Evidence-Based Reviews

Triple reuptake inhibitors: What to expect from ‘mega-antidepressants’

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Rapid onset of action could make serotonin-norepinephrine-dopamine reuptake blockers a clinically useful option for patients with depression


 

References

The first triple reuptake inhibitors are at least several years from approval, but this novel antidepressant class represents an intriguing strategy for treating depression. Several pharmaceutical companies are developing these compounds—with at least one in phase-III clinical trials.

Adding a dopamine reuptake component to serotonin and norepinephrine reuptake blockade could result in an antidepressant with a more rapid onset of action, greater efficacy, and fewer side effects. This article updates what is known about triple reuptake inhibitors and suggests their potential role among first-line antidepressants and in treating patients who have not responded adequately to existing agents.

Role of Monoamines in Depression

Remission—the absence of depression signs and symptoms—is the optimum goal in treating depression. Patients who do not meet this goal are more likely to relapse and to relapse more rapidly than those whose symptoms are treated to remission. Incomplete response rates and delayed onset of action limit the efficacy of available antidepressants (Box).1-6

Box

Incomplete response, ‘therapeutic lag’ can limit antidepressants’ efficacy

Antidepressant response. An estimated 60% to 70% of depressed patients respond to antidepressants, but only 20% to 40% achieve remission; 15% of depressed patients do not respond to any available antidepressants.1,2

Delayed onset of action with most antidepressants means that depression does not improve noticeably for at least 1 week and typically 3 weeks or more.3,4 Many patients remain greatly impaired during this “therapeutic lag” and can perceive that the medication isn’t helping them with signs and symptoms such as:

  • persistent sad mood
  • decreased interest in pleasurable activities (anhedonia)
  • changes in body weight or appetite
  • changes in sleep patterns
  • difficulty thinking or concentrating
  • feelings of worthlessness or guilt
  • low energy, fatigue, or increased agitation
  • recurrent thoughts of death or suicide
  • poor self-esteem.

Newer antidepressants such as selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and dual serotonin/norepinephrine reuptake inhibitors generally are better tolerated and easier to use than tricyclics and monoamine oxidase inhibitors. Even the newer antidepressants can cause side effects such as weight gain and sexual dysfunction, however, and might not be more efficacious than older antidepressants.5,6

Monoamine hypothesis. Although the precise pathophysiology of depression is unclear, dysfunction of monoamine neurotransmission has been a central hypothesis in depression research for decades. This hypothesis is based in part on observations that antidepressants alter monoamine neurotransmission via acute pharmacologic effects at the synapse.

Three major mechanisms account for the acute actions of antidepressants on monoamines:

  • inhibition of monoamine oxidase, the enzyme that degrades serotonin, norepinephrine, and dopamine
  • blockade of neurotransmitter reuptake by binding to transporters
  • antagonism of presynaptic neurotransmitter receptors, resulting in an increase in neurotransmitter release.4
Most antidepressants act by increasing the synaptic availability of serotonin (such as fluoxetine and paroxetine); norepinephrine (such as reboxetine); norepinephrine and serotonin (such as duloxetine and venlafaxine); or norepinephrine, serotonin, and dopamine (such as phenelzine). Although controversial, some clinical data suggest that antidepressants that elevate synaptic levels of both norepinephrine and serotonin have greater efficacy and higher remission rates than antidepressants that are selective for norepinephrine or serotonin.7

Monoamine oxidase inhibitors (MAOIs)—the only available antidepressants known to elevate synaptic levels of norepinephrine, serotonin, and dopamine—are recommended for use in appropriately selected, treatment-resistant patients.8 Meta-analysis of clinical trial data suggests that MAOIs such as phenelzine are particularly effective in outpatients with atypical depression features.9 Even so, the clinical usefulness of MAOIs is limited by their potential for serious drug-drug interactions.

Other mechanisms. Because the synaptic actions of available antidepressants on monoamine neurotransmission occur within hours of administration, the several-week delay in onset of therapeutic action suggests that monoamine dysfunction might not be solely responsible for depression’s pathophysiology. Recent investigations suggest that chronic antidepressant use could cause alterations in gene expression, neuronal plasticity, and downstream signaling pathways that underlie the therapeutic effect.10

Even so, medications that target serotonin, norepinephrine, and dopamine remain mainstays of depression pharmacotherapy.

Triple Reuptake Inhibitors

Novel antidepressants that do not involve direct action on monoamines are under investigation (Table 1). Several compound classes—such as neurokinin and glucocorticoid receptor antagonists—are reported to be in phase-III clinical trials, with projected approval within 5 years.11

Table 1

Mechanisms of select antidepressants in development

Drug class/targetProposed mechanism of action
Triple reuptake inhibitorsBlock serotonin, norepinephrine, and dopamine reuptake
CRF1 antagonistsBlock receptors for corticotropin releasing factor; regulate HPA axis
NK receptor antagonistsBlock substance P receptor; offer antidepressant/anxiolytic properties
Glutamate acting drugsBlock or modulate NMDA receptor
Anti-glucocorticoid agentsBlock glucocorticoid receptors; modulate HPA axis feedback
cAMP signal transductionIncreases cAMP levels; may affect neuroplasticity
cAMP: Cyclic adenosine monophosphate
CRF: Corticotropin releasing factor
HPA: Hypothalamic-pituitary-adrenal (axis)
NK: Neurokinin
NMDA: N-methyl-D-aspartate
Even so, many strategies remain focused on directly targeting monoaminergic circuits because this mechanism of action is compelling and understandable. Among these are agents projected to reach the market by 2010

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