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. Author manuscript; available in PMC: 2026 Jun 1.
Published in final edited form as: Res Child Adolesc Psychopathol. 2025 Jan 25;53(6):877–890. doi: 10.1007/s10802-025-01293-2

Association Between Early Childhood P300 Deficits and Risk for Preadolescence Depressive Disorder Mediated by Responsiveness to PCIT-ED Treatment

Nicholas J Santopetro 1, Joan L Luby 3, Deanna M Barch 2, Katherine R Luking 4, Laura Hennefield 3, Kirsten E Gilbert 3, Diana J Whalen 3, Greg Hajcak 5
PMCID: PMC12137013  NIHMSID: NIHMS2055072  PMID: 39862380

Abstract

Preschool-onset major depressive disorder (PO-MDD) is an impairing pediatric mental health disorder that impacts children as young as three years old. There is limited work dedicated to uncovering neural measures of this early childhood disorder which could be leveraged to further understand both treatment responsiveness and future depression risk. Event-related potentials (ERPs) such as the P300 have been employed extensively in adult populations to examine depression-related deficits in cognitive and motivational systems. Few studies examine the prospective relationships between depression and P300, especially in young children. Moreover, limited research examines the relationship between P300 with psychotherapy treatment responsiveness in youths. The current study sought to examine the prospective relationships between pre-intervention P300 (i.e., choice-locked) elicited from the doors task in depressed preschool children (i.e., PO-MDD; ages 3-to-6) with reductions in depressive symptoms after completing an 18-week long dyadic psychotherapy intervention (n = 59). We also explored relations to risk for depression assessed at a follow-up visit during preadolescence (ages 8-to-12; n = 82). Those with PO-MDD exhibiting reduced choice (doors)-locked P300 demonstrated worse treatment response to psychotherapy and were more likely to meet criteria for depression during preadolescence. Moreover, the relationship between pre-intervention P300 and later preadolescence depression was significantly mediated by response to treatment. These findings suggest that deficits in brain systems linked to the choice-locked P300 component (i.e., cognitive and motivational) might be indicative of non-responsiveness to early dyadic psychotherapeutic intervention efforts for depression which impacts risk for recurrent patterns of depression in youths.

Keywords: ERP, P300, PO-MDD, Prospective, Treatment, Depression

Introduction

Preschool-onset major depressive disorder (PO-MDD) is an impairing childhood mental health disorder with onset as early as age three (Luby et al., 2003; Stalets & Luby, 2006). Diagnostic criteria for PO-MDD are consistent with the criteria for Major Depressive Disorder (MDD) but developmentally translated. Homotypic continuity has been observed, as children suffering from PO-MDD are at risk of experiencing recurrent depressive disorders as they age into late childhood and adolescence (Luby et al., 2009b; Gaffrey et al., 2018). Children suffering from PO-MDD experience significant impairments across many life domains, including difficulties at home, with family members, and at school or daycare (Luby et al., 2009a, b). They are also significantly more likely to experience suicidal thoughts and behaviors that persist into preadolescence relative to peers who did not experience preschool depression (Hennefield et al., 2023). Currently, there is limited work dedicated to uncovering the neural underpinnings of this early childhood depressive disorder. Elucidating validated neurological markers of this disorder can further our overall comprehension of the etiology of depression as well as more accurately identify children most at risk – efforts that can collectively better inform early intervention efforts. Indeed, early prevention efforts in youths have shown to significantly buffer worsening depressive symptoms (King & Vidourek, 2012; Rapee, 2013).

Depressive disorders, including PO-MDD, are characterized by impairments in broad cognitive systems which can often present as poorer attention, memory, processing speed, and cognitive control (Rock et al., 2014; Hammar & Årdal, 2009). Moreover, these cognitive problems are pervasive in that they often do not remit even when the depressive episode has remitted (Conradi et al., 2011) and these symptoms are associated with relapse and poorer adaptive functioning (Perini et al., 2019). Employing event-related potentials (ERPs) can further our insight into depression related cognitive neurological deficits as well as assist in identifying individuals most a risk to experience depressive disorders (Hajcak et al., 2019). ERPs are direct measures of brain activity, believed to be generated by postsynaptic potentials (PSPs) throughout the cortex, recorded at the scalp via continuous electroencephalogram (EEG) that are elicited from specific stimuli or responses (“events”) during psychological paradigms. The P300 component, a positive deflection occurring approximately 300ms after stimulus presentation in an experimental task, is often associated with general cognitive processes such as attentional allocation, evaluative processing, context updating, decision-making, and inhibitory control (Polich, 2012; Hajcak & Foti, 2020). There is extensive research suggesting that the P300 is sensitive to task demands, primarily the salience of the stimuli deriving the P300 component. Stimuli can derive their salience from the context of the task and the instructions the participants receive before partaking in the task. For example, in the classic oddball paradigm participants are asked to respond to an infrequent target stimulus and ignore a more frequent standard stimulus resulting in larger P300 amplitude to targets as they require a swift action (response) and smaller P300 amplitude to standards as they typically do not require any action from the participant (Polich & Margala, 1997).

