High Familial Risk For Depression Research Articles

Characterising depression trajectories in young people at high familial risk of depression

BackgroundParental depression is a common and potent risk factor for depression in offspring. However, the developmental course of depression from childhood to early-adulthood has not been characterized in this high-risk group. MethodsUsing longitudinal data from 337 young people who had a parent with a history of recurrent major depressive disorder (MDD), we characterized trajectories of broadly defined depressive disorder using latent class growth analysis. We used clinical descriptions to further characterise trajectory classes. ResultsTwo trajectory classes were identified: childhood-emerging (25 %) and adulthood-emerging (75 %). The childhood-emerging class showed high rates of depressive disorder from age 12.5, which persisted through the study period. The adulthood-emerging class showed low rates of depressive disorder until age 26. Individual factors (IQ and ADHD symptoms) and parent depression severity (comorbidity, persistence and impairment) differentiated the classes but there were no differences in family history score or polygenic scores associated with psychiatric disorder. Clinical descriptions indicated functional impairment in both classes, but more severe symptomatology and impairment in the childhood-emerging class. LimitationsAttrition particularly affected participation in young adulthood. Factors associated with attrition were low family income, single parent household status and low parental education. ConclusionsThe developmental course of depressive disorder in children of depressed parents is variable. When followed up to adult life, most individuals exhibited some functional impairment. An earlier age-of-onset was associated with a more persistent and impairing course of depression. Access to effective prevention strategies is particularly warranted for at-risk young people showing early-onsetting and persistent depressive symptoms.

Neural Circuit Markers of Familial Risk for Depression Among Healthy Youths in the Adolescent Brain Cognitive Development Study

BackgroundFamily history of depression is a robust predictor of early-onset depression, which may confer risk through alterations in neural circuits that have been implicated in reward and emotional processing. These alterations may be evident in youths who are at familial risk for depression but who do not currently have depression. However, the identification of robust and replicable findings has been hindered by few studies and small sample sizes. In the current study, we sought to identify functional connectivity (FC) patterns associated with familial risk for depression. MethodsParticipants included healthy (i.e., no lifetime psychiatric diagnoses) youths at high familial risk for depression (HR) (n = 754; at least one parent with a history of depression) and healthy youths at low familial risk for psychiatric problems (LR) (n = 1745; no parental history of psychopathology) who were 9 to 10 years of age and from the Adolescent Brain Cognitive Development (ABCD) Study sample. We conducted whole-brain seed-to-voxel analyses to examine group differences in resting-state FC with the amygdala, caudate, nucleus accumbens, and putamen. We hypothesized that HR youths would exhibit global amygdala hyperconnectivity and striatal hypoconnectivity patterns primarily driven by maternal risk. ResultsHR youths exhibited weaker caudate–angular gyrus FC than LR youths (α = 0.04, Cohen’s d = 0.17). HR youths with a history of maternal depression specifically exhibited weaker caudate–angular gyrus FC (α = 0.03, Cohen’s d = 0.19) as well as weaker caudate–dorsolateral prefrontal cortex FC (α = 0.04, Cohen’s d = 0.21) than LR youths. ConclusionsWeaker striatal connectivity may be related to heightened familial risk for depression, primarily driven by maternal history. Identifying brain-based markers of depression risk in youths can inform approaches to improving early detection, diagnosis, and treatment.

Developing and validating a prediction model of adolescent major depressive disorder in the offspring of depressed parents.

