Major depressive disorders (MDD) are serious public and individual mental health illnesses predicted to be the leading health burden worldwide by 2030 . First episodes of MDD often occur during childhood or adolescence, with additional episodes likely to recur in some 65% of cases [2, 3]. Further to this, Harrington and Clark  report that childhood or adolescence onsets of affective disorder are evident in approximately 30% of adult cases. Adolescence can therefore be considered a critical period where the initial stages and trajectories of depression emerge . Prior history of depression is associated with an increased risk of recurrence of MDD irrespective of concomitant level of prior or subsequent environmental adversity [6, 7] indicating a key role for the illness per se in influencing natural history within individuals and making the delivery of effective treatment at the earliest stages of the illness highly important in relapse prevention.
Tackling this debilitating illness most effectively at the first emergence of an episode in adolescence could be seen as a crucial prevention strategy that may reduce the risk of recurrence of future episodes and prove integral for the long-term improvement of individual health outcomes. In this respect, structural and functional neuroimaging measures, either alone or in combination, have been used to identify brain areas indicative of efficacious treatment given in adulthood [8–10]; reviewed in [11, 12]. Furthermore, structural and functional neuroimaging measures could have important prognostic clinical potential by identifying those individuals who are most likely to benefit from one or more forms of treatment [8, 11].
Treatments for MDD in adolescence
The United Kingdom (UK) National Institute for Health and Care Excellence (NICE) guidelines recommend a stepped-care approach for patients with MDD, where treatment options advance alongside escalating need for care. Although not always successful in leading to remission, provision of treatment, either in the form of psychotherapy, pharmacotherapy, or both, often is essential in order to interrupt the cycle of episodic relapse and recurrence in MDD. In adolescents with MDD, a form of psychotherapy such as cognitive behavioral therapy (CBT) is first provided which may or may not be accompanied by pharmacotherapy treatment with selective serotonergic reuptake inhibitors (SSRIs) such as fluoxetine (20 mg-60 mg).
A pragmatic randomised controlled superiority trial by our group compared SSRI and specialist clinical care (SCC) with a combined treatment regime of SCC + SSRI + CBT and showed that the addition of CBT was no more effective than SCC + SSRI at effecting remission by 28 weeks of treatment . Although that study did not have a CBT-only or non-treatment control group, March and colleagues  noted that CBT alone was not superior to placebo in effecting remission by 12 weeks and both were less effective than fluoxetine alone or combination therapy.
Brain imaging studies of MDD in adults
The IMPACT and MR-IMPACT research programmes aim to establish the extent to which psychotherapies with or without fluoxetine diminish the risk for relapse at 86 weeks after treatment and reveal neural regions or patterns of activity associated with treatment remission, recovery or relapse. A meta-analysis conducted by Fu and colleagues  compared neuroimaging evidence for volumetric and functional changes associated with symptom improvement following treatment (pharmacological, psychological, and combined approaches) for depression. Functional activity in bilateral regions of pregenual anterior cingulate cortex (pgACC) and right subgenual anterior cingulate cortex (sgACC)/medial orbitofrontal cortex (OFC) positively correlated with treatment response, with greater activity in those regions associated with an increased likelihood of responding to treatment for depression , mirroring findings from an earlier study . A negative correlation between activation in right anterior insula and right putamen and treatment response also was observed . Notably, a recent report by McGrath and colleagues  suggested that metabolic activity in right anterior insula could differentiate pharmacological versus psychological treatment response in patients with moderate to severe depression with the potential to optimize initial treatment selection in MDD.
In terms of brain structural predictors of treatment response, regional volume reductions in the right hippocampus, as determined through manual segmentation techniques, were associated with poorer response to treatment . Although lacking sufficient power, reduced volume in bilateral dorsolateral prefrontal cortex (dlPFC), a region involved in the cognitive regulation of emotion, was associated with poorer response to treatment for depression. It is noteworthy that a recent meta-analysis of treatment effects in MDD observed across fMRI studies also identified bilateral dlPFC as a treatment-sensitive region . Considered together, treatment response in MDD appears to be predicted by a number of key areas within the fronto-limbic network [17–19] including pgACC, sgACC, hippocampus, and prefrontal cortices. Increased activity in perigenual ACC (pgACC and sgACC regions) has been linked to successful treatment by pharmacological agents whereas decreased activity in this region has been linked to successful treatment by psychological therapy [8, 9, 20]; summarized in .