Reduced P300 amplitude, elicited from oddball tasks, has most commonly been observed in depressed adults (Zhou et al., 2019; Bruder et al., 2009; Gangadhar et al., 1993; Nan et al., 2018; Roschke & Wagner, 2003; Urretavizcaya et al., 2003). This effect has recently been documented in a wide range of other tasks as well, such as the flanker task, go-no go task, monetary doors task, and monetary incentive delay (MID) task (Klawohn et al., 2020; Ruchsow et al., 2008; Santopetro et al., 2021a, b, c; White et al., 2021). A smaller literature has examined the P300 in youth with depression. Across various tasks such as the oddball, flanker, and MID tasks, a reduced P300 is found in female adolescents with a history of depression (Houston et al., 2003) and adolescents with elevated depressive symptoms (Santopetro et al., 2021a, b, c; Thompson et al., 2023). Taken together, these data suggest that a reduced P300 amplitude likely reflects the broad cognitive system impairments that are common in depressive disorders (American Psychiatric Association, 2013; Rock et al., 2014; Hammar & Årdal, 2009).

There is mixed support for the P300 as a predictor of depression treatment response. In adult samples, several studies found that larger pre-treatment P300 amplitude was associated with better outcomes to a variety of depression treatments (i.e., antidepressants, electroconvulsive therapy, and CBT; Bruder et al., 1995; Ancy et al., 1996; Gangadhar et al., 1993; White et al., 2021); however, other studies have not detected this relationships (i.e., antidepressants and yoga; Vandoolaeghe et al., 1998; Murthy et al., 1998). To our knowledge, no studies have examined the potential utility of the P300 as a correlate of depression treatment response in children or adolescents. The few studies that have examined the relationship between P300 and risk or course of future depressive episodes in youth suggest that a reduced P300 predicts worse course of depressive symptoms over two years (Santopetro et al., 2020) and differentiates adolescents with or without a history of PO-MDD (Santopetro et al., 2023). Critically, the prospective relationship of the P300 with later depression risk has not been thoroughly investigated during childhood.

Parent-Child Interaction Therapy (PCIT) is an effective treatment for early childhood externalizing behaviors (Thomas et al., 2017). However, there is limited work examining the effectiveness of PCIT as a treatment for other forms of early childhood psychopathology such as PO-MDD. Recent efforts employed a novel Parent-Child Interaction Therapy Emotion Development (PCIT-ED) protocol consisting of three components; a child-directed interaction (CDI) module to teach parents to positively interact with their children in play without negativity, a parent-directed interaction (PDI) module which teaches parents how to use firm and nurturing limit-setting techniques to address misbehaviors, and a novel emotional development (ED) module to train parents to serve as an emotion teacher and coach to the child to facilitate the child’s emotional development (Luby et al., 2018). Results indicated that children suffering from PO-MDD that received PCIT-ED treatment exhibited significant improvements in depressive symptoms compared to children with PO-MDD in the wait list condition (Luby et al., 2018). Additional findings underscored the importance of the novel emotion development (ED) module of the novel PCIT-ED intervention on reducing depressive symptoms as well as emotional regulation compared to other modules (Luby et al., 2020).

The current study utilizes neural data collected from children (ages 3-to-6) with PO-MDD prior to their engagement with a parent-child psychotherapy including both short-term (~ 5 weeks post-treatment) and long-term (3-to-6 years post-treatment) follow-up clinical data. Key analyses examine whether pre-intervention P300 amplitudes, elicited from a computerized guessing task, prospectively predicts (1) response to an 18-week long Parent Child Interaction Therapy-Emotion Development (PCIT-ED) depression treatment during early childhood, (2) risk for future depressive episodes during preadolescence, and (3) if treatment response mediates the relationship between preschool P300 and depression risk in preadolescence. Based on previous literature, we hypothesize that larger P300 amplitude would predict greater responsiveness to the intervention (i.e., greater PO-MDD symptom reductions). We also predict that larger P300 amplitude would predict reduced odds of experiencing a future depressive disorder at the later follow-up visit during preadolescence.

Methods

Participants

The current data is part of a longitudinal project examining follow-up outcomes for children and families that initially completed a novel PCIT-ED intervention for early childhood depression. Detailed information regarding the initial RCT and results demonstrating the effectiveness of the PCIT-ED intervention have been published elsewhere (Luby et al., 2018, Barch et al., 2018, and Luby et al., 2020). EEG findings regarding the reward positivity (RewP) ERP component and treatment responsiveness (e.g. change in RewP as a result of treatment) have also already been examined and published (Barch et al., 2018). The current study instead focuses on the prospective role of the P300 in predicting both response to PCIT-ED treatment during early childhood, and depression later in preadolescence (ages 8-to-12 years old). Exclusion criteria for this sample included the presence of the following at preschool/pre-intervention: Autism Spectrum Disorder (ASD), serious neurological or chronic medical disorders, significant developmental delays, antidepressant medication use, or ongoing psychotherapy. Informed written consent was provided to families and obtained before participation in the current project. The study was approved by the Institutional Review Board at Washington University School of Medicine.