Parental depression is common and is a major risk factor for depression in adolescents. Early identification of adolescents at elevated risk of developing major depressive disorder (MDD) in this group could improve early access to preventive interventions. Using longitudinal data from 337 adolescents at high familial risk of depression, we developed a risk prediction model for adolescent MDD. The model was externally validated in an independent cohort of 1,384 adolescents at high familial risk. We assessed predictors at baseline and MDD at follow-up (a median of 2-3 years later). We compared the risk prediction model to a simple comparison model based on screening for depressive symptoms. Decision curve analysis was used to identify which model-predicted risk score thresholds were associated with the greatest clinical benefit. The MDD risk prediction model discriminated between those adolescents who did and did not develop MDD in the development (C-statistic = .783, IQR (interquartile range) = .779, .778) and the validation samples (C-statistic = .722, IQR = -.694, .741). Calibration in the validation sample was good to excellent (calibration intercept = .011, C-slope = .851). The MDD risk prediction model was superior to the simple comparison model where discrimination was no better than chance (C-statistic = .544, IQR = .536, .572). Decision curve analysis found that the highest clinical utility was at the lowest risk score thresholds (0.01-0.05). The developed risk prediction model successfully discriminated adolescents who developed MDD from those who did not. In practice, this model could be further developed with user involvement into a tool to target individuals for low-intensity, selective preventive intervention.

Morphological Biomarkers in the Amygdala and Hippocampus of Children and Adults at High Familial Risk for Depression.

Major Depressive Disorder (MDD) is highly familial, and the hippocampus and amygdala are important in the pathophysiology of MDD. Whether morphological markers of risk for familial depression are present in the hippocampus or amygdala is unknown. We imaged the brains of 148 individuals, aged 6 to 54 years, who were members of a three-generation family cohort study and who were at either high or low familial risk for MDD. We compared surface morphological features of the hippocampus and amygdala across risk groups and assessed their associations with depression severity. High- compared with low-risk individuals had inward deformations of the head of both hippocampi and the medial surface of the left amygdala. The hippocampus findings persisted in analyses that included only those participants who had never had MDD, suggesting that these are true endophenotypic biomarkers for familial MDD. Posterior extension of the inward deformations was associated with more severe depressive symptoms, suggesting that a greater spatial extent of this biomarker may contribute to the transition from risk to the overt expression of symptoms. Significant associations of these biomarkers with corresponding biomarkers for cortical thickness suggest that these markers are components of a distributed cortico-limbic network of familial vulnerability to MDD.

P323. Blunted Amygdala Activity to Positive Memories in Young Adults With High Familial Risk for Depression

Depression is associated with a tendency to recall fewer specific and fewer positive autobiographical memories (AMs), and reduced amygdala hemodynamic activity when recalling positive AMs. This amygdala response may be a causal mechanism underlying depression, yet whether it is a precursor to disease onset is unclear. This study evaluates if blunted amygdala activity during positive AM recall is detectable in healthy individuals at risk for major depressive disorder (MDD), to inform its utility as an early therapeutic target aimed at disease prevention.

Maternal Response to Positive Affect Moderates the Impact of Familial Risk for Depression on Ventral Striatal Response to Winning Reward in 6- to 8-Year-Old Children

BackgroundA growing body of research has demonstrated that adolescent offspring of depressed parents show diminished responding in the ventral striatum to reward. More recent work has suggested that altered reward responding may emerge earlier than adolescence in offspring at familial risk for depression, although factors associated with neural alterations in childhood remain poorly understood. MethodsWe tested whether 6- to 8-year-old children, 49% at heightened risk for depression via maternal history, showed altered neural responding to winning reward. We evaluated whether maternal socialization of positive emotion moderated the association between familial risk and child neural response to reward. Participants were 49 children 6 to 8 years of age (24 with a maternal history of recurrent or chronic depression, 25 with no maternal history of any psychiatric disorder). Children underwent functional magnetic resonance imaging while completing the Doors Guessing Task, a widely used reward guessing task. Mothers reported their use of encouraging and dampening responses to child positive affect. ResultsFindings demonstrated that children at high familial risk for depression showed lower ventral striatum responding to winning reward relative to low-risk children, but only when mothers used less encouragement or greater dampening responses to their child’s positive emotion expressions. ConclusionsNeural reward alterations in the ventral striatum may emerge earlier than previously thought, as early as 6 to 8 years of age, specifically in the context of maternal discouragement of child positive emotions. Clinical interventions that focus on coaching mothers on how to encourage child positive emotions may be beneficial for supporting child reward-related brain development.

