Treatment-Resistant Depression

What we need are agents with novel mechanisms of action. As indicated in Table 2, there is a rich pipeline of candidates. Some of these agents, such as agomelatine, are relatively far along in the clinical trial process with human subjects. Others, such as amibegron and sipatrigine, have been shown to be efficacious only in animal models of depression and their benefit is therefore highly speculative.^15-17 Some of the drugs have been tried as augmentation agents as well (eg, riluzole(Drug information on riluzole)). Agents such as pramipexole(Drug information on pramipexole), memantine, riluzole, and ketoconazole(Drug information on ketoconazole) are already available in the United States.

Proposed mechanisms of action vary widely, but 2 development strategies are generating a great deal of activity:

• Agents are being developed that affect corticosteroid function at various levels. (Glucocorticoids have figured prominently in recent theories as major agents in stress-induced neuronal injury and cell death leading to depression.¹⁸⁾

• Compounds are being developed that induce the synthesis of brain-derived neurotrophic factor (BDNF), particularly through their effects on glutamate receptors.

In a sense, these 2 strategies are related: it has been proposed that BDNF acts as a modulator of neuronal repair and even neurogenesis in response to cortisol-induced brain injury. The findings with ketamine(Drug information on ketamine) are particularly exciting. A recent study reported that ketamine, through its activity as an N-methyl-D-aspartate (NMDA)-receptor antagonist, increases synaptic glutamate and therefore stimulates a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (both NMDA and AMPA receptors are subtypes of glutamate receptors).¹⁹ AMPA potentiators are known to induce BDNF production more rapidly than current antidepressants.²⁰ It has been hypothesized that a more rapid induction of BDNF would lead to a faster onset of antidepressant action. In a study by Zarate and colleagues,²¹ the onset of the antidepressant effect of ketamine occurred within 2 hours. Unfortunately, the drug must be given by intravenous infusion, but because the effect persisted for 7 days, ketamine treatment may be useful if given as a series.

Another NMDA-receptor antagonist now available in the United States is memantine (FDA-approved for Alzheimer disease). Memantine was shown to be effective in an open-label study in major depression. In a double-blind, randomized trial it showed comparable effects to escitalopram(Drug information on escitalopram) in patients with major depression and alcohol(Drug information on alcohol) dependence.^22,23 However memantine(Drug information on memantine) failed to separate from placebo in a double-blind, placebo-controlled study in major depression.²⁴ The less robust antidepressant properties of memantine when compared with those of ketamine may be due to differing NMDA receptor binding properties between the 2 compounds.²¹

Combining agents

In this category there are 2 similar strategies: (1) combination, that is, combining 2 FDA-approved antidepressants with presumably complementary mechanisms of action; and (2) augmentation, in which a drug not approved as an antidepressant is used with an FDA-approved antidepressant. Such pairings can be used either at the beginning of therapy to speed the response (an accelerator strategy) or to improve the overall response, thereby enhancing the odds of achieving remission. As noted, when combining agents, one must be aware of possible CYP450-based pharmocokinetic interactions or other pharmacological interactions, such as the risk of serotonin syndrome when an SSRI is combined with an MAOI.

Combination strategies. Of the 2 strategies, the addition of a second antidepressant is the more intuitively obvious. Randomized controlled trials have supported the superior efficacy of a TCA/SSRI combination, as well as a mirtazapine(Drug information on mirtazapine)/SSRI combination; open studies have done the same for TCA/MAOI and SSRI/bupropion combinations.²⁵ A positive retrospective chart review of 10 patients treated with a combination of duloxetine(Drug information on duloxetine) and bupropion has also been published.²⁶