The current study utilized pre-intervention EEG data collected during a computerized point-based guessing task (i.e., doors task; Proudfit, 2015) to elicit ERPs associated with motivational and cognitive neural processes (i.e., choice-locked P300 and the gain/loss-feedback P300). Follow-up clinical interview data was collected shortly after the 18-week PCIT-ED intervention (M = 23.79 weeks, SD = 4.03, after the pre-intervention visit), and again 3-to-6 years later (M = 3.76 years, SD = 0.82). The average number of completed PCIT-ED sessions by families was 15.35 (SD = 7.75). These data were employed to examine both responsiveness to PCIT-ED treatment and later preadolescence depression status, respectively. A total of 137 preschool aged children who experienced PO-MDD and their caregivers participated in both the initial RCT project and the later follow-up visit that occurred approximately 3-to-6 years after completing the RCT (sample retention was 59.8% and likely affected by COVID-19; see Hennefield et al., 2023 for additional details pertaining to this follow-up). However, of the initial 137 participants, 83 participants had completed the doors task while continuous EEG recorded at the pre-intervention visit and returned for the later follow-up visit. Additionally, one participant did not have usable EEG activity at the electrode site of interest (i.e., site Oz) for the doors-locked ERP component (i.e., choice-locked P300) and two participants did not have usable data at the electrode site of interest (i.e., site Pz) for the feedback-locked ERP components (i.e., gain-feedback P300 and loss-feedback P300). Therefore, the total sample size for doors (choice)-locked prospective analyses with later depression status consisted of 82 participants and the total sample size for feedback-locked prospective analyses with later depression status consisted of 81 participants. It is very important to highlight that the total sample size for prospective analyses regarding responsiveness to PCIT-ED treatment consisted of 59 participants as some participants originally randomized to the waitlist condition did not opt to receive the PCIT-ED intervention. More specifically, families in the wait list condition were offered, but not required to complete, PCIT-ED on completion of the waiting period if the child remained symptomatic. Those families that did complete PCIT-ED after the waitlist were included for these analyses.

There were no significant differences in baseline income-to-needs ratio, sex, or race between children experiencing PO-MDD that completed the EEG procedures compared to children with PO-MDD that did not complete EEG that were not utilized in the current investigation. However, these groups did significantly differ in age such that children that completed the EEG protocol were significantly older (M = 5.62 years, SD = 0.89) than children who did not complete EEG (M = 4.84 years, SD = 1.04), t(135) = 4.69, p<.001. The average age of the sample at the pre-intervention/preschool visit was 5.62 years (SD = 0.88) and 10.04 years (SD = 0.91) at the later preadolescence follow-up visit. The sample was predominately male (70%), and most participants identified as White (78%) with the remainder identifying as Black (9%), Asian (1%), or more than one race (12%).

Measures

Early Childhood Depression

The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children–Early Child Version (K-SADS-EC) was used to determine PO-MDD diagnoses at the pre-intervention visit (ages 3-to-6 years). The K-SAD-EC is a semi structured clinical interview for DSM-5 disorders adapted for use in young children. This interview has sound psychometric properties demonstrating good test-retest reliability and construct validity (Gaffrey et al., 2010). All K-SADS-EC interviews were conducted with caregivers by master’s level clinicians, videotaped, reviewed for reliability, and calibrated for accuracy. Satisfactory interrater reliability was maintained monthly with an overall Cohen’s kappa of 0.74 for PO-MDD diagnosis.

Response to PCIT-ED Treatment: PO-MDD Symptom Reduction

The K-SAD-EC was also administered to caregivers after completing the PCIT-ED intervention approximately 20 weeks after the pre-intervention visit. Data from this clinical interview were utilized to determine PO-MDD symptom reduction. More specifically, children that no longer met criteria for PO-MDD at the post-therapy assessment and demonstrated a 50% or greater reduction in their PO-MDD symptoms were classified as remitted (i.e., treatment responders), whereas children who still met for PO-MDD criteria and did not exhibit such a reduction in depressive symptoms were considered non-responders to PCIT-ED treatment, consistent with definitions of depression remission in the literature.

Preadolescence Depression Status

The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL) was employed at the longer-term follow-up visit to assess for the presence of a current depressive disorder. Very similar to the K-SAD-EC, the K-SADS-PL is a semi-structured age-appropriate (ages 6-to-18) diagnostic interview for DSM-5 disorders that was administered separately to a primary caregiver and preadolescent participant by a trained researcher. Caregivers reported on their child’s symptoms for two primary periods: (1) since the preschool period (i.e., after participation in the RCT and associated post-treatment assessments), and (2) current (over the prior month). Preadolescents also reported on their own lifetime and current symptoms and scoring incorporated both child and caregiver reports. The K-SADS-PL generates reliable and valid child psychiatric diagnoses (Kaufman et al., 1997) and interrater reliability for current depressive disorders (i.e., Major Depressive Disorder [MDD] or Depressive Disorder Not Otherwise Specified [NOS]) at the follow-up visits was Cohen’s kappa of 0.74 based on parent report and 0.63 for child report.

Income-to-needs Ratio

The income-to-needs ratio was determined by dividing total family income by the federal poverty level based on family size at the time of the pre-intervention visit. Income-to-needs ratio is included as a covariate in all analyses as it is linked to both increased risk for psychopathology (Evans & France, 2022) and a blunted P300 component (Santopetro et al., 2023).