Links between depressive symptoms and the observer perspective for autobiographical memories and imagined events: a high familial risk study

ABSTRACT Depression is associated with increased observer visual perspective for positive autobiographical memories. However, it is unclear if this relationship (1) is present in individuals at high familial risk of depression; (2) is a general bias extending to future imagined events; and (3) is independent of general cognition and other cognitive biases. We examined the association of observer perspective, valence (positive, negative, neutral) and temporality (memories, future imagined events) with depressive symptoms in 29 young adults at high familial risk for depression. Increased observer perspective for memories was associated with dimensional depressive symptoms controlling for IQ and autobiographical specificity. There was weak evidence that increased observer perspective for future events was associated with a diagnostic measure of depressive symptoms, but limited evidence that perspective by valence interactions were associated with depressive symptoms. Results indicate depressive symptoms are associated with an observer perspective bias in autobiographical thinking regardless of temporality or valence.

An Eye-Tracking Study of Attention Biases in Children at High Familial Risk for Depression and Their Parents with Depression

Attention biases (AB) are a core component of cognitive models of depression yet it is unclear what role they play in the transgenerational transmission of depression. 44 children (9–14 years) with a high familial risk of depression (HR) were compared on multiple measures of AB with 36 children with a low familial risk of depression (LR). Their parents: 44 adults with a history of depression (HD) and 36 adults with no history of psychiatric disorder (ND) were also compared. There was no evidence of group differences in AB; neither between the HR and LR children, nor between HD and ND parents. There was no evidence of a correlation between parent and child AB. The internal consistency of the tasks varied greatly. The Dot-Probe Task showed unacceptable reliability whereas the behavioral index of the Visual-Search Task and an eye-tracking index of the Passive-Viewing Task showed better reliability. There was little correlation between the AB tasks and the tasks showed minimal convergence with symptoms of depression or anxiety. The null-findings of the current study contradict our expectations and much of the previous literature. They may be due to the poor psychometric properties associated with some of the AB indices, the unreliability of AB in general, or the relatively modest sample size. The poor reliability of the tasks in our sample suggest caution should be taken when interpreting the positive findings of previous studies which have used similar methods and populations.

Differential neural responding to affective stimuli in 6- to 8-year old children at high familial risk for depression: Associations with behavioral reward seeking

ObjectiveChildren of depressed parents are at increased risk for psychopathology. One putative mechanism of risk appears to be altered processing of emotion-related stimuli. Although prior work has evaluated how adolescent offspring of depressed parents may show blunted reward processing compared to low-risk youth, there has been less attention to how young children with this familial history may differ from their peers during middle childhood, a period of critical socio-affective development MethodThe current study evaluated 56 emotionally healthy 6-to 8-year children who were deemed at high-risk (n = 25) or low-risk (n = 31) for depression based on maternal history of depression. Children completed a behavioral reward seeking task in the laboratory and an fMRI paradigm assessing neural response to happy faces, a social reward. ResultsFindings demonstrated that high-risk children showed blunted responding to happy faces in the dorsal striatum compared to low-risk children. Further, lower responding in the dorsal striatum and dorsolateral prefrontal cortex was related to lower behavioral reward seeking, but only in high-risk children. ConclusionFunction within neural reward regions may be altered in high-risk offspring as young as 6- to 8-years of age. Further, neural reward responding may be linked to lower behavioral response to obtain reward in these high-risk offspring.