While clear support can be garnered for a fronto-limbic pathophysiology of MDD, disruption to other neural and neuroendocrine circuits such as the hypothalamic-pituitary-adrenal (HPA-axis), cortico-striato-pallidal-thalamo-cortical (CSPTC) loop, default mode network, and reward network (further discussed in [12, 16, 21, 22]) have been discussed in relation to MDD. Following CBT treatment significant interaction effects have been observed in the amygdala and dorsal ACC for patients with MDD compared to healthy control participants  with treatment normalizing the previously elevated and reduced responding in these respective regions. Interestingly, the meta-analysis by our group  showed decreased functional activation in the amygdala in adults with MDD relative to healthy controls, perhaps indicating that the common notion of an over-active limbic system in MDD is incorrect or that the treatment strategies formerly undertaken by adults with MDD elicit considerably sustained effects in the amygdala. Dorsal ACC is not part of the fronto-limbic network  but may modulate both reward and HPA axis networks [22, 23], suggesting the interaction of multiple neural systems in MDD . In line with a multiple systems approach, the amygdala is part of the fronto-limbic circuit and CSPTC loop [16, 19], and interacts with the HPA-axis , thus disruption to this region alone could lead to perturbations downstream affecting many neural systems. Different subtypes of depression (some of which remain to be identified) could also be associated with impairment to different neural systems, or with disruption to multiple neural systems at varying weights.
Brain imaging studies of MDD in adolescence
Given the aberrant patterns of brain structure and function observed in adults with MDD, we can ask whether depression in adolescence is similar to depression in adulthood and whether common neural mechanisms underlie pharmacological and/or psychological effectiveness in spite of developmental processes occurring in the adolescent brain. Far fewer neuroimaging investigations of depression have been conducted in adolescents, with no single meta-analysis performed to our knowledge. Recent studies, however, suggest similar perturbations in brain structure and function in regions including, but not limited to, dlPFC, OFC, sgACC, and amygdala, irrespective of patient age [25–27]. Furthermore, fluoxetine may exert effects via common neural mechanisms in both adolescents and adults with MDD , and CBT treatment response was unaffected by age in a small group of adolescents with MDD . These neuroimaging studies together suggest that MDD and effective treatment thereof may be instantiated by comparable mechanisms in adolescents and adults.
Limitations of neuroimaging studies of MDD
There are, however, several limitations of previous neuroimaging research studies of MDD. Often mixed are cases that may represent distinct subtypes of MDD hence limiting the generalizability of findings. Furthermore, many treatment investigations of MDD have not examined treatment effects past 16 weeks, which is a relatively short time window considering that recovery may take up to 2 years in some cases , and that remission rates are 50% in first episode cases of clinic groups by 2 years . Longitudinal investigations across the entire period of recovery are needed to understand why some individuals recover from MDD whereas others do not. The sample sizes of many neuroimaging studies are relatively small considering the substantial clinical heterogeneity across MDD cases. A failure to find statistically significant differences across the whole-brain may have prompted some studies to investigate case–control differences within hypothesis-driven regions of interest (ROI), which apply more lenient criteria for evaluating the statistical significance of results. When coupled with a relatively underpowered sample, inadvertent consequences of adopting ROI approaches are the potential to inflate Type I and Type II error rates due to the possibility of scanning an unrepresentative sample of MDD cases and a failure to include all regions where significant differences may occur across groups or conditions. Larger sample sizes permitting whole-brain examinations of volumetric and functional activation differences are therefore needed in order to better understand the pathophysiology of depression in adolescence.
Neuroimaging examinations of adolescents with MDD provide an opportunity to reveal and differentiate pathophysiological and therapeutic neural structure and function between first episode sporadic as well as at risk recurrent forms of this disorder. Using a repeated-measures design in selected cases that have completed psychological treatment provides a longitudinal neuroimaging investigation of therapeutic effects that have the added potential of revealing neural sites that constitute state or trait markers of illness and treatment insensitivity.
MR-IMPACT will therefore examine neural markers of moderate to severe unipolar depression in adolescence and neurobiological predictors of recovery from depression. Specific objectives of MR-IMPACT are as follows:
To define the profile of brain structural and functional differences in adolescent patients with depression at baseline compared to a group of healthy adolescent participants.
To assess baseline measurements of brain structure, functional activation and connectivity, focusing on neural systems implicated in adult MDD (ACC and other fronto-limbic components) as predictors of symptomatic response to each of the three types of psychological treatments in the short-to-medium term (up to 86 weeks after the start of treatment).
To measure changes in brain functional activation and connectivity before and after a course of CBT and development-related changes in brain function measured in a comparison group of healthy participants to permit identification of treatment-related changes in brain function.