Antidepressants actions

Selected for clinical trials as a compound to calm agitated patients, imipramine was relatively ineffective. However, it was observed to be effective in the treatment of certain depressed patients (38). Early studies on the mechanism of action showed that imipramine potentiates the effects of the catecholamines, primarily norepinephrine. This finding, along with other evidence, led to the hypothesis that the compound exerts its antidepressant effects by elevating norepinephrine levels at central adrenergic synapses. Subsequent studies have shown that the compound is a potent inhibitor of norepinephrine reuptake and, to a lesser extent, the uptake of serotonin, thus fitting the hypothesis that had been developed to explain the antidepressant actions ofMAOIs. 

Curtis, A and Valentino, RJ (1994) Corticotropin-releasing factor neurotransmission in locus coeruleus a possible site of antidepressant action. Brain Res. Bull. 35 581-587. 

Delgado, PL, Miller, HE, Salomon, RM, Licinio, J, Heninger, GR, Gelenberg, AJ and Charney, DS (1993) Monoamines and the mechanism of antidepressant action effects of catecholamine depletion on mood of patients treated with antidepressants. Psychopharmacol. Bull. 29 389-396. 

Taylor, Matthew J., Nick Freemantle, John R. Geddes and Zubin Bhagwagar, Early Onset of Selective Serotonin Reuptake Inhibitor Antidepressant Action Systematic Review and Meta-Analysis , Archives of General Psychiatry 63 (2006) 1217-23... 

All antidepressant drugs have some effects on sleep architecture. Suppression of REM sleep associated with the treatment of depression was such a consistent finding in early studies that it was seen as essential for the antidepressant action. 

This belief was further supported by the evidence of a correlation between the clinical response and REM sleep suppression as well as a temporal relationship between the onset of clinical response and REM sleep suppression. However, some of the later studies suggested that REM sleep suppression is not necessary for the antidepressant action (Gillin 1983). For example, some studies show evidence of no change or even an increase in REM sleep with the treatment of depression (Gillin et al. 2001). Recently, Landolt Gillin (Landolt and Gillin 2002) have also demonstrated that the antidepressant response to phenelzine treatment does not depend on elimination of REM sleep or inhibition of slow wave activity in non-REM sleep. However, the generalization of some of these studies is limited because of their small sample size. 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Numerous open studies, and seven controlled studies, have shown that valproate is effective in the treatment of acute mania. It has also been claimed to have an antidepressant action. Recent studies have shown that valproate is effective in the long-term treatment of bipolar disorder. 

Monoaminooxidase is a complex enzymatic system that is present in practically every organ that catalyzes deamination or inactivation of various natural, biogenic amines, in particular norepinephrine (noradrenaline), epinephrine (adrenaline), and serotonin. Inhibition of MAO increases the quantity of these biogenic amines in nerve endings. MAO inhibitors increase the intercellular concentration of endogenous amines by inhibiting then-deamination, which seems to be the cause of their antidepressant action. 

The mechanism of antidepressive action of this series of drugs is likely associated with their inhibition of the oxidizing deamination process of the neurotransmitters norepinephrine, epinephrine, dopamine, and serotonin, which participate in the transmission of nerve excitement in the CNS. A major drawback of these drugs is the high toxicity associated with their inhibition of not only MAO, but also a number of other nonspecific enzymes. 

The antidepressant action of amoxapine is comparable to that of imipramine and amitriptyline. It exhibits antagonistic activity on dopamine (D2) receptors. Amoxapine is intended more for relieving symptoms in patients with neurotic or situational depression. It has a number of serious side effects. Synonyms of this drug are asendin, amoxan, moxadil, and others. 

Our understanding of the mechanism of antidepressant action has evolved over time. In the late 1950s, the first molecules introduced for the treatment of MDD were the so-called tricyclic antidepressants (TCAs), represented by imipramine (7). Subsequent experience with TCAs supported the role of both 5-HT and NE, although these drug molecules act on other neuronal systems as well. Despite their elfectiveness, the use of TCAs was limited due to poor tolerability and safety concerns, in particular, severe toxicity when taken in overdose. 

The field of antidepressant research was revolutionized in the late 1980s by the introduction of selective serotonin reuptake inhibitors (SSRIs), exemplified by fluoxetine (9). In addition to their antidepressant action, SSRIs have also proven effective for a broad range of psychiatric illnesses, and, more importantly, they demonstrated an improved tolerability profile as compared to TCAs and MAOIs due to their increased selectivity. On the other hand, SSRIs proved inferior to TCAs and MAOIs in their reduced antidepressant effects, slower onset of action, lower remission rates, and decreased ability to control the physical symptoms associated with depression. 