The role of familial risk, parental psychopathology, and stress for first-onset depression during adolescence

BackgroundAdolescence represents a critical developmental period during which the initial onset of depression emerges. Family risk for depression is a salient risk factor for the initial onset of Major Depressive Disorder (MDD). We examined the effects of familial risk, stress, and behavior on the risk of developing first-onset depression. MethodsAdolescents aged 12 to 15 with high (n = 166) or low (n = 159) familial risk for depression were assessed annually for up to five years. Stress was assessed using the Stressful Life Events Schedule and Childhood Trauma Questionnaire. The Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version was administered to the adolescents and their parents to assess lifetime psychiatric conditions and diagnose MDD onset. Survival and path analyses were used in tandem to determine the risk for first-onset depression as well as the contributions of additional direct and indirect pathways to onset. ResultsHigh-risk adolescents were eight times more likely to develop first-onset depression compared with low-risk adolescents. The path analyses revealed that the presence of maternal behavioral disorders and increased recent life stress directly predicted an initial onset of MDD in high-risk adolescents. LimitationsThe small samples used in this study limit the generalizability of these findings. ConclusionsAdolescents at high familial risk for depression had an increased risk for the emergence of first-onset depression during adolescence. Stress and maternal behavioral psychopathology directly contributed to depression onset independently of familial risk, while childhood trauma exerted an indirect effect on first-onset MDD through recent stress.

Examining the relationship between stressful life events and overgeneral autobiographical memory in adolescents at high familial risk of depression

ABSTRACTDifficulty remembering specific events from the personal past, known as overgeneral autobiographical memory (AM), may be a marker of vulnerability to adolescent depression but little is known about how overgeneral AM arises in this age group. Stressful life events (SLEs) are strongly implicated in the onset of depression and are considered important in theoretical work on AM. We investigated whether exposure to lifetime and recent SLEs contributed to the development of overgeneral AM in a sample of adolescents at high familial risk of depression (n = 257) and examined the effects of gender and memory valence. Whether AM mediated the relationship between SLEs and MDD was also assessed. Exposure to a higher number of lifetime SLEs was associated with an increase in specific AMs. Associations of recent SLEs with AM differed by gender. For girls, more recent SLEs were associated with more overgeneral AMs. For boys, more recent SLEs were associated with fewer overgeneral AMs and more specific AMs. AM did not mediate the relationship between SLEs and subsequent DSM-IV depressive symptom count. Results suggest a complex relationship between AM and SLEs and that overgeneral AM and SLEs may have independent effects on future depression.

Hippocampal shape alterations in healthy young women with familial risk for unipolar depression

BackgroundAlthough reduced hippocampal volume (HCV) is a common finding in depression, it is unclear whether the structural alterations leading to reduction of HCV are pre-existing risk factors before the onset of clinical symptoms or a cumulative process that begins with the onset of clinical symptoms. The aim of the present study was to understand the anatomical status of the hippocampus prior to the clinical symptoms in subjects with high familial risk for depression. MethodsTwenty-seven young women (mean age: 22.3 ± 2.1 years) who were at high risk for familial unipolar depression and 26 age- and gender-matched healthy controls (mean age: 22.1 ± 2.1 years) with low familial risk for depression were included in the study. Total hippocampal volumes were measured by manual tracing. For 3D shape differences, the spherical harmonic basis functions (SPHARM) software was used. The segmented images were parameterized, and the point-to-point based group difference was compared by the Hotelling's T-squared test with total brain volume and Beck Depression Scale as covariates. ResultsAlthough there was no difference in overall HCVs, shape analyses revealed a contracted area on the Cornu Ammonis (CA) 1 region of the right hippocampus head in the high-risk group compared to the low-risk group. Cross-sectional design and small sample size, including only females, were the main limitations of this study. ConclusionThis study with shape analyses provided data suggesting that local structural hippocampal alterations in the CA1 region might be associated with depression vulnerability in women at high risk.

Genetic Correlates of Spirituality/Religion and Depression: A Study in Offspring and Grandchildren at High and Low Familial Risk for Depression.

