Depression antidepressant action

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. 

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. 

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. 

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. 

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]. 

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). 

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). 

Although postsynaptic DA agonists and presynaptic Dj autoreceptor antagonists share a common property of enhancing DA transmission, Dj autoreceptor agonists have been developed specifically to block DA transmission as an alternative approach to antipsychotic therapy (Benkert et al. 1992). A variety of such compounds are available (Seyfried and Boettcher 1990), four of which—talipexole, pramipexole, roxindole, and OPC-4392 —have been evaluated as antipsychotics in schizophrenic patients (Benkert et al. 1992). Only roxindole has been tested in depression, and then only in two uncontrolled pilot studies over 4 weeks of treatment (Benkert et al. 1992 M. Kellner et al. 1994). Response rates similar to those of imipramine were observed, with a fast onset of action in some patients. Roxindole s antidepressant action may lie in its ability to selectively stimulate supersensitive postsynaptic Dj receptors, and thereby enhance DA function, or in its additional properties as an inhibitor of serotonin reuptake and as a 5-HT, receptor agonist (Benkert et al. 1992 Seyfried et al. 1989). 

Sampson D, Willner P, Muscat R Reversal of antidepressant action by dopamine antagonists in an animal model of depression. Psychopharmacology 104 491-495, 1991... 

Sharp T, Bramwell SR, Lambert P, et al Effect of short- and long-term administration of lithium on the release of endogenous 5-HT in the hippocampus of the rat in vivo and in vitro. Neuropharmacology 30 977-984, 1991 Sharpley AL, Cowen PJ Effect of the pharmacological treatment on sleep of depressed patients. Biol Psychiatry 37 85-98, 1995 Sharpley AL, Walsh AES, Cowen PJ Nefazodone—a novel antidepressant— may increase REM sleep. Biol Psychiatry 31 1070-1073, 1992 Shaw DM, Harris B, Lloyd AT, et al A comparison of the antidepressant action of citalopram and amitriptyline. Br J Psychiatry 149 515-517, 1986 Shaw PJ, Ince PG A quantitative autoradiographic study of H-3-Kainate binding sites in the normal human spinal-cord, brain stem, motor cortex. Brain Res 641 39-45, 1994... 

Serotonin precursors (L-tryptophan. 5-hydroxytryptophan) have some antidepressant action, whereas a reduction in the blood levels of tryptophan in remitted depressed patients can provoke clinical relapse. 

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. 

The positive effects of the monoamine oxidase inhibitor isoniazid and the amine reuptake blocker imipramine were both discovered by accident. Isoniazid was being used as an antitubercular drug when patients reports of elation led Nathan Kline to test and to demonstrate its antidepressant power. Ronald Kuhn had synthesized imipramine, a tricyclic molecule, as a possible me-too analog of chlorpromazine. When Kuhn found that it had little or no antipsychotic potential, he tried it out on depressives, and voila They got better. After a while, that is. As with isoniazid, imip-ramine s antidepressant action was evident only after one to four weeks of administration. 

FIGURE 5—16. Tricyclic antidepressants exert their antidepressant action by blocking the neurotransmitter reuptake pump, thus causing neurotransmitter to accumulate. This accumulation, according to the monoamine hypothesis, reverses the prior neurotransmitter deficiency (see Fig. 5—14) and relieves depression by returning the monoamine neuron to the normal state. 

One theory to explain the ultimate mechanism of delayed therapeutic action of antidepressants is the neurotransmitter receptor hypothesis of antidepressant action (Figs. 6—1 through 6—6). This is a hypothesis related to the neurotransmitter receptor hypothesis of depression discussed in Chapter 5 (Figs. 5—60 through 5—62). As previously discussed, this latter hypothesis proposes that depression itself is linked to abnormal functioning of neurotransmitter receptors. 

Whether or not neurotransmitter receptors are abnormal in depression, the neurotransmitter receptor hypothesis of antidepressant action proposes that antidepressants, no matter what their initial actions on receptors and enzymes, eventually cause a desensitization, or down regulation, of key neurotransmitter receptors in a time course consistent with the delayed onset of antidepressant action of these drugs (Figs. 6—1 through 6—6). 

FIGURE 6-2. The neurotransmitter receptor hypothesis of antidepressant action—part 1. Shown here is the monoaminergic neuron in the depressed state, with up regulation of receptors (indicated in the red circle). 

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