Procedures

PCIT-ED Intervention

The initial single-blind randomized controlled trial compared PCIT-ED to a waiting list control condition. Participants on the wait list were offered PCIT-ED on completion of the waiting period if the child remained symptomatic. The PCIT-ED intervention consisted of CDI and PDI limited to six sessions for each module. The novel ED module followed the CDI and PDI modules and consisted of eight sessions. The ED module utilized the basic teaching/coaching techniques employing the bug in the ear method to address parental response to the child’s expression of intense and dysregulated emotion by validating the child’s emotion, helping them to label it, and teaching adaptive emotion regulation. Moreover, live in vivo stressors were employed to elicit symptoms of frustration, guilt, and sadness. During these exposures, the parent was coached by the therapist on how to effectively interact with their child. Homework was assigned in order to practice emotion skills, which is similar to the homework assigned during the CDI and PDI modules. Fidelity monitoring of PCIT-ED was completed by an observing co-therapist at random sessions. Integrity and fidelity checklists were done at each session by the therapist, consistent with PCIT protocol and the current protocol demonstrated acceptable fidelity (Luby et al., 2018).

Doors Task

The doors task consisted of three, 20 trial blocks, with each trial beginning with the presentation of two identical images of doors. Participants were instructed to select either the left or right door and were told that they would gain 10 points each time they opened a correct door and lose 5 points each time they opened an incorrect door. Prior to the start of the task the experimenter showed the participants three containers of prizes and explained that if they received a certain number of points in the upcoming game, they could receive a prize from one of the containers. This exchange was designed to encourage the child to engage in the task and to make it relevant to the children.

The images of the doors were presented until participants selected a door. Then, a fixation cross was displayed for 1000 ms, which was followed by a feedback stimulus presentation for 2000 ms. The feedback stimulus was indicated by a green arrow pointing upward following gains (+ 10 points) or a red arrow pointing downward following losses (−5 points). Gain and loss trials were equiprobable and presented pseudo-randomly.

EEG Recording & Processing

Continuous EEG was recorded during the computerized doors task using a 32-channel active ActiCap slim electrode (Ag/AgCl) actiCHamp system (Brain Products GmbH, Gilching, Germany). The electrodes were situated on the scalp in accordance with the international 10/20 system electrode system, and electrode site Cz served as the online recording reference. Electrodes were also placed behind the ears on the left and right mastoids. Electro-oculogram (EOG) was collected from four electrodes: one placed above and below the left eye, and one to the sides of each eye. Data was digitized at a sampling rate of 500 Hz with 24 bits of resolution.

EEG analyses were performed offline using Brain Vision Analyzer (version 2.2; Brain Products, Gilching, Germany). First, EEG data was referenced to averaged mastoids (i.e., TP9 and TP10), then filtered with low and high filter cutoffs set at 0.1 Hz and 30 Hz, respectively. Ocular artifacts were corrected using the Gratton et al. (1983) procedure. Automatic artifact rejection was implemented, rejecting any data with a voltage step greater than 50 μV, a voltage difference of 300 μV within a trial, or a maximum voltage difference of less than 0.50 μV within 100 ms intervals.

ERP Quantification & Internal Consistency

Data was segmented starting 200 ms before the presentation of the door and gain/loss feedback stimuli to 800 ms after presentation. Next, these segments were baseline-corrected using the 200 ms pre-stimulus interval and then averaged. The choice-locked P300 was quantified as the mean amplitude at electrode site Oz from 250 ms to 450 ms following the presentation of the doors stimuli. Lastly, the gain- and loss-feedback P300 were quantified as the mean amplitude at electrode site Pz from 500 ms to 700 ms following the presentation of the gain and loss feedback stimuli, respectively. All ERP quantifications were based on a combination of a priori information from past publications that have examined these P300 components, especially in child samples (e.g., Belden et al., 2016; Barch et al., 2018; Santopetro et al., 2023) and confirmed utilizing a collapsed localizer approach (Luck & Gaspelin, 2017) in which parameters were chosen in the time range and electrode sites showing maximal activity for each respective P300 component collapsed across the entire sample.

The correlation between choice-locked P300 amplitude, gain-feedback P300 amplitude, and loss-feedback P300 amplitude on odd and even trials was additionally examined to measure internal consistency (Levinson et al., 2017) and corrected using the Spearman-Brown prophecy formula (Nunnally et al., 1967). The choice-locked P300 amplitude exhibited excellent internal consistency at the pre-intervention/preschool visit, r = .90, while the gain-feedback P300 (r = .80) and loss-feedback P300 (r = .79) exhibited good internal consistency at the pre-intervention/preschool visit.

Statistical Analyses

All data analyses were performed using SPSS Statistics software (Version 27.0; IBM Corp., Armonk, N.Y., USA) and jamovi (version 2.2.5; The jamovi project, 2021). Power analyses were conducted utilizing G*Power Analysis Software (version 3.1.9.7). We first utilized bivariate correlations, Chi-square tests, and independent samples t-tests to examine initial associations between pre-intervention measures (ERPs, age, income-to-needs ratio, sex, psychotropic medication status), PCIT-ED treatment response (i.e., significant PO-MDD symptom reductions), and long-term follow-up depression status during preadolescence. Next, we further conducted two separate multiple logistic regressions to predict (1) PCIT-ED treatment response and (2) preadolescence depression risk utilizing the pre-intervention ERPs as independent variables (i.e., choice-locked P300 and gain/loss-feedback P300) while controlling for pre-intervention age and income-to-needs ratio. P300 measures were examined as independent variables in separate models (i.e., total of four logistic regressions). Lastly, a mediation model was conducted to understand further if the initial significant relationship between pre-intervention ERPs and other important variables with later childhood depression status were mediated by responsiveness to PCIT-ED treatment. The criterion of statistical significance for all analyses was p<.05.

