From the Editor

10 Recent paradigm shifts in the neurobiology and treatment of depression

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The serendipity of half a century ago that hatched hoary theories of the etiology of psychopathology is fading rapidly. Transformative models are now emerging to change the landscape of psychiatry.


 

References

Nowhere is that change in landscape more apparent than in major depression, the No. 1 disabling condition in all of medicine, according to the World Health Organization. The past decade has gen­erated at least 10 paradigm shifts in the neurobiology and pharmacotherapeutics of depression.


Clinging to simplistic tradition

Most contemporary clinicians con­tinue to practice the traditional model of depression, which is based on the assumption that depression is caused by a deficiency of monoamines: sero­tonin (5-HT) and norepinephrine (NE). The entire antidepressant armamentar­ium approved for use by the FDA was designed according to the amine defi­ciency hypothesis. Depressed patients uniformly receive reuptake inhibitors of 5-HT and NE, but few achieve full remission, as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study showed.1

As scientific paradigm shifts infil­trate clinical practice, however, the tired notion of “chemical imbalance” will yield to more complex and evidence-based models.

Usually, it would be remarkable to witness a single paradigm shift in the understanding of a brain disor­der. Imagine the disruptive impact of multiple scientific shifts within the past decade! Consider the follow­ing departures from the old dogma about the simplistic old explanation of depression.


1. From neurotransmitters to neuroplasticity

For half a century, our field tenaciously held to the monoamine theory, which posits that depression is caused by a deficiency of 5-HT or NE, or both. All antidepressants in use today were developed to increase brain mono­amines by inhibiting their reuptake at the synaptic cleft. Now, research points to other causes:
• impaired neuroplasticity
• a decrement of neurogenesis
• synaptic deficits
• decreased neurotrophins (such as brain-derived neurotrophic factor)
• dendritic pathology.2,3


2. From ‘chemical imbalance’ to neuroinflammation

The simplistic notion that depression is a chemical imbalance, so to speak, in the brain is giving way to rapidly emerging evidence that depression is associated with neuroinflammation.4

Pro-inflammatory cytokines are elevated in the plasma of depressed patients, and subside when the acute episode is treated. Current antidepres­sants actually have anti-inflammatory effects that have gone unrecognized.5 A meta-analysis of the use of anti-inflammatory agents (such as nonste­roidal anti-inflammatory drugs and aspirin) in depression shows promising efficacy.6 Some inflammatory markers, such as C-reactive protein, already have been reported to predict response to some antidepressants, but not to others.7


3. From 5-HT and NE pathways to glutamate NMDA receptors

Recent landmark studies8 have, taken together, demonstrated that a single IV dose of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (a psychotogenic drug of abuse FDA-approved only as an anesthetic) can produce clinical improvement of severe depression and even full remission for several days. Such studies demonstrate that the old dogma of 5-HT and NE deficiency might not be a valid over­arching hypothesis of the depression syndrome.

Long-term maintenance studies of ketamine to document its safety and continued efficacy need to be con­ducted. The mechanism of action of ket­amine is believed to be a rapid trigger for enhancing neuroplasticity.


4. From oral to parenteral administration

Several studies have been published showing the efficacy of IV or intranasal administration of new agents for depres­sion. Ketamine studies, for example, were conducted using an IV infusion of a 150-mg dose over 1 hour. Other IV studies used the anticholinergic scopolamine.9

Intranasal ketamine also has been shown to be clinically efficacious.10 Inhalable nitrous oxide (laughing gas, an NMDA antagonist) recently was reported to improve depression as well.11

It is possible that parenteral admin­istration of antidepressant agents may exert a different neurobiological effect and provide a more rapid response than oral medication.


5. From delayed efficacy (weeks) to immediate onset (1 or 2 hours)

The widely entrenched notion that depression takes several weeks to improve with an antidepressant has collapsed with emerging evidence that symptoms of the disorder (even sui­cidal ideation) can be reversed within 1 or 2 hours.12 IV ketamine isn’t the only example; IV scopolamine,9 inhalable nitrous oxide,11 and overnight sleep deprivation13 also exert a rapid thera­peutic effect. This is a major rethinking of how quickly the curtain of severe depression can be lifted, and is great news for patients and their family.


6. From psychological symptoms to cortical or subcortical changes

Depression traditionally has been recog­nized as a clinical syndrome of sadness, self-deprecation, cognitive dulling, and vegetative symptoms. In recent stud­ies, however, researchers report that low hippocampus volume14 in healthy young girls predicts future depression. Patients with unremitting depression have been reported to have an abnor­mally shaped hippocampus.15

In addition, gray-matter volume in the subgenual anterior cingulate (Brodmann area 24) is hypoplastic in depressed persons,16 making that area a target for deep-brain stimulation (DBS). Brain morphological changes such as a hypoplastic hippocampus might become useful biomarkers for identify­ing persons at risk of severe depression, and might become a useful adjunc­tive biomarker for making a clinical diagnosis.

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