties with the TCAs amitriptyhne, clomipramine and imip-ramine, but it is the first selective SNRI, with low affinity for muscarinic, histaminic and a-adrenergic receptors. At low doses serotonergic effects predominate, but at higher doses the reuptake of noradrenaline is significantly blocked (Melichar et al. 2001). It is available as immediate and extended release (XR) preparations. 

This group includes compounds with actions on a range of neurotransmitter systems. Their antidepressant efficacy is mediated by reuptake inhibition of serotonin and noradrenaline, although side-effects such as sedation may also be useful. Their use in anxiety disorders is supported by a long history of clinical experience and a reasonable evidence base from controlled trials. Studies support the use of clomipramine (a potent serotonin reuptake inhibitor) in panic disorder and OCD (Lecrubier et al. 1997 Clomipramine Collaborative Study Group 1991), of imipramine in panic disorder and GAD (Cross-National Collaborative Panic Study 1992 Rickels et al. 1993), and of amitriptyline in PTSD (Davidson et al. 1993a). No controlled studies support the use of TCAs in social anxiety disorder. 

Mirtazapine has a novel mechanism of action that in theory should promote anxiolytic effects, although evidence from studies of anxiety disorders is awaited. It increases synaptic release of serotonin and noradrenaline via blockade of presynaptic inhibitory a2-adrenoceptors, as well as blocking post-synaptic 5-HT2 and 5-HT3 serotonin receptors and Hi histamine receptors. Mirtazapine has good efficacy for anxiety symptoms associated with depression (Fawcett and Barkin 1998), and in controlled studies was superior to... 

Venlafaxine and milnacipran are two members of a new class of antidepressants that have selective effects on the reuptake of both serotonin and noradrenaline—serotonin noradrenaline reuptake inhibitors (SNRIs). In theory, based on the findings of B. M. Baron and colleagues [1988 and of J. C. Nelson and colleagues (1991), the combination of these two pharmacological actions should be associated with superior efficacy either in terms of rapid onset of action or extra efficacy at the end of treatment. 

Milnadpran is a rather newer SNRI licensed as an antidepressant in France. It is associated with clear-cut efficacy judged on the placebo-controlled studies [Lecrubier et al. 1996 Macher et al. 1989]. Milnacipran inhibits the reuptake of both noradrenaline and serotonin (Moret et al. 1985]. It has a relatively short half-life and is given optimally in a dose of 50 mg twice daily. The proportion of reuptake inhibition between serotonin and noradrenaline is approximately equal with this antidepressant, and so one would expect that milnacipran would be more effective than SSRIs, assuming the theory is correct that two actions are better than one. 

In depression, serotoninergic and/or noradrenergic neurotransmission is assumed to be deficient. One of the approaches to increase the availability of these neurotransmitters is to inhibit the activity of MAO, the enzyme involved in the degradation of serotonin and noradrenaline. Older drugs such as phenelzine and recently also moclobemide are representatives of this therapeutic approach used in some forms of depression. 

Another approach to correct neurotransmission is to inhibit the reuptake of the neurotransmitters into their presvnaptic endings. If the presynaptic reuptake mechanism of a neurotransmitter is blocked then more of the neurotransmitter will stay in the synaptic cleft and be functionally available. Many antidepressant drugs, called reuptake inhibitors , are thought to act via this mechanism. If selective for serotonin they are called selective serotonin reuptake inhibitors (SSRIs, Chapter 1), but if selective for both serotonin and noradrenaline they are called serotonin noradrenaline reuptake inhibitors (SNRIs). Most older antidepressants, such as the tricyclic compounds amitriptyline, imipramine and clomipramine, have little specificity for any of the neurotransmitters fluoxetine, paroxetine, citalopram and a few others are specific for serotonin venlafaxine is a representative of the SNRIs. A more recent mixed-uptake inhibitor is mirtazepine, and some similar compounds are about to be launched. 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

Noradrenaline (norepinephrine) reuptake inhibitors (NARIs) Serotonin and noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) Atypical... 

Nutt DJ The neuropharmacology of serotonin and noradrenaline in depression. Int Clin Psychopharmacol 2002 17(Suppl 1) S1. 

The dorsal horn of the spinal cord contains many transmitters and receptors. Some of these include peptides, eg. substance P, somatostatin and neuropeptide Y excitatory amino acids, e.g. glutamate and aspartate inhibitory amino acids, e.g. y-aminobutyric acid (GABA) nitric oxide endogenous opioids adenosine and the monoamines, e.g. serotonin and noradrenaline. There is, therefore, diverse therapeutic potential for... 

Table 1 Clinical properties of serotonin and noradrenaline reuptake inhibitors (only those drugs are included for which a resonable number of reports on controlled clinical trials are available). For more detailed information see Onghena and van Houdenhove (1992), Philipp and Fickinger (1993), McQuay et al. (1996), and Ansari (2000).

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