Possible genetic correlates of spirituality and depression have been identified in community samples. We investigate some of the previously identified candidates in a sample of families at both high and low-risk for depression. Offspring and grandchildren of individuals at high and low-risk for depression, participating in a multi-wave thirty-year longitudinal study, were assessed for seven SNPS drawn from four single gene candidates associated with systems implicated in both depression and spirituality: Serotonin (5-HT1B and 5-HT2A), Dopamine (DRD2), Oxytocin (OT) and Monoamine Vesicular Transporter (VMAT1). Dopamine (DRD2) Serotonin (5-HT1B), their Transporter (VMAT1) and Oxytocin (OXTR) were positively associated with a high level of importance of spirituality or religion (S/R) in the group at low familial risk for depression. DRD2 minor allele was associated with both lifetime major depressive disorder (MDD) and spirituality in the low-risk group for depression. No SNPs were related to S/R in the group at high familial risk for depression. OXTR was associated with lifetime MDD in the full sample. Genes for dopamine, serotonin, their vesicular transporter, and oxytocin may be associated with S/R in people at low familial risk for depression. Genes for dopamine may be associated both with S/R and increased risk for depression in people at low-risk for depression, suggesting a common pathway or physiology to mild to moderate depression. MDD is associated with oxytocin across risk groups. In the high-risk group, phenotypic expression of S/R may be suppressed. The shared association of DRD2 by S/R and depression, generally found to be inversely related, calls for further research on their common physiological pathways, and the phenotypic expression of these pathways based upon use and environment. Prevention for offspring at high familial risk for depression might include support for the development of child spirituality.

Antecedents of New-Onset Major Depressive Disorder in Children and Adolescents at High Familial Risk

Early-onset major depressive disorder (MDD) is common in individuals at high familial risk of depression and is associated with poor long-term mental health, social, and educational outcomes. To examine the developmental pathways that lead to first-episode adolescent-onset MDD (incident cases) in those at high familial risk and to postulate a theoretically informed model that enables simultaneous testing of different pathways to incident adolescent-onset MDD composed of contributions from familial/genetic and social risk factors, as well as effects via specific clinical antecedents. This investigation was a 4-year longitudinal study (April 2007 to March 2011) among offspring of depressed parents in the general community. Analyses were conducted between September 1, 2015, and May 27, 2016. Participants were 337 families in whom the index parent (315 mothers and 22 fathers) had experienced at least 2 episodes of MDD (recruited through primary care) and among whom there was a biologically related child in the age range of 9 to 17 years living with the index parent (197 girls and 140 boys with a mean [SD] age of 12.4 [2.0] years) at baseline. Offspring with MDD before the study or at baseline (n = 27), offspring with an episode of MDD that had remitted by follow-up (n = 4), and offspring with missing baseline MDD data (n = 2) were excluded. Ninety-two percent (279 of 304) of families completed the follow-up. The primary outcome was new-onset offspring MDD, and the secondary outcome was the total DSM-IV MDD symptom score. On average, children and adolescents had a mean (SD) of 1.85 (1.74) (range, 0-8.5) DSM-IV symptoms of MDD at follow-up. Twenty (6 males and 14 females) had new-onset MDD, with a mean (SD) age at onset of 14.4 (2.0) years (range, 10-18 years). Irritability (β = 0.12, P = .03) and fear and/or anxiety (β = 0.38, P < .001) were significant independent clinical antecedents of new adolescent-onset MDD, but disruptive behavior (β = -0.08, P = .14) and low mood (β = -0.03, P = .65) were not. The results were similar for the DSM-IV symptom count at follow-up. All the measured familial/genetic and social risk indicators directly influenced risk for new-onset MDD rather than indirectly through acting on dimensional clinical antecedents. There are multiple pathways to first-onset adolescent depression in individuals at familial risk. Irritability and fear/anxiety may be additional clinical phenomena to be included as targets in primary preventive interventions focusing on the child. In addition to targeting these phenomena in parents and children, depression prevention methods in high-risk groups may need to take into consideration social risks, such as poverty and psychosocial adversity.

6.149 RELIGION AND SPIRITUALITY PREDICT LOWER RATES OF SUICIDE ATTEMPTS AND IDEATION IN CHILDREN AND ADOLESCENTS AT RISK FOR MAJOR DEPRESSIVE DISORDER

Depression is an established risk-factor for suicide (World Health Organization, 2015). Religion and spirituality (R/S) have been protective against depression and suicide in adults (Koenig, 2001). The impact of R/S on depression and suicidality in children has, however, been less well studied and has yielded mixed results (Dew, 2008). In particular, little work has been done on children at high familial risk for depression and the potential impact of R/S on suicidality in at-risk children. The purpose of this study was to test the potential moderating effects of R/S on suicidality in children at risk for depression.

