Antidepressants inhibition

In animal studies, high levels of cortisol have been shown to induce (increase) the activity of the enzyme tryptophan 2,3-dioxygenase in the liver, thereby decreasing the bioavailability of tryptophan to the brain. It is interesting to note that low acute doses of a number of different antidepressants inhibit the activity of this enzyme and, as a result, increase brain tryptophan concentrations, thus stimulating 5-HT synthesis (Badawy and Evans, 1982). In this way a link between the two key monoamine neurotransmitters and the hormone may be seen namely, reduced brain NA activity leads to decreased inhibition of the HPA axis, while increased levels of cortisol reduce 5-HT activity in the brain. Activation of the HPA axis has also been shown to result in tissue atrophy, in particular of the limbic system s hippocampus, and a reduction in the levels of neurotrophic factors responsible for the maintenance and optimal function of brain neurons (Manji et al., 2001). In conclusion, manipulation of the HPA axis (Nemeroff, 2002) and stimulation of neurotrophic factor activity (Manji et al., 2001) might open up new avenues for the treatment of affective disorders. 

It is believed that tricyclic antidepressants inhibit the (neuronal) reuptake of norepinephrine (noradrenaline) and/or serotonin by presynaptic nerve endings, thus blocking one of the leading mechanisms of their inactivation, and thereby increasing the concentration of the indicated amines potentiating their effects. It should be noted that, as a rule, secondary amines, which are representatives of tricyclic antidepressants, exhibit high activity, blocking the neuronal reuptake of norepinephrine, while tertiary amines act more on the neuronal reuptake of serotonin. 

Destruction or removal of transmitter from site of action Tolcapone (COMT inhibitor) Phenelzine (MAO inhibitor) Tricyclic antidepressants (inhibit neuronal transport) Physostigmine (cholinesterase inhibitor)... 

Imipramine and other tricyclic antidepressants inhibit not only the reuptake of catecholamines into presynaptic nerve raidings but have the same effect on serotonin. 

Wahlstrom, A., Lenhammar, L., Ask, B., Rane, A. Tricyclic antidepressants inhibit opioid receptor binding in human brain and hepatic morphine glucuronidation. Pharmacol. Toxicol. 75(1), 23-27, 1994. 

Because reboxetine and bupropion share with desipramine the ability to block the NE uptake pump, some clinician may want to combine them with an SSRI. Bupropion, however, should be used cautiously with fluvoxamine, fluoxetine, and paroxetine because these three antidepressants inhibit one or more CYP enzymes to a substantial degree at their lowest, usually effective antidepressant dose. Therefore, the dose of bupropion should be kept low and TDM could be used to ensure that unusually high levels of bupropion or its active metabolites do not develop. 

The Inhibition of Monoamine Uptake by Antidepressant Inhibition of Reuptake... 

Lahti, R. A. Maickel, R. P. 1971, The tricyclic antidepressants - inhibition of norepinephrine uptake as related to potentiation of norepinephrine and clinical efficacy, Biochemical Pharmacology, vol. 20, pp. 482-486. 

Mass spectrometric detection has also been directly interfaced with microchip separations for drug detection. These studies, detecting imipramine and desipramine in fortified human plasma, show analysis of spiked analytes in clinical sample matrices for drug detection [3]. These widely used tricyclic antidepressants inhibit the reuptake of the neurotransmitters serotonin and norepinephrine in the central nervous system. Unfortunately, the 5-mg/mL detection limit found for these antidepressants with this method is not low enough to detect typical clinical levels of the drugs. Combinatorial library characterization and preclinical drug delivery studies should benefit, however, since the concentra-... 

Steroid X R agonist (D2-R) [antidepressant inhibits prolactin release]... 

Since IL-6 stimulates Prostaglandin E2 (PGE2) and antidepressants inhibit the IL-6 production, an inhibiting action of antidepressants on PGE2 would be expected, too (Poliak and Yirmiya, 2002). Over twenty years ago it was suggested that antidepressants inhibit PGE2 (Mtabaji et al., 1977). A recent in-vitro study showed that both tricyclic antidepressants and selective serotonin inhibitors attenuated cytokine-induced PGE2 and nitric oxide production by inflammatory cells (Yaron et al., 1999). 