Power Analysis

A power analysis was conducted utilizing G*Power Analysis Software (version 3.1.9.7) for two independent means t-tests. Effect sizes (i.e., Cohen’s d) calculated from previous studies examining P300 in relation to depression treatment response (Ancy et al., 1996; White et al., 2021) and the P300 association with future course of depression (Santopetro et al., 2020, 2023) varied suggesting small-medium to large effect sizes between P300 and treatment responsiveness (d = 0.34 −1.29) as well as small to medium-large effect sizes between P300 with future course of depression (d = 0.23 − 0.60). At 0.80 power and imputing the Cohen’s d effect sizes outlined above it was determined that the sample sizes needed to detect the potential P300 and treatment response association ranged from 22 to 274 participants, and that the sample sizes needed to detect the potential prospective P300 and depression association ranged from 72 to 470 participants. Although both sample sizes in the current study fall within these ranges it is very important to note that this is a very large range, and the current samples fall within the lower limits of this range.

Results

Child age at the pre-intervention visit was not significantly associated with any of the P300 components elicited from the doors task, r’s < 0.16, p’s > 0.147. Children of families with higher income-to-needs ratio exhibited larger gain- and loss-feedback P300 amplitudes, r(78) = 0.30, p = .007 and r(78) = 0.26, p = .019, respectively. Table 1 presents demographic, clinical, and ERP differences between children with PO-MDD who experienced improvements (i.e., 50% or more depressive symptom reduction) after PCIT-ED treatment compared to children with PO-MDD who did not improve after PCIT-ED treatment (i.e., non-responders). Child age was associated with PO-MDD treatment response status such that younger children were more likely to respond positively to PCIT-ED. There were no significant sex differences in choice-locked or loss-feedback P300 in the current sample; however, females exhibited significantly smaller gain-feedback locked P300 amplitude (M = 3.70 μV, SD = 8.08) compared to males (M = 11.59 μV, SD = 10.52), t(80) = 3.29, p = .002, d = 0.80.

Table 1.

Pre-intervention demographic, clinical, and ERP measures in responders to PCIT-ED treatment (n = 37) and non-responders to PCIT-ED treatment (n = 22) based on PO-MDD symptom reduction

Responders Non-responders p
Demographics & Clinical
 Age (Years) 5.39 (0.81) 6.05 (0.77) 0.003
 Sex (% female) 32% 27% 0.677
 Income-to-needs ratio 3.17 (1.20) 3.04 (1.34) 0.701
 Race (%) 0.448
  White 76% 86%
  Black/African American 5% 9%
  Asian 3% 0%
  More than one race 16% 5%
 Psychotropic medication (%) 3% 9% 0.280
ERP
 Choice-locked P300 at Oz (μV) 15.19 (10.20) 9.59 (9.67) 0.044
 Gain-feedback P300 at Pz (μV) 9.10 (10.30) 10.00 (12.49) 0.768
 Loss-feedback P300 at Pz (μV) 13.47 (12.73) 12.72 (10.38) 0.818

Note. Means are presented, standard deviations in parentheses

Table 2 shows demographic and clinical differences between preschool-aged children with a current depressive disorder at the later follow-up visit (i.e., preadolescence) compared to preschool-aged children with no depressive disorder at the preadolescence visit. Older children and children from lower income-to-needs ratio families experienced higher rates of preadolescence depression. Importantly, children who experienced significant decreases in PO-MDD symptoms in response to the PCIT-ED intervention (e.g. remitted) were less likely to experience depression in preadolescence, X2(1) = 16.79, p <.001.

Table 2.

Pre-intervention demographic, clinical, and ERP measures in PO-MDD children that experienced current MDD (n = 29) at the long-term follow-up visit in preadolescence and PO-MDD children that did not experience current MDD in preadolescence (n = 53)

Follow-up MDD No follow-up MDD p
Demographics & Clinical
 Age (Years) 6.00 (0.80) 5.41 (0.85) 0.003
 Sex (% female) 24% 33% 0.384
 Income-to-needs ratio 2.60 (1.47) 3.21 (1.11) 0.057
 Race (%) 0.010
  White 69% 83%
  Black/African American 21% 2%
  Asian 3% 0%
  More than one race 7% 15%
 Psychotropic medication (%) 3% 6% 0.669
 *PCIT-ED treatment response (% improved) 30% 83% < 0.001
ERP
 Choice-locked P300 at Oz (μV) 9.90 (10.84) 13.26 (9.32) 0.145
 Gain-feedback P300 at Pz (μV) 9.84 (10.93) 8.93 (10.28) 0.709
 Loss-feedback P300 at Pz (μV) 12.62 (10.23) 14.35 (11.94) 0.513

Note. Means are presented, standard deviations in parentheses.

*

PCIT-ED treatment response consists of a subset of 59 participants that completed PCIT-ED

Logistic Regressions: Choice-Locked P300

To determine which variables showed unique associations, we conducted a multiple logistic regression predicting PO-MDD treatment response status utilizing pre-intervention age, income-to-needs ratio, and choice-locked P300 amplitude simultaneously as predictors. The overall model predicting response to PCIT-ED treatment was significant, but only age and choice-locked P300 amplitude emerged as a unique predictors of treatment response (Table 3). Younger children and children exhibiting larger choice-locked P300 amplitude pre-intervention responded better to PCIT-ED treatment. Figure 1 visualizes choice-locked (i.e., doors-locked) neural activity differences between children that experienced significant depressive symptom reductions after completing PCIT-ED compared to children that did not respond to the PCIT-ED intervention.

