Trends in the Development of New Antidepressants. Is there a Light at the End of the Tunnel?

Abstract

Since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) in mid-1950's, treatment of depression has been dominated by monoamine hypotheses. The well-established clinical efficacy of TCAs and MAOIs is due, at least in part, to the enhancement of noradrenergic or serotonergic mechanisms, or to both. Unfortunately, their very broad mechanisms of action also include many unwanted effects related to their potent activity on cholinergic, adrenergic and histaminergic receptors.The introduction of selective serotonin reuptake inhibitors (SSRIs) over twenty years ago had been the next major step in the evolution of antidepressants to develop drugs as effective as the TCAs but of higher safety and tolerability profile. During the past two decades SSRIs (fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram) gained incredible popularity and have become the most widely prescribed medication in the psychiatric practice. The evolution of antidepressants continued resulting in introduction of selective and reversible monoamine oxidase inhibitors (eg. moclobemid), selective noradrenaline (eg. reboxetine), dual noradrenaline and serotonin reuptake inhibitors (milnacipram, venlafaxin, duloxetin) and drugs with distinct neurochemical profiles such as mirtazapine, nefazadone and tianeptine. Different novel serotonin receptor ligands have also been intensively investigated. In spite of the remarkable structural diversity, most currently introduced antidepressants are 'monoamine based'. Furthermore, these newer agents are neither more efficacious nor rapid acting than their predecessors and approximately 30% of the population do not respond to current therapies.By the turn of the new millennium, we are all witnessing a result of innovative developmental strategies based on the better understanding of pathophysiology of depressive disorder. Several truly novel concepts have emerged suggesting that the modulation of neuropeptide (substance P, corticotrophin-releasing factor, neuropeptide Y, vasopressin V 1b , melanin-concentrating hormone-1), N-methyl-D-aspartate, nicotinic acetylcholine, dopaminergic, glucocorticoid, δ-opioid, cannabinoid and cytokine receptors, gamma-amino butyric acid (GABA) and intracellular messenger systems, transcription, neuroprotective and neurogenic factors, may provide an entirely new set of potential therapeutic targets, giving hope that further major advances might be anticipated in the treatment of depressive disorder soon.The goal of this review is to give a brief overview of the major advances from monoamine-based treatment strategies, and particularly focus on the new emerging approaches in the treatment of depression.

Antidepressant Efficacy of the Antimuscarinic Drug Scopolamine

“…23,24 Some tricyclic antidepressant (TCA) agents exerted potent antimuscarinic actions, 25-27 but these effects were thought primarily to produce adverse effects without contributing to therapeutic efficacy. [28][29][30] As a result, during the past 2 decades, efforts to develop new antidepressant drug treatments emphasized the development of compounds that specifically lack antimuscarinic effects. 31…”

“…23,24 Some tricyclic antidepressant (TCA) agents exerted potent antimuscarinic actions, [25][26][27] but these effects were thought primarily to produce adverse effects without contributing to therapeutic efficacy. [28][29][30] As a result, during the past 2 decades, efforts to develop new antidepressant drug treatments emphasized the development of compounds that specifically lack antimuscarinic effects. 31 Herein we report the results of 2 studies that each demonstrate rapid, potent antidepressant responses to the antimuscarinic agent scopolamine hydrobromide in depressed patients with MDD or BD.…”

Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

“…1,2 Although its etiology is unknown, some theories suggest that biological factors may be implicated. 3 One such theory is the monoamine hypothesis, which suggests that an imbalance in cerebral monoamines such as dopamine, norepinephrine, and, especially, serotonin is responsible for depressive symptomatology. 3 The monoamine hypothesis is the theory on which the leading commercially available antidepressants are based.…”

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

“…In up to 15% of individuals with major depressive disorder the cause of death is suicide. According to a World Health Organization forecast, by the year 2020 depression will become the second leading cause of premature death and disability worldwide (Pacher and Kecskeméti, 2004). Although significant advances have been made in the treatment of mood disorders during the past decades, ϳ30% of the population do not respond to current therapies, and the search for novel pharmacological approaches continues (reviewed in Pacher and Kecskeméti, 2004).…”