Pathophysiology of Depression

It appears that depression is related to a disturbance in CNS neurotransmission involving certain chemicals know as amine neurotransmitters. These transmitters include 5-hydroxytryptamine (serotonin), norepi- 

However, the exact problem in CNS amine neurotransmission remains a subject of much debate. One leading theory is that depression may be caused by an increased sensitivity of the presynaptic or postsynaptic receptors for these transmitters. That is, the neurochemistry of the brain has been changed in some way to make the amine receptors more sensitive to their respective amine neurotransmitters (norepinephrine, serotonin, and to a lesser extent, dopamine).21 This theory is based primarily on the finding that antidepressant drugs prolong the activity of amine neurotransmission in the brain, thereby causing a compensatory decrease in the sensitivity of the amine receptors.21,47 

Antidepressants enhance stimulation of postsynaptic and presynaptic receptors 

FIGURE 7-1 T Theoretic basis for the mechanism and treatment of depression. Functionally active receptor sites are indicated by an Depression is believed to be initiated by increased postsynaptic or presynaptic receptor sensitivity. Drugs that enhance stimulation of these receptors ultimately lead to receptor down-regulation, thus resolving the depression [see text for details]. 

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S100A10 was found to interact with the serotonin IB receptor increasing its presence at the cell membrane. S100A10 was found to be closely associated with the pathophysiology of depression. 

The results with tacl and NK1R mice in these models of depression strongly support the idea that the tachykinin system is involved in the pathophysiology of depression. 

Stress is thought to be an important factor in the pathophysiology of depression and anxiety disorders. It seems possible that the reduced stress reactivity of NKl receptor- and tael-deficient mice has contributed to the behavioral phenotypes observed in the animal models of anxiety and depression. 

Ressler KJ, Nemeroff CB (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12 2-19 Reul JMHM, Holsboer F (2002) Corticotropin-releasing hormone receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol 2 23-33 Rex A, Marsden CA, Fink H (1993) 5-HTlA receptors and changes in extracellular 5-HT in the guinea-pigprefrontal cortex—involvementin aversive behaviour. J Psychopharmacol 7 338-345... 

Owens MJ and Nemeroff CB. (1994). Role of serotonin in the pathophysiology of depression focus on the serotonin transporter. Clin Chem 40 288-295. 

Ressler, K.J. and Nemeroff, C.B. (2000) Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 12(Suppl 1) 2—19. 

An imbalance in the cholinergic/aminergic interactions may result from the deficient activity of a certain aminergic system or the hyperactivity of the cholinergic system or any quantitative combination of the two, which could very well be responsible for the pathophysiology of depression (M. Berger and Riemann 1993 Soldatos and Paparrigopoulos 1995). 

The mechanisms by which thyroid hormones enhance antidepressant activity are still unknown. It is of interest that thyroid hormone increases net activity of several neurotransmitters that are putatively involved in the pathophysiology of depression in a way that is descriptively similar to that of estrogens. Receptors for the two hormones belong to the same superfamily. As was previously mentioned [Pfaff 1996], these issues are currently being explored, and clarifications are expected shortly. 

The effect of increased neurotrophins could mitigate hippocampal changes associated with exposure to stress. Although theoretical, this model of antidepressant action is supported by empirical studies of the pathophysiology of depression in patients ( 69, 70) as well as animal models (71, 72). These theories also link back to the neuroanatomical findings that began this section. 

Goodwin FK, Wirz-Justice A, Wehr T. Evidence that the pathophysiology of depression and the mechanism of action of antidepressant drugs involve alterations in circadian rhythms. Adv... 

The monoamine hypothesis, like the neurotrophic hypothesis, is at best incomplete. Many studies have not found an alteration in function or levels of monoamines in depressed patients. In addition, some candidate antidepressant agents under study do not act directly on the monoamine system. These include glutamate antagonists, melatonin agonists, and glucocorticoid-specific agents. Thus, monoamine function appears to be an important but not exclusive factor in the pathophysiology of depression. 

Finally, sex steroids are also implicated in the pathophysiology of depression. Estrogen deficiency states, which occur in the postpartum and postmenopausal periods, are thought to play a role in the etiology of depression in some women. Likewise, severe testosterone deficiency in men is sometimes associated with depressive symptoms. Hormone replacement therapy in hypogonadal men and women may be associated with an improvement in mood and depressive symptoms. 

Q4 The pathophysiology of depression is believed to involve the depletion of noradrenaline (norepinephrine) and serotonin (5-HT) at nerve endings in the brain. These monoamines are important in determining mood. 

Dunlop BW, Nemeroff CB. The role of dopamine in the pathophysiology of depression. Arch. Gen. Psychiatry. 2007 64 327-... 

Additionally, COX-2 inhibitors influence—either directly or via CNS-immune mechanisms—the CNS serotonergic system. In a rat model, treatment with rofecoxib was followed by an increase of serotonin in the frontal and the temporo-parietal cortex (Sandrini et al., 2002). Since the lack of serotonin is one of the pinpoints in the pathophysiology of depression, a clinical antidepressant effect of COX-2 inhibitors would be expected due to this effect. A possible mechanism of the antidepressant action of COX-2 inhibitors is the inhibition of the release of IL-1 and IL-6. Moreover, COX-2 inhibitors also protect the CNS from effects of quinolinic acid (Salzberg-Brenhouse et al., 2003). 

The involvement of the central nervous system serotonin function in the pathogenesis and treatment of affective disorders has been a subject of intensive research during the past 30 years.33 36 Studies using serotonin precursors and agonists as pharmacologic probes and measurements of cerebrospinal fluid monoamine metabolite levels indicated that alterations in central nervous system serotonin function may be involved in the pathophysiology of depression. Since the synthesis of serotonin depends on dietary intake of the precursor tryptophan, many studies have utilized tryptophan depletion techniques by which patients were fed a tryptophan-free diet for various time intervals. 

Evidence from preclinical and clinical data suggests that GABA plays a role both in the pathophysiology of depression and bipolar disorder and in the mechanisms of action of antidepressant agents. - Low GABA concentrations and receptor activity in the brain cause depression, palpitation, insomnia, learning disorders, and memory failure. - GABA concentration in the CSF is inversely correlated with the severity of depression. ... 

Norepinephrine (NE) and serotonin (5-HT) are key neurotransmitters involved with the pathophysiology of depression. Norepinephrine reuptake inhibitors (NRIs) increase extracellular... 

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