Table 3.

Logistic regression model predicting PO-MDD symptom reduction after PCIT-ED treatment (responder, non-responder)

Pre-intervention variables Prediction of Group Status (Responder, Non-responder)
R 2 X 2 Adj. OR 95% CI p
Model 0.34 16.67 0.001
 Age 0.25 [0.10, 0.62] 0.002
 Income-to-needs ratio 1.15 [0.70, 1.90] 0.576
 Choice-locked P300 1.10 [1.02, 1.18] 0.011

Note. Logistic regression was used to predict the dichotomous dependent variable group status (0 = non-responder, 1 = responder). Adj. OR = Adjusted Odds Ratio. The Nagelkerke R2 and chi-square statistic are reported for the logistic regression model

Fig. 1.

Fig. 1

Pre-intervention choice-locked (i.e., doors-locked) waveforms in responders to PCIT-ED treatment (n = 37) and non-responders to PCIT-ED treatment (n = 22) based on PO-MDD symptom reduction

The overall model predicting MDD status in preadolescence was significant and age, income-to-needs ratio, and choice-locked P300 amplitude each emerged as unique predictors (Table 4). Children who were older at the initial assessment, had lower income-to-needs ratio, and exhibited smaller choice-locked P300 amplitude pre-intervention were more likely to meet criteria for a depressive disorder during preadolescence. Figure 2 visualizes choice-locked (i.e., doors-locked) neural activity differences between children who experienced a depressive disorder at the long-term follow-up compared to children who did not experience a depressive disorder.

Table 4.

Logistic regression model predicting follow-up preadolescence MDD status (MDD, no MDD)

Pre-intervention variables Prediction of Group Status (MDD, no MDD)
R 2 X 2 Adj. OR 95% CI p
Model 0.31 20.68 < 0.001
 Age 3.20 [1.59, 6.44] 0.001
 Income-to-needs ratio 0.62 [0.41, 0.94] 0.026
 Choice-locked P300 0.93 [0.87, 0.98] 0.013

Note. Logistic regression was used to predict the dichotomous dependent variable group status (0 = no MDD, 1 = MDD). Adj. OR = Adjusted Odds Ratio. The Nagelkerke R2 and chi-square statistic are reported for the logistic regression model

Fig. 2.

Fig. 2

Pre-intervention choice-locked (i.e., doors-locked) waveforms in PO-MDD children that experienced current MDD (n = 29) at the long-term follow-up visit in preadolescence and PO-MDD children that did not experience current MDD in preadolescence (n = 53)

Mediation Model: Pre-Intervention Choice-Locked P300 and Age with Preadolescence Depression Mediated by PCIT-ED Treatment Responsiveness

Given that pre-intervention choice-locked P300 amplitude and age were significant predictors of both PCIT-ED treatment responsiveness and risk for depressive disorders into preadolescence, a mediation model was conducted simultaneously examining if the initial associations between pre-intervention P300 amplitude and/or age with preadolescence depression is mediated by treatment response. The model demonstrated that both the 95% CI [−0.01, −0.001] of the pre-intervention choice-locked P300 amplitude association with later childhood depression through PCIT-ED responsive and the 95% CI [0.02, 0.18] of the pre-intervention age association with later childhood depression through PCIT-ED responsive did not contain 0, thus, the mediating effects were confirmed. More detailed statistical information regarding the mediation model is reported in Table 5; Fig. 3 displays the statistical diagram of the mediation model.

Table 5.

Mediation model predicting follow-up preadolescence MDD status (MDD, no MDD) from pre-intervention choice-locked P300 and age mediated by PCIT-ED treatment response (n = 59)

Type Effect ß SE z 95% CI p
Indirect P300 = > Treatment Response = > MDD Status −0.14 0.00 −2.17 [−0.01, −0.001] 0.030
Age = > Treatment Response = > MDD Status 0.18 0.04 2.47 [0.02, 0.18] 0.013
Component P300 = > Treatment Response 0.33 0.01 2.82 [0.01, 0.03] 0.005
Age = > Treatment Response −0.42 0.07 −3.62 [−0.37, −0.11] < 0.001
Treatment Response = > MDD Status −0.42 0.13 −3.39 [−0.67, −0.18] < 0.001
Direct P300 = > MDD Status −0.12 0.01 −1.01 [−0.02, 0.01] 0.312
Age = > MDD Status 0.20 0.06 1.65 [−0.02, 0.25] 0.100
Total P300 = > MDD Status −0.22 0.01 −2.12 [−0.02, −0.001] 0.034
Age = > MDD Status 0.36 0.06 3.44 [0.08, 0.31] < 0.001

Fig. 3.

Fig. 3

Statistical diagram of mediation model predicting follow-up preadolescence MDD status (MDD, no MDD) from pre-intervention choice-locked P300 and age mediated by PCIT-ED treatment response (n = 59)

Logistic Regressions: Gain- and loss-feedback P300

The overall model predicting PCIT-ED treatment response was significant, X2 (4) = 10.17, p = .038, but only age emerged as a unique predictor of PCIT-ED treatment response (OR = 0.32, 95% CI = 0.15–0.72). Gain-feedback P300 amplitude (OR = 0.97, 95% CI = 0.90–1.04), loss-feedback P300 amplitude (OR = 1.05, 95% CI = 0.97–1.13), and income-to-needs ratio (OR = 1.06, 95% CI = 0.65–1.72) were not significant predictors of responsiveness to PCIT-ED treatment.