Increased Default Mode Network Connectivity in Individuals at High Familial Risk for Depression.

Research into the pathophysiology of major depressive disorder (MDD) has focused largely on individuals already affected by MDD. Studies have thus been limited in their ability to disentangle effects that arise as a result of MDD from precursors of the disorder. By studying individuals at high familial risk for MDD, we aimed to identify potential biomarkers indexing risk for developing MDD, a critical step toward advancing prevention and early intervention. Using resting-state functional connectivity MRI (rs-fcMRI) and diffusion MRI (tractography), we examined connectivity within the default mode network (DMN) and between the DMN and the central executive network (CEN) in 111 individuals, aged 11-60 years, at high and low familial risk for depression. Study participants were part of a three-generation longitudinal, cohort study of familial depression. Based on rs-fcMRI, individuals at high vs low familial risk for depression showed increased DMN connectivity, as well as decreased DMN-CEN-negative connectivity. These findings remained significant after excluding individuals with a current or lifetime history of depression. Diffusion MRI measures based on tractography supported the findings of decreased DMN-CEN-negative connectivity. Path analyses indicated that decreased DMN-CEN-negative connectivity mediated a relationship between familial risk and a neuropsychological measure of impulsivity. Our findings suggest that DMN and DMN-CEN connectivity differ in those at high vs low risk for depression and thus suggest potential biomarkers for identifying individuals at risk for developing MDD.

Impact of a Father Figure's Presence in the Household on Children's Psychiatric Diagnoses and Functioning in Families at High Risk for Depression.

The consequences of living in single-parent households on children's wellbeing are well documented, but less is known about the impact of living in single-mother households among children with high familial risk for depression. Utilizing data from an ongoing three-generation study of high-risk families, this preliminary study examined a sample of 161 grandchildren of probands diagnosed with major depressive disorder, comparing those in single-parent households to those in dual-parent households with household status defined as the full-time presence of a resident male in the home. High-risk children were compared across households in terms of psychiatric diagnoses (measured by Schedule for Affective Disorders and Schizophrenia for School-Age Children; K-SADS-PL) and global functioning (assessed by Global Assessment Scale, child version; C-GAS). Results indicated that high-risk children in single-parent households had 4.7 times greater odds for developing a mood disorder and had significantly lower mean C-GAS scores (p = 0.01) compared to those in dual-parent households. Differences remained significant when controlling for household income, child's age, and either parent's depression status. There were no significant differences between high-risk children across households when household status was instead defined as legal marital status. This study has several limitations: sample size was small, pro-bands were recruited from a clinical population, and participants had not passed completely through the period of risk for adult psychiatric disorders. These findings point towards the importance of identifying and closely monitoring children at risk for depression, particularly if they reside in households without a resident father figure.

Maternal caregiving and girls' depressive symptom and antisocial behavior trajectories: an examination among high-risk youth.

Past research has identified maternal depression and family of origin maltreatment as precursors to adolescent depression and antisocial behavior. Caregiving experiences have been identified as a factor that may ameliorate or accentuate adolescent psychopathology trajectories. Using a multilevel approach that pools the unique attributes of two geographically diverse, yet complementary, longitudinal research designs, the present study examined the role of maternal caregiver involvement as a factor that promotes resilience-based trajectories related to depressive symptoms and antisocial behaviors among adolescent girls. The first sample comprises a group of US-based adolescent girls in foster care (n = 100; mean age = 11.50 years), each of whom had a history of childhood maltreatment and removal from their biological parent(s). The second sample comprises a group of UK-based adolescent girls at high familial risk for depression (n = 145; mean age = 11.70 years), with all girls having biological mothers who experienced recurrent depression. Analyses examined the role of maternal caregiving on girls' trajectories of depression and antisocial behavior, while controlling for levels of co-occurring psychopathology at each time point. Results suggest increasing levels of depressive symptoms for girls at familial risk for depression but decreasing levels of depression for girls in foster care. Foster girls' antisocial behavior also decreased over time. Maternal caregiver involvement was differentially related to intercept and slope parameters in both samples. Results are discussed with respect to the benefits of applying multilevel (multisample, multiple outcome) approaches to identifying family-level factors that can reduce negative developmental outcomes in high-risk youth.

