Novel mechanism-based treatments for pediatric anxiety and depressive disorders

Abstract

Pediatric anxiety and depressive disorders are common, can be highly impairing, and can persist despite the best available treatments. Here, we review research into novel treatments for childhood anxiety and depressive disorders designed to target underlying cognitive, emotional, and neural circuit mechanisms. We highlight three novel treatments lying along a continuum relating to clinical impact of the disorder and the intensity of clinical management required. We review cognitive training, which involves the lowest risk and may be applicable for problems with mild to moderate impact; psychotherapy, which includes a higher level of clinical involvement and may be sufficient for problems with moderate impact; and brain stimulation, which has the highest potential risks and is therefore most appropriate for problems with high impact. For each treatment, we review the specific underlying cognitive, emotional, and brain circuit mechanisms that are being targeted, whether treatments modify those underlying mechanisms, and efficacy in reducing symptoms. We conclude by highlighting future directions, including the importance of work that leverages developmental windows of high brain plasticity to time interventions to the specific epochs in childhood that have the largest and most enduring life-long impact.

Fig. 1. Attention bias modification (ABM) as a mechanism-based treatment for anxiety disorders.

a Children with anxiety may attend towards threatening rather than neutral stimuli, reinforcing their anxiety. This attention bias towards threat may be associated with an imbalance in brain systems that orient attention, including increased influence by brain systems involved in the involuntary capture of attention by salient stimuli and decreased influence by brain systems involved in top-down, executive control. b ABM is a low-risk cognitive training program in which individuals with anxiety disorders are implicitly trained over 100 s of trials to attend to neutral rather than threatening stimuli. c ABM has been linked to decreases in attention bias to threat and may be associated with a rebalancing of brain systems that orient attention. d Following ABM, anxiety symptoms are reduced. Shaded yellow areas on the brain indicate the fronto-parietal network, FPN, involved in top-down executive control. Shaded teal areas indicate the ventral attention network, VAN, involved in the involuntary capture of attention by salient stimuli.

Fig. 2. Parent Child Interaction Therapy: Emotion Development (PCIT: ED) as a mechanism-based treatment for preschool onset depression.

Nurturing, empathic caregiving with high emotional competence is associated with decreasing depression in preschool children. PCIT:ED was developed to increase empathic and emotionally responsive caregiving and tested for its ability to reduce preschool depression. a In PCIT:ED, the parent is taught by the therapist how to play with the child like a play therapist: following the child’s lead, showing interest in the child, and being non-intrusive. b In a second phase, the therapist coaches the caregiver on emotion socialization, emphasizing validation and tolerance for intense emotions as well as teaching the parent to model adaptive emotion regulation. c Following PCIT:ED, empirical evidence indicates that the child develops enhanced emotional competence, and depressive symptoms are significantly reduced.

Fig. 3. Key findings in research on the interface among resting state functional magnetic resonance imaging (rsfMRI), major depressive disorder (MDD), and transcranial magnetic stimulation (TMS).

a Functional brain networks demonstrate correlated blood-oxygen level-dependent (BOLD) activity over time, measured using resting rsfMRI. The default mode (DMN), salience (SN), and executive control networks (ECN) have all been implicated in the pathophysiology of anxiety and depressive disorders. b The left panel illustrates positive (orange) and negative (blue) correlations in BOLD activity of the dorsolateral prefrontal cortex (DLPFC) with the subgenual anterior cingulate cortex (sgACC), which is depicted in the middle panel. The right panel shows BOLD timeseries from the sgACC and portions of the DLPFC illustrated in blue, showing the negative correlation between these timeseries. The blue portions of the DLPFC largely reside within the ECN, whereas the sgACC largely resides within the DMN; activity from these two networks is known to be negatively correlated at rest, potentially representing top-down control of the DLPFC over the sgACC. c Machinery that allows a clinician to place a TMS coil over a region of the scalp related to the DLPFC. d Some evidence suggests that TMS is most effective for depression when targeted at the portion of the DLPFC that is most negatively correlated with the sgACC, potentially because this strengthens the top-down control of the ECN over the DMN. Panel d illustrates data based on adults that could be studied for extension to adolescents. The top panel colors the lateral cortex based on correlations in BOLD activity with the sgACC and the overlaid dots indicate TMS targets that were successful (red) or unsuccessful (blue). Note that successful applications target the portion of the portion of the DLPFC that is negatively correlated with the sgACC. The bottom panel is a plot that shows theoretical findings that might be expected across adolescents if they replicate findings from adults. In these theoretical findings, TMS targets at parts of the DLFPC with the most negative connectivity with the sgACC (x-axis) would be expected to result in greater levels of improvement in symptoms of MDD following TMS (y-axis).