Maes M, Song C, Lin AH, Bonaccorso S, Kenis G, De Jongh R, Bosmans E, Scharpe S (1999) Negative immunoregulatory effects of antidepressants Inhibition of interferon-gamma and stimulation of interleukin-10 secretion. Neuropsychopharmacology 20 370-379. 

Tricyclic antidepressants inhibit the uptake of catecholamines, such as adrenaline, into sympathetic neurons and can enhance the cardiovascular effects, so that even the small amounts of adrenaline present as additives in some local anesthetics can have a marked effect on the cardiovascular system. 

Tricyclic antidepressants inhibit the uptake of catecholamines, such as ephedrine, into sympathetic neurons and can enhance their cardiovascular effects (41). 

Table 8.8 Antidepressants Inhibition of Human Serotonin (SERT), Norepinephrine (NET), and Dopamine (DAT) Transporters ...

Tricyclic antidepressants were named after their characteristic chemical structure, although a number of the newer drugs in this group have a different chemical structure but still share similar pharmacological profiles. Tricyclic antidepressants inhibit the re-uptake of serotonin and noradrenaline into nerve endings. This leads to a build up of neurotransmitter at receptor sites in synapses. They also reduce the number of some receptors, which may contribute to the therapeutic action, but their complete mechanism of action is unknown. Examples of tricyclic antidepressants include imipramine and amitriptyline (for use of amitriptyline in neuropathic pain see Chapter 12). 

Desipramine is a tricyclic antidepressant, inhibits reuptake of norepinephrine and serotonin in CNS, and is indicated in relief of symptoms of depression. Desipramine (75 to 150 mg p.o./day in divided doses) is indicated in endogenous depression major depression with melancholia or psychotic symptoms depression associated with organic brain disease, alcoholism, schizophrenia, or mental retardation and the depressive phase of manic-depressive disorder. Desipramine is absorbed rapidly from the GI tract, distributed widely in the body, and appears also in breast miUc. It is bound to plasma proteins to the extent of 90%, undergoes extensive first-pass metabolism, and its metabolites are excreted in urine. Desipramine strongly blocks the norepinephrine uptake mechanism and has no effect on the uptake of serotonin. Desipramine has weak alpha -adrenergic and... 

Tricyclic antidepressants inhibit uptake into neuron decreasing antihypertensive effects. Other interactions similar to reserpine (above). 

Le Dinh T, Freneaux E, Labbe G, Letteron P, Degott C, Geneve J, Berson A, Larrey D, Pessayre D (1988) Amineptine, a tricyclic antidepressant, inhibits the mitochondrial oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. J Pharmacol Exp Ther 247 745-750 Le Roy F, Bisbal C, Silhol M, Martinand C, Lebleu B, Salehzada T (2001) The 2-5A/RNase L/RNase inhibitor (RLl) pathway regulates mitochondrial mRNAs stability in interferon-a-treated H9 cells. J Biol Chem 276 48473 8482 Le Roy F, Silhol M, Salehzada T, Bisbal C (2007) Regulation of mitochondrial mRNA stability by RNase L is translation-dependent and controls IFNalpha-induced apoptosis. Cell Death Differ 14 1406-1413... 

Not understood. One suggestion is that the tricyclic antidepressants inhibit the metabolism of the anticoagulant (seen in animals with nortriptyline or amitriptyline and warfarin, but not with desipramine and acenocoumarol ), but tricyclics are not established known inhibitors of the metabolism of any drug so this seems unlikely. Another idea is that the tricyclics slow gastrointestinal motility thereby increasing the time available for the dissolution and absorption of dicoumarol. ... 

The tricyclic antidepressants inhibit the activity of the uptake mechanism by which some chemical transmitters (serotonin (5-HT) or noradrenaline (norepinephrine)) re-enter nerve endings in the CNS. In this way they raise the concentrations of the chemical transmitter in the receptor area. If depression represents some inadequacy in transmission between the nerves in the brain, increasing the amount of transmitter may go some way towards reversing this by improving transmission. 

Instead of synaptosomes, blood platelets can also be used for uptake inhibition studies. Platelets contain an uptake mechanism for 5-HT and for NA which has properties analogous to that of nerve endings. This process can be studied effectively in vitro and it has been shown that tricyclic antidepressants inhibit the uptake of 5-HT and NA by platelets [19]. Measurements of the inhibition of uptake of monoamines by platelets, obtained from patients under treatment can provide an indication of the uptake inhibiting effectiveness of compounds in clinical trials. 

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