A period of at least 2 weeks therapy with adequate doses of any of the antidepressants that are available at the moment is required before antidepressant action can be expected. When there is a therapeutic response antidepressant medication should be continued for a minimum of 6-12 months. It has to be realized that there are estimates that even under treatment 15-25% of the patients will continue to have symptoms of depression. 

Valentino RJ, Curtis AL, Parris DG, Wehby RG (1990) Antidepressant actions on brain noradrenergic neurons. J Pharmacol Exp Ther 253 833-840... 

The precise molecular mechanism responsible for the antidepressant action of the TCA drugs is unknown, although a number of hypotheses have been generated. Many of these involve alterations in neurotransmission of norepinephrine or serotonin or both. 

Isocarboxazid, phenelzine, and tranylcypromine are irreversible nonselective inhibitors of both MAO-A and MAO-B. However, it appears that inhibition of MAO-A, not MAO-B, is important to the antidepressant action of these agents. 

The first inhibitors of flavin-dependent MAO that were developed for clinical use were hydrazines and hydrazides. The chance discovery that the antitubercular drug, 4-pyridine carboxylic acid hydrazide (isoniazid, 40), was also a potent MAO inhibitor led to the development of the related drug, iproniazid (41), used for the treatment of depressive illness. Although this compound demonstrated remarkable antidepressant action, its clinical value was seriously compromised by side effects [19]. 

Frazer, A. (2000) Norepinephrine involvement in antidepressant action. / Clin Psychiatry 61 25—30. 

CREB expression occurs (Nibuya et al., 1995, 1996). Brain-derived neurotrophic factor is an attractive candidate for mediating antidepressant action. In addition to its known effects on neuronal survival and differentiation, it also has been shown to play a role in synaptic plasticity. Furthermore, administration of BDNF directly into rat hippocampus has been demonstrated to have antidepressant-like action in several models of depression (Siuciak et ah, 1996). 

Willner, P. (1997) The mesolimbic dopamine system as a target for rapid antidepressant action. Int Clin Psychopharmacol 12 Suppl 3 S7-S14. 

Source. Adapted from Delgado PL, Price LH, Miller HL, et al Rapid Serotonin Depletion as a Provocative Challenge Test for Patients With Major Depression Relevance to Antidepressant Action and the Neurobiology of Depression. Psychopharmacology Bulletin 27 321-330, 1991. Used with permission. 

O ver the past 10-15 years, much of the discussion of new antidepressant action has centered on serotonin (5-hydroxytryptamine [5-HT]). For a time, this caused other possible mechanisms to be neglected to some extent. It is appropriate to review the limitations of the serotonergic approach and examine what might lie beyond serotonin for the treatment of depression. 

On the basis of the large placebo-controlled studies, mirtazapine has undoubted antidepressant action and is licensed in both Europe and the United States [Claghorn and Lesem 1995 Sitsen et al. 1995). The evidence for superior efficacy is again limited by the failure to set up studies that were large enough to provide an adequate test of two active antidepressants. Nevertheless, mirtazapine has been shown to be more effective than trazodone in hospitalized patients with major depression (van Moffaert et al. 1995) and in a more recent study, mirtazapine was more effective than fluoxetine given in a dose of 20 mg [S. A. Montgomery 1996). 

The role of dopamine is discussed more thoroughly in Finder, Chapter 14, in this volume. Several antidepressants are thought to have enhanced antidepressant action attributed to extra effects on the dopamine system. Bupropion, which is available as an antidepressant in the United States only, has an indirect effect on dopamine. An appropriate minimum effective dose was not established in the early clinical trial development program, and the rather high doses used in clinical practice may have contributed to the number of reports of convulsions. The rate, which is acceptable at lower doses of 450 mg/day, rises to unacceptable levels at higher doses [J. A. Johnston et al. 1991). 

Amineptine, which is available as an antidepressant in some countries in Europe, is a selective dopamine reuptake inhibitor. Amineptine is an old drug and was not subjected to the rigorous trial methodology applied to more recent antidepressants. There are suggestions that amineptine may be associated with early onset of antidepressant action, but this has not been thoroughly studied (Garattini 1997). Some concerns have been expressed that amineptine may be associated with abuse potential, and theoretically these two phenomena may be linked through the dopamine system because of an amphetamine-like effect. 

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