Elsevier

Drug Discovery Today

Volume 10, Issue 8, 15 April 2005, Pages 578-585
Drug Discovery Today

Review
Strategies for producing faster acting antidepressants

https://doi.org/10.1016/S1359-6446(05)03398-2Get rights and content

Abstract

Existing antidepressant treatments exhibit limited efficacy and a slow onset of action. Several neurobiological adaptive mechanisms might delay the clinical effects of antidepressants, whose therapeutic action is primarily triggered by an increase of serotonergic and noradrenergic neurotransmission. Here, we review several potential mechanisms that could be useful to increase the speed of current antidepressant drugs, such as additional blockade of aminergic autoreceptors or antagonism of certain postsynaptic (5-HT2A, 5-HT2C) receptors. The potential use of strategies not based on monoaminergic transmission, such as CRF and NK1 receptor antagonists, or more novel strategies, based on glutamatergic or GABAergic transmission or on intracellular messengers, are also reviewed.

Section snippets

Treatments based on dual reuptake inhibition

As outlined previously, most antidepressant drugs inhibit 5-HT and/or NA reuptake. There is evidence suggesting that dual reuptake blockers, such as the tricyclic clomipramine or the selective 5-HT/NA reuptake inhibitor (SNRI) venlafaxine, are more rapid and/or efficacious than SSRIs [5, 6, 10, 11]. Another drug (duloxetine), with the ability to selectively block 5-HT and NA transporters, has also been approved for the treatment of depression in the USA and Europe. Hence, dual-action drugs

Autoreceptor antagonists

Serotonergic neurones are endowed with two sets of autoreceptors, located in the somatodendritic level in the midbrain raphá nuclei (5-HT1A) and in 5-HT axons (5-HT1B/1D) in projection areas. The activation of 5-HT1A autoreceptors by 5-HT or selective agonists suppresses cell firing and impulse-dependent 5-HT release, whereas 5-HT1B receptors control 5-HT synthesis and release at terminal level. The increase of extracellular 5-HT produced by reuptake blockade activates 5-HT1A receptors in the

Possible role of 5-HT2A/2C receptors in the augmentation of antidepressant response

Several open-label and double blind placebo-controlled studies show that some antidepressants (e.g. mirtazapine and mianserin) and atypical antipsychotics could augment the clinical response to SSRIs in treatment-resistant patients (for review, see [26]). Often, these responses have been observed shortly after administration of these drugs, which suggests that addition of the second drug induces rapid antidepressant changes. One common characteristic of mirtazapine, mianserin and the atypical

5-HT7 receptors

The affinity of clinically effective antidepressant drugs for the 5-HT7 receptor [36], and the finding that chronic administration of antidepressant drugs down-regulates 5-HT7-mediated responses and receptor binding in limbic areas [37, 38], form the basis for a possible involvement of this receptor in depressive states and antidepressant response. Furthermore, the presence of the 5-HT7 receptor gene transcripts and protein in midbrain, hypothalamic, cortical and limbic areas [39, 40] suggests

NK1 receptor antagonists

NK1 receptor antagonists constitute a new drug class, although a clear-cut therapeutic outcome has not prevailed so far. Substance P (SP) is the preferred endogenous agonist for NK1 receptors. The connection between SP and depression is based on several preclinical and clinical observations.

  • First, the administration of SP or SP agonists evokes a stress response in animals [41] that can be prevented by NK1 receptor antagonists [42].

  • Second, there is a colocalization of SP with brain serotonergic

CRF antagonism

Abnormal hypothalamic-pituitary-adrenal (HPA) activity has been implicated in the pathophysiology of depression and anxiety disorders [58, 59]. Indeed, depressed patients frequently show increased plasmatic levels of cortisol [60]. The HPA axis is mainly controlled by the neuropeptide corticotrophin-releasing factor (CRF), secreted by neurones whose cell bodies are in the paraventricular nucleus of the hypothalamus (PVN) and other brain areas. Two CRF receptor subtypes have been described: CRF1

Glutamate-acting drugs

Based on the potential occurrence of glutamatergic abnormalities in major depression, several alternative drugs focusing on ionotropic glutamate receptors have been suggested, with a special focus on the NMDA receptor. Hence, chronic treatment with clinically active antidepressants results in adaptive modifications in this receptor subtype [65], whereas antagonists acting at this receptor, such as AP7 or ACPC, induce antidepressant-like effects in animal models [66]. Eliprodil, which acts at

Antiglucocorticoid agents

The functionality of the HPA axis, altered in depression, is feedback regulated by glucocorticoid receptors (GR), which are localized in the brain and the periphery. Their potential use as targets for antidepressant drugs is supported by: (a) their abnormal function in depressed patients, (b) altered behaviour in transgenic mice expressing a complementary antisense GR mRNA, and (c) increased GR expression following treatment with tricyclic antidepressants and selective NE reuptake inhibitors,

Neuroplasticity

The exact role of neuroplasticity in depression is still debated, particularly with regard to the temporal pattern of clinical improvement. However, mood disorders, including stress and depression, seem to be associated with an impairment of the mechanisms controlling neuroplasticity and cell survival in brain [4]. Supporting this, a reduction of the hippocampal volume in depressed patients and cortical neuronal loss has been reported [73], although such observations are not universal [74].

Modulation of post-receptor mechanisms: the cAMP transduction pathway

Chronic antidepressant treatment upregulates the expression of CREB, therefore, compounds that increase cAMP levels could be a valid strategy in the treatment of depression. Phosphodiesterase-IV (PDE-IV) mediates the breakdown of cAMP: therefore, PDE-IV inhibitors could have antidepressant properties. Rolipram, a selective inhibitor of PDE-IV, showed an antidepressant pharmacological profile and increased hippocampal cell proliferation [81]. However, its development was halted due to severe

Concluding remarks

To date, successful attempts to improve the speed of action of antidepressants have been based on pharmacological approaches based on monoaminergic systems. This includes the combination of 5-HT reuptake blockade - which represents >80% of all antidepressant treatments on its own (e.g. SSRIs) - with (a) NE reuptake blockade (to produce SNRIs) or (b) aminergic receptor blockers, either presynaptic (pindolol) or postsynaptic, such as the atypical antipsychotics. Indeed, the complex pharmacology

Acknowledgements

Work supported by grants from La Maratò TV3 and CICYT (BF101-0592). A. Bortolozzi and P. Celada are recipients of a Ramòn y Cajal contract from the Ministry of Science and Technology. Support from the CIEN network (IDIBAPS-ISCIII RTIC C03/06) and Generalitat de Catalunya (2001-SGR00355) is also acknowledged.

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