The overall model predicting MDD status in preadolescence was significant, X2 (4) = 17.69, p = .001. Age (OR = 2.94, 95% CI = 1.46–5.91) and income-to-needs ratio (OR = 0.64, 95% CI = 0.42–0.98) were unique predictors of depressive disorders at the follow-up visit. Gain-feedback P300 amplitude (OR = 1.07, 95% CI = 1.00–1.15) and loss-feedback P300 amplitude (OR = 0.94, 95% CI = 0.88–1.01) were not significant predictors of preadolescence depression.

Discussion

In the current study we observed that depressed preschoolers with a reduced choice-locked P300 amplitude were less likely to respond to a PCIT-ED treatment and, because of this lack of treatment response, were more likely to experience depression during preadolescence. Importantly, these effects were not explained by differences in child age or income-to-needs ratio. This is the first study to examine whether the choice-locked P300 assessed in preschool prospectively predicts treatment response and risk for future depression in preadolescence. Findings are in line with prior work in adult populations wherein choice-locked (i.e., doors-locked) P300 amplitude, but not feedback-locked P300s, was significantly reduced among adults suffering from depressive disorders (Santopetro et al., 2021a, b, c) and adolescents with a history of PO-MDD (Santopetro et al., 2023). These findings also extend those in adult and adolescent samples that suggest reduced P300 amplitude is predictive of worse response to treatments such as antidepressants, electroconvulsive therapy, and CBT (Bruder et al., 1995; Ancy et al., 1996; Gangadhar et al., 1993; White et al., 2021) as well as a more severe course of depression (Santopetro et al., 2020, 2021a, b, c). To our knowledge, the current study is among the first to simultaneously investigate the utility of the P300 as a predictor of both treatment responsiveness and future depression onset in a sample of young children, providing novel insight into a potential pathway for pediatric depression recurrence involving underlying psychophysiological deficits and non-responsiveness to early intervention efforts.

Deficits in pre-intervention P300 activity, particularly choice-locked P300, likely reflect trait-like impairments in general cognitive and motivational neural systems that may contribute to depression symptoms and thereby impact clinical outcomes such as treatment responsiveness and depression relapse. For example, P300 deficits in depression may be specific to symptoms of anhedonia (Urretavizcaya et al., 2003; Santopetro et al., 2021a, b, c, 2022), a particularly pernicious core symptom of depression linked to a more chronic and recurrent course and treatment resistance (Vinckier et al., 2017). As a blunted choice-locked P300 amplitude is thought to show impaired attention allocation to imperative stimuli that require a response, depressed preschoolers with this neural feature in our study might have had more difficulty engaging with and benefiting from PCIT-ED treatment. In particular, children exhibiting smaller P300 amplitude may have had difficulties learning certain emotional skills during the novel Emotional Development (ED) module in which the parent served as an emotion teacher and coached their child to facilitate the child’s ability to recognize and label emotions, a task that requires focused cognitive skills. However, it is very important to highlight that it remains unclear if P300 amplitude is a unique predictor of PCIT-ED response or if it is a more general indicator of treatment response to psychotherapy. Future studies should examine the specific associations between P300 amplitude with various facets of depression as well as with clinical outcomes following other depression interventions in youth to further understand the exact functionality and predictive utility of P300 deficits in pediatric depression. Additionally, research efforts utilizing novel interventions such as processing speed training and neurofeedback protocols in healthy samples of adults suggest preliminary evidence that P300 amplitude can be modulated (i.e., increased) by these efforts (O’Brien et al., 2013; Noble et al., 2024). It is therefore plausible that employing such cognitive interventions alongside traditional psychotherapy treatment could improve clinical outcomes. However, the utility of such cognitive interventions in relation to alleviating depression related deficits in cognitive functioning has not been thoroughly examined, especially in pediatric samples.

We observed significant prospective effects regarding pre-intervention child age with treatment responsiveness as well as significant mediation between age and future depression onset via PCIT-ED treatment response very similar to, yet separate from, the P300 results described above. More specifically, younger children appeared to respond better to PCIT-ED treatment which then lowered their likelihood for future depression in preadolescence. These results suggest the importance of earlier identification and intervention for preschool depression. Past publications have highlighted the importance of parent and family involvement in child mental health intervention outcomes (Dardas et al., 2018; Ladis et al., 2019) and it is thus plausible that younger children with PO-MDD particularly benefited more from the parent-focused depression treatment (i.e., PCIT-ED) employed compared to older children with PO-MDD. This may be true as the parent has a powerful influence on the younger child’s emotional functioning, a feature that diminishes as children enter school age when peers become more important. However, this claim needs to be further replicated and explored in future investigations as past meta-analytic reviews have posited that child and adolescent age typically does not significantly predict outcomes of youth mental health interventions (Nilsen et al., 2013).

