The prevalence of depression is high, and the burdens that it places on society are enormous. Research in the past few decades has led to the discovery, refinement and testing of new, effective treatments for depression. Nonetheless, our best treatments currently produce symptom remission in fewer than two-thirds of the patients who receive them, and sustained recovery is achieved in approximately one-third of treated patients. Neuroscience research has the potential to enhance our ability to match patients to the treatments that would most benefit them, and to provide clues as to how to refine the treatments so that they can be delivered more effectively and efficiently.
Future investigations should include, in addition to neuroimaging studies aimed at identifying potential predictors, assessments of other important depression-relevant phenomena, so that imaging, symptom, cognitive, genetic and patient-history variables can be linked to the outcomes of psychotherapeutic or medication treatments. A study by Nemeroff and colleagues provides an excellent example of the prediction of differential outcomes of ADM and Cognitive Behavioural Analysis System of Psychotherapy (CBASP,117 a variant of CT), using an important early-history variable.118 Adult patients who reported early-childhood trauma before randomization to ADM or CBASP improved more with CBASP than with ADM, suggesting a correspondence between the targets of CBASP and the pathological processes that were set in motion by the early-childhood trauma.118 Genetic studies have also shown the potential to reveal links between polymorphisms and the cognitive processes that are targeted in psychotherapies such as CT,119 suggesting the possibility that in the future genotyping could be used as a prognostic tool.
The formulation of depression that we have discussed, which focuses on uncontrolled limbic reactivity in conjunction with decreased prefrontal control, could inform the development and refinement of treatments for depression, as well as the differential prediction of response to generally effective treatments. Detecting such moderating effects for treatment response is in its infancy. The formulation suggests that patients with increased limbic reactivity in the absence of decreased regulatory control would be prime candidates for ADM, whereas those with prominent difficulties in emotion regulation, especially if it is associated with decreased prefrontal function, might benefit more from CT. As noted by Kazdin, differential moderation always implies differences in the mechanisms that are engaged by the treatments.120 Direct comparisons in which patients who are heterogeneous with respect to these underlying neural characteristics are randomized to the respective modalities are needed if models such as the one we have proposed are to be subjected to rigorous tests.
The evidence shows that that CT is as efficacious as ADM, and that its effects are more enduring. Thus, even if CT and ADM work through the same mechanisms in the same temporal order to reduce depressive symptoms, any enduring effects of CT must be produced by mechanisms that are not mobilized in the same way by ADM. The model that is proposed in this article suggests that CT helps patients learn to recruit prefrontal regulatory brain mechanisms – a skill that these patients could continue to use long after treatment ends. Exploring the neural bases of these effects should enhance our understanding of the nature of depression and allow us to develop more powerful and targeted preventive interventions.
Most of the published research that compared the changes in brain function that are associated with CT and ADM used resting-state assessments. Challenge paradigms, in which emotional stimuli are presented to depressed individuals during neuroimaging assessment after the end of treatment, could elucidate some of the mechanisms of recovery that are associated with online emotion regulation. Such paradigms, alone or in combination with resting-state studies, could also indicate which neurocognitive features can be used to predict which patients are most likely to benefit from continued treatment.
Another virtually unexplored area is the examination of the time-course of recovery from depression after treatment. That is, although CT and ADM might initially work through different mechanisms, the initial increases in PFC activity that are associated with CT could lead, after a prolonged period of recovery, to stable decreases in the activity or reactivity of the amygdala. Similarly, decreased amygdala activity associated with ADM treatment could disinhibit prefrontal resources and lead, over time, to increased reliance on prefrontal function, so that in the presence of an affective stimulus normal emotion regulation can occur. Thus, examination of brain function months or years into recovery could reveal similar effects of CT and ADM. Research examining these hypotheses would require the imaging of depressed individuals not only before and immediately following treatment, but also long after recovery.
Careful attention to the temporal relations between cognition and emotion and their underlying neural substrates may be needed to tease apart the mechanisms that underlie different interventions, especially when these interventions produce comparable short-term outcomes, as seems to be the case for CT and ADM. Different treatments might produce similar outcomes through the same or different mechanisms, whereas different outcomes always reflect differential mechanisms or between-treatment differences in the potency of the effects on common mechanisms.121
Given that a measure of an underlying process might reflect a cause of change in one modality and a consequence of change in another, it is important to assess purported mechanisms repeatedly across the course of treatment and to examine temporal patterns of covariation with subsequent outcomes as a function of differential treatment.89
Clinical experience suggests that patients treated with CT first learn to apply the CT strategies each time they experience their habitual tendency to process information in a negatively biased manner. That is, they acquire and then implement ‘compensatory skills’. Repeated application of these skills seems to result in the alteration of the patient's general beliefs about themselves, as inferred from an increasing tendency, over time, for patients' prepotent reactions to be free of the negative biases that are characteristic of depressed people and of people who are prone to depression. This process is referred to as the ‘accommodation’ of beliefs to new evidence.122 It is tempting to speculate that this progression in clinical course reflects, and is reflected by, a progression of changes over time in distinct neural mechanisms, with initial gains being mediated by increased inhibitory cortical control exercised by conscious processes, and the maintenance of these gains resulting from a reduction in the frequency and intensity of maladaptive negative reactions to life events, produced by a tempered reactivity in relevant limbic regions.