Newer Medications for Complicated Depression

Michael E. Thase, MD

Departments of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia Veterans Affairs Medical Center, and Pittsburgh Medical Center, Philadelphia and Pittsburgh

Recently Introduced Antidepressant Medications

Of the antidepressant medications that have been introduced in this century, no unique or novel class of medication has been developed. Escitalopram is a stereoisomer of the SSRI citalopram. Duloxetine is a fairly new antidepressant that belongs to the SNRI class, and desvenlafaxine is a metabolite of the older SNRI venlafaxine. Selegiline is an MAOI with a novel skin patch delivery system meant to minimize the need for dietary control. Unfortunately, the skin patch system has only been approved at the minimum effective dose. Patients who require higher doses would still have to monitor their diets the same way they would with the older MAOIs. In short, the field has seen the introduction of new drugs from existing drug classes and metabolites and stereoisomers of older drugs, but nothing with a novel mechanism of action, and, therefore, no real improvement in antidepressant efficacy has occurred.

Current antidepressant pharmacotherapy is, at best, moderately effective for most patients and efficacy across all drug classes is similar but underwhelming. The SSRIs are the leading choice for first-line treatment in major depressive disorder. However, the popularity of SSRIs is mostly attributable to the improved safety and tolerability profile of the class compared with other antidepressants. Future antidepressant pharmacotherapies will most likely require innovative mechanisms of action to resolve the unmet needs associated with contemporary medications.

Novel Targets for Antidepressants

Triple reuptake inhibitors, with an effect possibly akin to what clinicians create when they combine bupropion with an SNRI, could potentially be useful. Interest also exists in the development of a mixed serotonergic drug with an effect similar to what one might get when mixing a 5-HT2 medication like mirtazapine with a serotonin reuptake inhibitor.


A more promising possibility would be antagonists of the glutamate receptors such as the N-methyl-d-aspartate receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. Glutamate is an excitatory amino acid that is involved either directly or indirectly with pathological levels of central nervous system arousal and probably with suppression of neurotrophins, which help maintain the health and well-being of neurons.

Targeting truly novel neuropeptides is important for future antidepressant development. Two promising prospects are antagonists of corticotropin-releasing hormone and modulators of brain-derived neurotrophic factor synthesis. Antidepressants of the future may act through a variety of pathways, but the ultimate goal is developing treatments that can alter the stress response of gene activity (AV 1AV 1).1


In summary, several antidepressants that have similar efficacy and safety profiles are available. Unmet needs in the pharmacotherapy of depression include treatments that target novel neurotransmitter mechanisms and have increased efficacy and onset of action compared with current antidepressant agents, while at least maintaining (if not improving) the existing level of safety and tolerability.

Drug Names

bupropion (Aplenzin, Wellbutrin, and others), citalopram (Celexa and others), desvenlafaxine (Pristiq), duloxetine (Cymbalta), escitalopram (Lexapro and others), mirtazapine (Remeron and others), selegiline (EMSAM), venlafaxine (Effexor and others)


α2-AR = α2-adrenergic receptor, 5-HT = serotonin, AC = adenylyl cyclase, AMPAR = α-amino 3-hydroxy-5-methylisoxazole propionate receptor, BDNF = brain-derived neurotrophic factor, CREB = cyclic adenosine monophosphate response element-binding protein, CRH = corticotrophin-releasing hormone, GC = guanlyl cyclase, Glu = glutamate, GR = glucocorticoid receptor, MAOI = monoamine oxidase inhibitor, MAPK = mitogen-activated protein kinase, NMDAR = N-methyl-d-aspartate receptor, NE = norepinephrine, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TrkB = tyrosine receptor kinase receptor B

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  1. Charney DS, Manji HK. Life stress, genes, and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci STKE. 2004;2004(225):re5.