Mode of action of antidepressant drugs

Sulser, Fridolin; Vetulani, Jerzy; Mobley, Philip L.

doi:10.1016/0006-2952(78)90226-5

Cited by 478 publications

(125 citation statements)

References 48 publications

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“…Zanko and Beigon (111) and Mann et al (56) reported increased density of â-adrenergic receptors in suicides, whereas De Paermentier et al (28) reported no change. Despite the lack of consensus, the time-course for therapeutic efficacy closely follows that reported for the downregulation of â-receptors (97,106). Furthermore, evidence from a wide range of preclinical and clinical studies supports the hypothesis that monoamine neurotransmission is involved in the pathology and/or the treatment of affective disorders (4,21,34,55,86,90).…”

Section: Introductionsupporting

confidence: 52%

The Promises and Pitfalls of Reboxetine

Page

2003

CNS Drug Reviews

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The antidepressant compound, morpholine, 2-[(2-ethoxyphenoxy)phenylmethyl]-, methanesulfonate, or reboxetine, is a selective noradrenergic reuptake inhibitor that acts by binding to the norepinephrine (NE) transporter and blocking reuptake of extracellular NE back into terminals. This compound has low affinity for other transporters and receptors. The development of reboxetine as a potential antidepressant stems from the prior demonstration that blockade of the NE transporter imparts antidepressant activity. Desipramine, lofepramine, and nortryptiline are examples of tricyclic antidepressant (TCA) compounds from the first generation of antidepressants that exert their effects by blockade of NE reuptake. Maprotiline, a non-tricyclic compound, is also a NE selective reuptake inhibitor. Unfortunately, these antidepressants are also associated with interactions with muscarinic, histaminergic, and adrenergic receptors, which are known to contribute to a variety of untoward side effects. Despite the positive pharmacological profile of reboxetine, i.e., selectivity and specificity, with relatively fewer side effects, its use as an antidepressant is currently limited to Europe. Reboxetine is marketed as Edronax ® in the UK, Norebox ® in Italy, and as Irenor ® in Spain. It is registered in Germany, Sweden, Denmark, Ireland, Austria and Finland. Based on studies conducted primarily outside the US, the FDA granted a preliminary letter of approval in 1999. However, more recent clinical studies conducted in the US and Canada, prompted by the FDA, resulted in a letter of non-approval. To date, it is unclear why the further development of reboxetine as an antidepressant in the US has been halted. Despite this setback, reboxetine has been a valuable pharmacological tool to assess the role of the noradrenergic system in preclinical studies of depressive disorder.

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Section: Introductionsupporting

confidence: 52%

The Promises and Pitfalls of Reboxetine

Page

2003

CNS Drug Reviews

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“…Even then, investigators need to recognize that the mechanism of action of antidepressants is still unknown. A growing body of evidence suggests, for example, that the major effects of antidepressants might be due to downregulation of alpha-2-adrenergic presynaptic receptors, or decreased sensitivity of postsynaptic beta-noradrenergic receptors and have little to do with blockade of reuptake (Crews and Smith 1978;Sulser et al 1978;Maas and Huang 1980 …”

Section: Discussionmentioning

confidence: 99%

Dexamethasone suppression test and selection of antidepressant medications

Greden

Kronfol²,

Gardner³

et al. 1981

Journal of Affective Disorders

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“…Furthermore, nearly all antidepressants diminish the ability of ␤ ARs to stimulate adenylate cyclase-mediated cAMP production in these regions (Vetulani and Sulser 1975;Charney et al 1981), and the time course for these receptor changes is consistent with the time course for clinical response to antidepressant treatment. Together, these observations have been cited as support for an alternative hypothesis of antidepressant action, which proposes that ␤ AR receptor down-regulation, and the consequent decrease in noradrenergic function, is responsible for antidepressant action (Sulser et al 1978;Charney et al 1981). In addition, antidepressants decrease tyrosine hydroxylase and tyrosine hydroxylase mRNA following chronic administration (Nestler et al 1990), and chronic exposure to either desipramine or electroshock decreases norepinephrine transporter binding (Bauer and Tejani-Butt 1992).…”

Section: Controversy Remains Regarding the Role Of Noradrenergic Systmentioning

confidence: 93%

Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy

Miller

Ekstrom

Mason

et al. 2001

Neuropsychopharmacology

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Controversy remains regarding the role of noradrenergic systems in determining clinical response to antidepressant pharmacotherapy. Pineal gland production of melatonin can serve as a physiologic index of noradrenergic function. The aim of this study was to examine the effects of antidepressant treatment on 24-hour urinary excretion of the principle metabolite of melatonin, 6-sulfatoxymelatonin in treatment responders and nonresponders. Twenty-four outpatients meeting DSM-III-R criteria for MajorThe introduction of effective antidepressant pharmacotherapies in the 1950s revolutionized the treatment of mood disorders. However, despite several decades of research, the mechanisms of action of antidepressants remain unclear. Elucidation of these mechanisms is of considerable clinical, as well as scientific, importance. Although the majority of patients respond to treatment, a substantial minority do not, and insights regarding the necessary psychobiologic components of treatment response could help predict, and perhaps prevent, some cases of treatment failure.Early observations focused attention on the role of norepinephrine (NE) in determining antidepressant response. All of the original antidepressants, including the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), enhance noradrenergic neurotransmission, either directly or via active metabolites. Based on these observations, early theories of antidepressant action proposed that clinical response is related to increased noradrenergic activity in the brain (Schildkraut 1969). Later studies found that most antidepressants, including those with minimal direct biochemical effects on NE, can influence noradrenergic systems. For example, lithium, electroconvulsive therapy, the dopamine reuptake inhibitor bupropion, and the serotonin (5-HT) reuptake inhibitor zimelidine all decrease "whole-body norepinephrine turnover"; that 24 , NO . 6 is, the 24-hour excretion of NE and its major metabolites (Linnoila et al. 1983;Rudorfer et al. 1984;. Central NE turnover, as measured by cerebrospinal fluid concentrations of the NE metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG), is also reduced by a variety of antidepressants, including the 5-HT specific reuptake inhibitor zimelidine (Potter et al. 1985). Based on these observations, it seems that increased noradrenergic function is an integral component of antidepressant treatments.On the other hand, a wide variety of antidepressants, including tricyclic NE and 5-HT reuptake inhibitors, monoamine oxidase inhibitors, and repeated electroconvulsive shock, down-regulate the density of ␤ -adrenergic receptor ( ␤ AR) ligand-binding sites in limbic brain regions, including the cerebral cortex and the hippocampus (Vetulani and Sulser 1975;Banerjee et al. 1977;Sugrue 1983). Furthermore, nearly all antidepressants diminish the ability of ␤ ARs to stimulate adenylate cyclase-mediated cAMP production in these regions (Vetulani and Sulser 1975;Charney et al. 1981), and the time course for these receptor changes ...

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Mode of action of antidepressant drugs

Cited by 478 publications

References 48 publications

The Promises and Pitfalls of Reboxetine

The Promises and Pitfalls of Reboxetine

Dexamethasone suppression test and selection of antidepressant medications

Noradrenergic Function and Clinical Outcome in Antidepressant Pharmacotherapy

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