The effectiveness of the current PCIT-ED treatment has been examined in other publications which detail that the children in the PCIT-ED group exhibited lower rates of depression, lower depression severity, and lower impairment compared with children in the wait list condition after 18 weeks (Luby et al., 2018). Further results suggested that the novel “emotion development” (ED) module of the PCIT-ED intervention appeared to have specific effects on reducing child depression and other forms of psychopathology such as externalizing problems compared to other modules of the intervention (Luby et al., 2020). This is the first investigation from this RCT sample to observe the effectiveness of the PCIT-ED treatment at reducing future risk for later depression onset approximately 3-to-6 years after completing the intervention and, to our knowledge, is among one of the first studies to demonstrate the long-term effects of early interventions for childhood depression. It is very important to highlight that these results regarding PCIT-ED effectiveness regarding future depression in preadolescence are preliminary as they only involve a smaller subset of the total PED-SI sample who completed EEG procedures since the primary aims of the current project were to understand the prospective associations between pre-intervention P300 with PCIT-ED treatment response and risk for future depression in preadolescence in preschool children suffering from PO-MDD. Future investigations will need to employ the full PED-SI sample, as well as replicate findings in new samples, to further expand upon these preliminary findings suggesting long-term benefits of PCIT-ED treatment into preadolescence as to provide a more comprehensive understanding of this clinical effect.

Lastly, we observed that pre-intervention income-to-needs ratio was a unique predictor of later depression risk in preadolescence but was not associated with PCIT-ED responsiveness. These results are in line with past publications that have demonstrated the influence of family income or socioeconomic status (SES) in relation to risk for psychopathology such as depression (Gilman et al., 2002, 2003). More specifically, researchers posit that lower income-to-needs ratio negatively impacts the family environment such as lack of perceived parental support which in turn can increase risk for depression symptomology in youths (Tracy et al., 2008). There were also significant relationships between income-to-needs ratio with feedback-locked P300 amplitude, but not choice-locked P300 amplitude, such that children from families reporting higher income-to-needs ratio exhibited larger gain and loss feedback-locked P300 amplitude. These findings are consistent with recent findings from our group that also observed significant associations between elevated gain and loss feedback-locked P300 measured during adolescence with higher childhood and adolescent income-to-needs ratio (Santopetro et al., 2023). Taken together, the current data further implicates childhood poverty as an important predictor of worse depression trajectory as well as suggests that feedback related P300 can be employed as a neural correlate in future investigations to further understand the impact of childhood poverty on neurocognitive development across childhood. Notably, income to needs did not predict response to treatment suggesting PCIT-ED should be available to depression preschoolers across the income spectrum.

The current study had limitations that are worth noting. First, the choice-locked P300 component is derived only from one stimulus-type/condition (i.e., the presentation of the two doors) which is different than the traditional oddball task (i.e., P300 elicited from target stimuli in oddball tasks). Although there are differences between the demands of the doors task and oddball tasks, the presentation of the door stimuli is still a task-relevant event requiring the participant to make a choice and neural activity locked to the doors stimuli likely reflects the participant’s task engagement, decision making, and motivation indexed by the amount of cognitive resources that are allocated (e.g., attention, stimuli processing) to the door stimuli, which is in line with previous conceptualizations as to the function of more traditional P300 components. Nevertheless, our exact understanding of the functional significance of the choice-locked P300 component is much more limited and future researchers should employ novel versions of the doors task to examine what specific experimental conditions or manipulations modulate the choice-locked P300 component to more fundamentally understand this neural potential. Next, there was limited ethnic and racial diversity of the sample as the current sample was predominately White which limits the generalizability of the current findings. Lack of representation in EEG/ERP research is an important problem that greatly hinders establishing meaningful normative data (Choy et al., 2022) and future researchers should strive to replicate current findings employing more diverse samples of children. Additionally, given the relatively small sample sizes, it is possible that the current observed findings may be an overestimate of actual effects and future studies should seek to replicate the current findings employing much larger sample sizes. Lastly, the aims of the current RCT project were specific to better understanding and more effectively treating early onset childhood depression, and therefore other forms of pediatric psychopathology were not thoroughly examined. Future studies will need to further elucidate if the P300 is a prospective neural correlate specific to depressive disorders during childhood, or if P300 deficits are a broad risk marker for general psychopathology.

In sum, the current study extends upon past prospective findings involving P300, treatment responsiveness, and course of depression to young children experiencing depression which, to our knowledge, has not been examined previously. More specifically, current results suggest that choice-locked P300 amplitude measured in early childhood is a reliable (i.e., strong psychometric properties) neural measure associated with depression treatment responsiveness (specifically parent-child therapy) in young children. Importantly, these effects were not explained by differences in child age at treatment or income-to-needs ratio. Furthermore, the relationship between P300 amplitude and depression onset in preadolescence was significantly mediated by response to PCIT-ED. Thus, choice-locked P300 could be leveraged to further assist clinicians in more accurately identifying potential non-responders to treatment which could inform necessary adjustments or additions to the treatment plan to ensure increased engagement and progress.

Funding

National Institute of Mental Health Grants K23MH118426 (DJW); R01MH090786 (DJW & KEG); K01MH127412 (LH), and R01MH117436 (JLL & DMB).

Footnotes

Conflict of Interest The authors have no conflicts of interest to declare that are relevant to the content of this article.

Ethical Approval The study was approved by the Institutional Review Board at Washington University School of Medicine.

Informed Consent Informed written consent was provided to families and obtained before participation in the current project.

Data Availability

Data or other materials are available through correspondence with the author.

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Data Availability Statement

Data or other materials are available through correspondence with the author.

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