Serotonin drugs increasing

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. 

Increased or decreased antidepressant response increased toxicity Decreased antihypertensive efficacy Decreased antihypertensive efficacy Increased hypoglycemic effects Possible additive lowering of seizure threshold Decreased antihypertensive efficacy tachycardia CNS stimulation Increased therapeutic and possibly toxic effects of both drugs hypertensive crisis delirium seizures hyperpyrexia serotonin syndrome Increased hypoglycemic effects... 

Ultimately, the effects of virtually aU existing antidepressants can be traced to the improvement of neurotransmission in the brain by one or more monoamine neurotransmitters, that is serotonin (5-HT, 4), norepinephrine (NE, 5), and dopamine (DA, 6). By blocking monoamine transporters, which remove the neurotransmitter from the synapse and extracellular space by uptake processes, the drugs increase extracellular levels of the transmitter and cause a cascade of intracellular events leading to the desired CNS effect. 

These drugs increase synaptic serotonin by selectively blocking the serotonin reuptake transporter. In preclinical and human studies acute doses tend to be anxiogenic (Bell and Nutt 1998) but chronic administration has anxiolytic effects, possibly due to downregulation of presynaptic autoreceptors (Blier et al. 1990). There are five SSRIs widely available citalopram, fluoxetine, fluvoxam-ine, paroxetine and sertraline. Escitalopram, the S-enantiomer of citalopram. 

FIGURE 6-36. Mechanism of action of serotonin selective reuptake inhibitors (SSRls)—part 2. When an SSRI is administered, it immediately blocks the serotonin reuptake pump (see icon of an SSRI drug capsule blocking the reuptake pump). However, this causes serotonin to increase initially only in the somatodendritic area of the serotonin neuron (left) and not in the axon terminals (right). 

The idea that depression is associated with changes in amine receptor sensitivity is summarized in Figure 7-1. For reasons that are still unclear, depression might occur because of an increase in postsynaptic receptor sensitivity to amine neurotransmitters, particularly norepinephrine and serotonin.4 Antidepressant drugs increase amine transmission by a variety of methods, thereby bringing about overstimulation of the postsynaptic receptor. (The exact method by which these drugs increase amine stimulation is discussed later in this chapter.) Overstimulation... 

HT and other monoamines affect emotions, whereas ACh and DA affect movement and emotions. Blocking serotonin transporters on presynaptic neurons with drugs increases synaptic concentrations of 5-HT, which makes depressed patients feel better. Other neurotransmitters, such as endogenous opiates, increase pleasure and decrease paia... 

The Australian Adverse Drug Reaction Advisory Committee has stated that tramadol may cause the serotonin syndrome, particularly when it is used at high doses or in combination with other drugs increasing serotonin le vel s of 20 reported cases of the serotonin syndrome associated with tramadol, 16 were taking potentially interacting medicines including SSRIs. Cases of the serotonin syndrome with specific SSRIs are discussed below. 

Meperidine is thought to inhibit both the 5-HT2A receptors and norepinephrine (NE) reuptake mechanism which may precipitate a serotonin syndrome, a toxic state secondary to excessive serotonin ago-nism of the CNS [3,4]. This adverse drug reaction occurs most commonly in patients who are using single or multiple medications that increase postsy-naptic serotonin levels. Inherited deficiencies in the metabolism of serotonin may contribute to the development of the syndrome. Hypertension, atherosclerosis, and hyperlipidemia are all associated with a reduction in endothelial MAO activity and thus a reduced capacity to metabolize serotonin may increase the risk of a serotonin crisis. The diagnosis... 

The TCAs, such as amitriptyline (Elavil) and dox-epin (Sinequan), inhibit reuptake of norepinephrine or serotonin at the presynaptic neuron. Drug classified as MAOIs inhibit the activity of monoamine oxidase a complex enzyme system that is responsible for breaking down amines. This results in an increase in endogenous epinephrine, norepinephrine and serotonin in the nervous system. An increase in these neurohormones results in stimulation of the CNS. The action of the SSRIs is linked to their inhibition of CNS neuronal uptake of serotonin (a CNS neurotransmitter). The increase in serotonin levels is thought to act as a stimulant to reverse depression. 

The various stimulants have no obvious chemical relationships and do not share primary neurochemical effects, despite their similar behavioral effects. Cocaines chemical strucmre does not resemble that of caffeine, nicotine, or amphetamine. Cocaine binds to the dopamine reuptake transporter in the central nervous system, effectively inhibiting dopamine reuptake. It has similar effects on the transporters that mediate norepinephrine and serotonin reuptake. As discussed later in this chapter in the section on neurochemical actions mediating stimulant reward, dopamine is very important in the reward system of the brain the increase of dopamine associated with use of cocaine probably accounts for the high dependence potential of the drug. 

It was of interest that, in spite of the recovery of serotonin uptake sites to control levels, the content of serotonin in the same brain region remained markedly (40 to 50 percent) below age-matched controls for as long as 1 year after MDMA administration. It is unclear from these data whether there is a regeneration of axons that have previously undergone degeneration or whether the increased density of uptake sites is a consequence of increased collateral sprouting of neurons unaffected by the drug treatment. 

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