Reduced reward anticipation in youth at high-risk for unipolar depression: A preliminary study

Offspring of depressed parents are at risk for depression and recent evidence suggests that reduced positive affect (PA) may be a marker of risk. We investigated whether self-reports of PA and fMRI-measured striatal response to reward, a neural correlate of PA, are reduced in adolescent youth at high familial risk for depression (HR) relative to youth at low familial risk for depression (LR). Functional magnetic resonance imaging assessments were conducted with 14 HR and 12 LR youth. All youth completed an ecological momentary assessment protocol to measure PA in natural settings and a self-report measure of depression symptomatology. Analyses found that HR youth demonstrated lower striatal response than LR youth during both reward anticipation and outcome. However, after controlling for youth self-reports of depression, HR youth demonstrated lower striatal response than LR youth only during reward anticipation. No significant differences were found between HR and LR youth on subjective ratings of PA or depressive symptoms. Results are consistent with previous findings that reduced reward response is a marker of risk for depression, particularly during reward anticipation, even in the absence of (or accounting for) disrupted subjective mood. Further examinations of prospective associations between reward response and depression onset are needed.

A “Taste” of What is to Come: Reward Sensitivity as a Potential Endophenotype for Major Depressive Disorder

l a t n a b g i c b N early 40% of patients diagnosed with major depressive disorder (MDD) experience a loss of interest and responsiveness to previously rewarding stimuli and activities, a condition referred to clinically as anhedonia (see [1] for review). Anhedonia is one of the most treatment-resistant aspects of depression (2), and there is good reason to believe that the pathophysiology underlying this symptom complex may at least partly involve hypoactivity within the mesolimbic dopamine pathway and related brain structures (3). One question that previously has remained relatively unexplored is whether the pathological reward–related hypoactivity within these brain regions is a state effect associated with a current depressive episode or is a predisposing and enduring trait of MDD? In this issue of Biological Psychiatry, McCabe et al. (4) present the findings of a study aimed at addressing this important question. The goal of their study specifically was to determine whether individuals who never have experienced a major depressive episode, but who are at elevated familiar risk for MDD, might exhibit the abnormal reward-related activity previously documented in individuals diagnosed with MDD. To accomplish this goal, the authors recruited two groups of young adults: one group had no personal or familial history of MDD, and the other had never personally met criteria for MDD but endorsed having at least one parent with MDD. Both subject samples underwent functional magnetic resonance imaging while performing a task in which they sometimes saw pleasant pictures of chocolate and tasted a pleasant chocolate solution or at other times saw disgusting pictures of moldy strawberries and tasted an aversive strawberry solution. The authors report that relative to the control subjects, the adolescents at high familial risk for depression exhibited less orbitofrontal cortex (OFC) activity to the chocolate stimuli, and increased lateral OFC, and insula activity to the aversive strawberry stimuli. These at-risk participants also exhibited decreased responses in the anterior cingulate cortex to both aversive and rewarding stimuli. One interpretation of these findings is that individuals at risk for depression may possess latent abnormalities in their psychological representations of reward and punishment that can be revealed only by measuring the activity of the brain regions underlying the neural representation of reward and punishment. The research strategy used by McCabe et al. (4) is significant in at least two respects. First, the study addresses a question that was unresolved from earlier research by this group using the same experimental paradigm. In the earlier study, McCabe et al. (5) demonstrated that unmedicated subjects with remitted MDD exhibit abnormal activity within reward-related brain regions, although