Biochemical hypotheses on antidepressant drugs: a guide for clinicians or a toy for pharmacologists?

Abstract

SynopsisThe development of knowledge about the mechanism of action of tricyclic and the so-called ‘atypical’ antidepressants (AD) is reviewed. The discovery of clinically active antidepressants with little or no effect on noradrenaline or serotonin uptake has disproved the widely accepted concept that inhibition of monoamine uptake is a prerequisite for antidepressant activity. Another serious objection to this hypothesis is that blockade of monoamine uptake occurs in a matter of minutes after administration while 2–3 weeks of repeated treatment are necessary for the clinical AD effect. Nevertheless, the effect of repeated treatment with AD is compatible with the hypothesis that changes in central monoamine transmission are involved in the clinical activity of these drugs. Major changes in monoamine function after repeated treatment with AD include: desensitization and reduced density of noradrenaline receptors coupled to the adenylcyclase system, opposite changes in the sensitivity of α1 (increased) and α2-adrenoreceptors (decreased), down regulation of serotonin2 receptors and complex changes in the behavioural and electrophysiological responsiveness to serotonin agonists, subsensitivity of presynaptic dopamine receptors and enhanced activity of the mesolimbic dopamine system, decreased and increased density of GABA-A and GABA-B receptors respectively and down regulation of [3H]benzodiazepine binding.It remains to be clarified whether some of these changes have larger roles than others or whether they all contribute to the AD activity. An important role of dopamine in the activity of AD drugs is suggested by findings in the forced swimming test, whereas both catecholamines seem to be involved in the attenuation of escape deficit provoked by inescapable shock (learned helplessness). No clear evidence for a role of serotonin (with the possible exception of serotonin1A receptors) or GABA has been obtained in these experimental models of depression. The general validity of these findings obviously rests on the assumption that these models represent significant aspects of human depression.

Antitussive Drugs—Past, Present, and Future

“…23) is the prototypical tricyclic antidepressant, with a broad range of pharmacological actions including effects on the adrenergic, serotonergic, muscarinic, and histaminergic systems (Garattini and Samanin, 1988). Low-dose amitriptyline is also used in chronic neuropathic pain states such as migraine, postherpetic neuralgia, and painful diabetic neuropathy and has recently been suggested to be useful in the treatment of cough.…”

Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly

“…In depressed patients an overactivity of the noradrenergic system and an increase in ␤-adrenergic sensitivity is observed, possibly linked to the stress component. 22 Despite the fact that long-term antidepressant treatment decreases the responsiveness of central ␤-adrenergic receptors, 23 the hypothesis of hypersensitive ␤-adrenergic receptors underlying depression is not fully sustained by experimental data.…”

“…30 An increase in 5-HT2 density has been shown in the cortex of suicide victims 30 and, further, chronic treatment with various antidepressant drugs appears to reduce 5-HT2 receptor function in the rat brain. 22,30 Blood platelets possess an uptake site for serotonin and 5-HT2 receptors structurally similar to their brain counterparts. Thus, changes in functional activity of the platelet membrane receptor may represent indirect markers of brain serotonin function.…”

“…Chronic antidepressant treatments are known to produce desensitization and reduced density of ␤-adrenoceptors, particularly the ␤1 subtype, 22,23 decreased ␣2-autoreceptor function, 22,27 and increased ␣1 post-synaptic receptor sensitivity. 22,27 The decreased number of ␤-adrenoreceptors is more evident following TCA and MAOi chronic treatment than following SSRIs administration, 54 and it is possible that these adaptive changes do not contribute to the antidepressant effects but ameliorate the activity in functionally linked serotoninergic and dopaminergic neuronal systems.…”

“…30 The fact that noradrenergic denervation in rat forebrain neurons prevents antidepressant-sensitization to serotonin suggests that noradrenergic neurons play a permissive role in the dynamic changes of 5-HT recep-tors. 22 In addition to TCAs and SSRIs there are drugs which act by modifying both noradrenergic and serotoninergic neurotransmission. Mirtazapine, a pyridine analogue of mianserin, is an antagonist of ␣2-autoreceptors and ␣2-heteroreceptors located on serotoninergic terminals, inducing an increase in noradrenaline and serotonin release respectively.…”