Biological markers, or biomarkers, are quantitative measurements that provide information about biological processes, a disease state, or response to treatment (29
). Biomarkers thus hold the potential to provide a better understanding of the etiology and pathophysiology of a complex and heterogeneous disorder like MDD; ultimately, particular target-based therapies could be matched to particular markers in subgroups of patients.
We tested the hypothesis that MEG could be used to provide a neurophysiologic biomarker associated with ketamine’s antidepressant effects. We measured ACC activity in response to rapid exposure to fearful faces in drug-free MDD patients and healthy control subjects. As expected, healthy subjects showed decreased neuromagnetic activity in the rostral ACC across repeated exposures, consistent with evidence that this region exhibits habituation to negative affective stimuli (8
). MDD patients showed the opposite pattern, that is, robust increases in ACC activity over repeated exposures. Notably, we found that this increase in ACC activity in MDD patients was positively correlated with rapid antidepressant response to ketamine, an NMDA antagonist recently shown to have rapid and sustained antidepressant properties in treatment-resistant subpopulations of MDD patients (5
Mayberg and colleagues (1997) first reported that higher rostral ACC (BA 24a/b) metabolism differentiated eventual treatment responders from non-responders to conventional antidepressants at six weeks. Higher pre-treatment ACC metabolism was subsequently shown to predict antidepressant response to sleep deprivation (30
) and paroxetine (3
). Using fMRI, other researchers found that stronger ventral ACC response during negative emotional processing predicted antidepressant response to venlafaxine (1
), while ACC activation during unsuccessful motor inhibitions predicted response to escitalopram in patients with MDD (13
). Finally, theta band activity (i.e., 4–8Hz neural oscillations) in the rostral ACC, as measured by EEG, was found to predict response to the tricyclic antidepressant nortriptyline (31
). The present study replicates previous findings and extends them to a novel, non-monoaminergic drug—ketamine—whose antidepressant effect occurs within hours.
The rapid antidepressant effects of ketamine have been postulated to occur via AMPA-mediated synaptic potentiation of critical neural circuits (32
). Increasing preclinical and clinical evidence demonstrates that synaptic plasticity, a fundamental mechanism of neuronal adaptation, is altered in mood disorders (34
). A growing body of data also suggests that AMPA receptor trafficking (including receptor insertion, internalization, and delivery to synaptic sites) plays a critical role in regulating activity-dependent regulation of synaptic strength, as well as various forms of neural and behavioral plasticity (35
). It is thus noteworthy that recent studies have shown that the chronic administration of antidepressants can increase synaptic AMPA GluR1 receptors (35
). Sleep deprivation is the only other known strategy that exerts an antidepressant effect as quickly (i.e., within hours or one day), and may share common cellular mechanisms with ketamine; Faraguna and colleagues (2008) demonstrated that sleep deprivation is also associated with enhanced AMPA-mediated synaptic plasticity (37
). In toto, the data suggest that AMPA-mediated synaptic potentiation in critical circuits may play an important role in antidepressant action; ketamine and sleep deprivation bring about AMPA-mediated synaptic potentiation rapidly, whereas conventional antidepressants do so in a delayed manner, through a cascade of intracellular signaling changes (35
In addition to ACC activity, pretreatment activity in the right amygdala may represent another useful biomarker of treatment response in patients with MDD. In the present study, amygdala response to fearful faces was negatively correlated with the antidepressant response observed 230 minutes after ketamine infusion. Lower amygdala activation was also found to predict treatment response to escitalopram and paroxetine in two previous studies of individuals with MDD (3
), however, the opposite association (i.e. greater pretreatment amygdala activation predicting antidepressant response) has been also observed (12
). Several factors could explain these divergent findings, including medication status, treatment response criteria, and duration between pretreatment measurement and symptom assessment.
Healthy subjects showed decreased neuromagnetic activity in the rostral ACC across repeated exposures to fearful faces, consistent with evidence that this region habituates to negative affective stimuli (8
). The emotional salience of a fearful face may weaken upon repeated exposures, and may require less engagement of regulatory mechanisms supported by the rostral ACC, explaining the decrease in activity observed in healthy subjects. In contrast, MDD patients showed robust increases in ACC activity over repeated presentations. As the correlation analyses suggest, patients who showed significant treatment response were those driving this increased activity at the group level. These findings could reflect two key differences between MDD patients and healthy controls. First, the emotional salience of a stimulus may weaken more slowly over time in MDD patients; for instance, there is evidence that MDD patients exhibit sustained amygdala activity to negative words compared to healthy controls (39
). Second, affective regulatory processes mediated by the rostral ACC may be delayed in MDD patients; that they become engaged eventually in some patients may reflect that the functional integrity of these processes is not entirely compromised. Antidepressants normalize the altered connectivity between the rostral ACC, limbic regions, and subcortical structures in individuals with MDD, suggesting indirectly that this circuit is not fully dysfunctional in treatment-responders (40
). Neurobiological mechanisms in patients might therefore display subtle quantitative abnormalities that are not necessarily qualitatively different from those in healthy individuals.
This study has several limitations. The lack of a placebo group might imply that the correlation between rostral ACC activation and antidepressant response is not directly related to ketamine administration; however, this is unlikely because we found a robust correlation with antidepressant response 230 minutes after ketamine infusion, a time point where we had previously showed that ketamine’s clinical effect robustly separates from placebo (6
). In addition, we studied patients with very severe and treatment-resistant MDD, and these individuals had a high rate of comorbid anxiety disorders; this may limit the generalizability of our findings. The associations between rostral ACC and right amygdala activity and antidepressant response appeared independent of the concomitant anti-anxiety response observed following ketamine administration; however, the partial correlations analyses were clearly underpowered and would require a larger sample size to demonstrate the specificity of these relationships.
Finally, we did not obtain MEG measures after the administration of ketamine, so it cannot be determined here whether ketamine directly regulates rostral ACC and amygdala function in patients who display antidepressant response. However, Deakin and colleagues (2008) recently found that ketamine directly regulates orbitofrontal cortex and subgenual ACC BOLD activity in healthy individuals, suggesting a direct link with our data (42
In conclusion, a growing number of studies suggest that targeting glutamatergically-mediated synaptic plasticity could be an effective strategy for treating MDD and other mood disorders (35
). Indeed, several therapies targeting this system show substantial early promise for the treatment of mood disorders (35
). Continued exploration of the antidepressant-like effects of glutamatergic drugs—like ketamine—may ultimately lead to the development of new treatments for MDD. The results presented here strongly implicate ACC dysfunction in the pathophysiology of MDD, and support the idea that pretreatment rostral ACC activation might be a useful biomarker for identifying a subgroup of patients who will respond favorably to ketamine within hours.