New and Emerging Classes of Antidepressants
Kiran Rabheru, MD, CCFP, FRCP, ABPN, Physician Leader, Geriatric Psychiatry Program, Regional Mental Health Care and Chair, Division of Geriatric Psychiatry, Associate Professor of Psychiatry, University of Western Ontario, London, ON.
Depression is the most common psychiatric disease in the elderly. Over 30% of community-dwelling elderly suffer from subsyndromal depression and over 10% of hospitalized elderly have syndromal major depressive disorder (MDD). Depression is frequently a persistent and recurrent disorder leading to increased morbidity and mortality, as well as poor quality of life.
Early antidepressant medications, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) were discovered through astute clinical observations. These first-generation medications are effective because they enhance serotonergic and/or noradrenergic function. Unfortunately, the TCAs also block histaminic, cholinergic and alpha-1 adrenergic receptor sites, causing unwanted side effects such as weight gain, dry mouth, constipation, urinary retention, confusion, drowsiness and dizziness. MAOIs interact with tyramine to cause potentially lethal hypertension and cause dangerous interactions with a number of prescribed and over-the-counter medications.1
A major goal of antidepressant development is to improve on preceding drug classes for greater specificity, fewer unwanted side effects and more rapid onset of action. To this end, antidepressants with significantly distinct pharmacological characteristics have been introduced in the last decade (Table 1), including the most widely prescribed single-receptor selective serotonin reuptake inhibitors (SSRIs). Other multiple-receptor antidepressants, including venlafaxine, mirtazapine, bupropion, trazodone and nefazodone, target one or more specific brain receptor sites with generally fewer side effects than their precursors.2,3
In spite of the remarkable structural diversity, most antidepressants that have been recently introduced modulate monoamine activity as a therapeutic strategy. These newer antidepressants, however, are not ideal, as they require two to six weeks of treatment to produce therapeutic effect and leave approximately 30% of patients unresponsive.4,5
The emergence of potential novel mechanisms of action beyond the monoaminergic synapse may provide an entirely new set of potential therapeutic targets and thus lead to important new developments.6 These approaches include the modulation of the neuropeptide substance P, N-methyl-D-aspartate (NMDA), gamma amino butyric acid (GABA), the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, and the brain-derived neurotrophic factor (BDNF) to promote neurogenesis.7
Substance P Antagonists
During the past decade, considerable progress has been made in understanding the neural circuits involved in the antidepressant and anxiolytic efficacy of the neuropeptide substance P (SP).8 Although best known as a pain neurotransmitter, SP also controls vomiting and various behavioural, neurochemical and cardiovascular responses to stress.9 Clinical trials have confirmed the efficacy of SP antagonists (SPAs) involving NK1 receptors in alleviating depression and emesis but, surprisingly, not pain. Pharmacological blockade or deletion of the NK1 receptor produces an antidepressant and anxiolytic-like profile in a range of behavioural assays that is distinct from that of established drugs.10 SPAs are generally well tolerated and do not induce sedation or motor impairment in preclinical species. This represents an important opportunity to exploit these molecules as novel therapeutic agents. SPAs are currently the best validated and most clinically advanced novel approach to treating MDD, and several compounds are in advanced clinical development.
N-methyl-D-aspartate
The N-methyl-D-aspartate (NMDA) receptor complex is a subtype of glutamate receptor and its dysfunction is involved in many neurological disorders associated with aging, including chronic pain, depression, stroke and Parkinson's disease. NMDA receptors are crucial for hippocampal cell plasticity and to encode the salient features of experience. Disruption of these plasticity mechanisms may underlie depressive as well as other age-related disorders. Both preclinical and recent clinical studies indicate that compounds which reduce transmission at NMDA receptors are effective antidepressants. Moreover, chronic administration of