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Objective Despite the clinical importance of chronic and severe irritability, there is a paucity of controlled trials for its pharmacological treatment. Here, we examine the effects of adding citalopram (CTP) to methylphenidate (MPH) in the treatment of chronic severe irritability in youth using a double-blind randomized placebo-controlled design. Method After a lead-in phase of open treatment with stimulant, 53 youth meeting criteria for severe mood dysregulation (SMD) were randomly assigned to receive CTP or placebo (PBO) for 8 weeks. A total of 49 participants, 48 of them (98%) meeting disruptive mood dysregulation disorder (DMDD) criteria, were included in the intent-to-treat analysis. The primary outcome measure was the proportion of response based on improvements of irritability at the week 8 of the trial. Results At the end of the trial, a significantly higher proportion of response was seen in those participants randomly assigned to CTP+MPH compared to PBO+MPH (35% CTP+MPH versus 6% PBO+MPH; odds ratio = 11.70, 95% CI = 2.00−68.16, p = 0.006). However, there were no differences in functional impairment between groups at the end of the trial. No differences were found in any adverse effect between treatment groups, and no trial participant exhibited hypomanic or manic symptoms. Conclusion Adjunctive CTP might be efficacious in the treatment of chronic severe irritability in youth resistant to stimulant treatment alone. Clinical trial registration information A Controlled Trial of Serotonin Reuptake Inhibitors Added to Stimulant Medication in Youth With Severe Mood Dysregulation; https://clinicaltrials.gov ; NCT00794040 .

Background Aberrations in both neural reward processing and stress reactivity are associated with increased risk for mental illness; yet, how these two factors relate to each other remains unclear. Several studies suggest that stress exposure impacts reward function, thus increasing risk for psychopathology. However, the alternative hypothesis, in which reward dysfunction impacts stress reactivity, has been rarely examined. The current study aimed to test both hypotheses using a longitudinal design. Methods Participants were 38 children (23 girls; 61%) from a prospective cohort study. A standard stress-exposure measure was collected at 7 years of age. Children performed a well-validated imaging reward paradigm at age 10, and a standardized acute psychological stress laboratory protocol was administered both at age 10 and at age 13. Structural equation modeling was used to examine bidirectional associations between stress and neural response to reward anticipation. Results Higher exposure to stressful life events at age 7 predicted lower neural response to reward anticipation in regions of the basal ganglia at age 10, which included ventral caudate, nucleus accumbens, putamen, and globus pallidus. Lower response to reward anticipation in medial prefrontal and anterior cingulate cortex predicted higher stress reactivity at age 13. Conclusions Our findings provide support for bidirectional associations between stress and reward processing, in that stress may impact reward anticipation, but also in that reduced reward anticipation may increase susceptibility to stress.

Humans refer to their mood state regularly in day-to-day as well as clinical interactions. Theoretical accounts suggest that when reporting on our mood we integrate over the history of our experiences; yet, the temporal structure of this integration remains unexamined. Here, we use a computational approach to quantitatively answer this question and show that early events exert a stronger influence on reported mood (a primacy weighting) compared to recent events. We show that a Primacy model accounts better for mood reports compared to a range of alternative temporal representations across random, consistent, or dynamic reward environments, different age groups, and in both healthy and depressed participants. Moreover, we find evidence for neural encoding of the Primacy, but not the Recency, model in frontal brain regions related to mood regulation. These findings hold implications for the timing of events in experimental or clinical settings and suggest new directions for individualized mood interventions.

Humans refer to their own mood state regularly in day-to-day as well as in clinical interactions. Theoretical accounts suggest that when reporting on our mood we integrate over the history of our experiences; yet, the temporal structure of this integration remains unexamined. Here we use a computational approach to quantitatively answer this question and show that early events exert a stronger influence on the reported mood compared to recent events. We show that a Primacy model accounts better for mood reports compared to a range of alternative temporal representations, and replicate this result across random, consistent or dynamic structures of reward environments, age groups and both healthy and depressed participants. Moreover, we find evidence for neural encoding of the Primacy, but not the Recency, model in frontal brain regions related to mood regulation. These findings hold implications for the timing of events in experimental or clinical settings and suggest new directions for individualized mood interventions.SignificanceHow we rate our own mood at any given moment is shaped by our experiences; but are the most recent experiences the most influential, as assumed by current theories? Using several sources of experimental data and mathematical modeling, we show that earlier experiences within a context are more influential than recent events, and replicate this finding across task environments, age groups, and in healthy and depressed participants. Additionally, we present neural evidence supporting this primacy model. Our findings show that delineating a temporal structure is crucial in modeling mood and this has key implications for its measurement and definition in both clinical and everyday settings.