Rachel D. Freed

Role of Reward Sensitivity and Processing in Major Depressive and Bipolar Spectrum Disorders

Since Costellos (1972) seminal Behavior Therapy article on loss of reinforcers or reinforcer effectiveness in depression, the role of reward sensitivity and processing in both depression and bipolar disorder has become a central area of investigation. In this article, we review the evidence for a model of reward sensitivity in mood disorders, with unipolar depression characterized by reward hyposensitivity and bipolar disorders by reward hypersensitivity. We address whether aberrant reward sensitivity and processing are correlates of, mood-independent traits of, vulnerabilities for, and/or predictors of the course of depression and bipolar spectrum disorders, covering evidence from self-report, behavioral, neurophysiological, and neural levels of analysis. We conclude that substantial evidence documents that blunted reward sensitivity and processing are involved in unipolar depression and heightened reward sensitivity and processing are characteristic of hypomania/mania. We further conclude that aberrant reward sensitivity has a trait component, but more research is needed to clearly demonstrate that reward hyposensitivity and hypersensitivity are vulnerabilities for depression and bipolar disorder, respectively. Moreover, additional research is needed to determine whether bipolar depression is similar to unipolar depression and characterized by reward hyposensitivity, or whether like bipolar hypomania/mania, it involves reward hypersensitivity.

Functional domains as correlates of suicidality among psychiatric inpatients

BACKGROUND Suicide remains poorly understood and unpredictable. Addressing this challenge, this study examined the independent contributions of several research domain criteria (RDoC) constructs in relation to suicidality in patients hospitalized for acute suicide risk. Specifically, we examined anhedonia, anxiety/entrapment, and attachment disturbances, reflecting disturbances in reward processes, negative valence systems, and social processes, respectively. METHODS Anhedonia, anxiety, entrapment, and fearful attachment, were assessed quantitatively in 135 adults hospitalized for suicidality. Current suicidality and suicidal history were assessed with the Columbia Suicide Severity Rating Scale. Bivariate analyses (with significance threshold of p<.01 to account for multiple comparisons) and multivariate models examined relationships between symptom dimensions and severity of suicidal ideation (SI). We also assessed differences between patients with a history of suicide attempt and those who exhibited only suicidal ideations. RESULTS Using bivariate analyses all symptoms except for fearful attachment correlated robustly with SI (r =.37-0.50, p<.001). However, when using multivariate analyses, only anhedonia (β=.28, p=.01) and entrapment (β=.19, p=.03) were independently associated with SI across the entire sample. No functional domain measures differed between patients with history of suicide attempt versus ideation only. LIMITATIONS The reliance on self-report data and a cross-sectional design. CONCLUSIONS Disturbances in reward and threat processing may represent independent factors in the development of suicidal ideation in this high suicide risk cohort. Future studies should assess their role as risk factors.

Neural correlates of RDoC reward constructs in adolescents with diverse psychiatric symptoms: A Reward Flanker Task pilot study

BACKGROUND There has been growing interest under the Research Domain Criteria initiative to investigate behavioral constructs and their underlying neural circuitry. Abnormalities in reward processes are salient across psychiatric conditions and may precede future psychopathology in youth. However, the neural circuitry underlying such deficits has not been well defined. Therefore, in this pilot, we studied youth with diverse psychiatric symptoms and examined the neural underpinnings of reward anticipation, attainment, and positive prediction error (PPE, unexpected reward gain). Clinically, we focused on anhedonia, known to reflect deficits in reward function. METHODS Twenty-two psychotropic medication-free youth, 16 with psychiatric symptoms, exhibiting a full range of anhedonia, were scanned during the Reward Flanker Task. Anhedonia severity was quantified using the Snaith-Hamilton Pleasure Scale. Functional magnetic resonance imaging analyses were false discovery rate corrected for multiple comparisons. RESULTS Anticipation activated a broad network, including the medial frontal cortex and ventral striatum, while attainment activated memory and emotion-related regions such as the hippocampus and parahippocampal gyrus, but not the ventral striatum. PPE activated a right-dominant fronto-temporo-parietal network. Anhedonia was only correlated with activation of the right angular gyrus during anticipation and the left precuneus during PPE at an uncorrected threshold. LIMITATIONS Findings are preliminary due to the small sample size. CONCLUSIONS This pilot characterized the neural circuitry underlying different aspects of reward processing in youth with diverse psychiatric symptoms. These results highlight the complexity of the neural circuitry underlying reward anticipation, attainment, and PPE. Furthermore, this study underscores the importance of RDoC research in youth.

Aggression Protects Against the Onset of Major Depressive Episodes in Individuals With Bipolar Spectrum Disorder

A growing body of research suggests that bipolar spectrum disorders (BSDs) are associated with high aggression. However, little research has prospectively examined how aggression may affect time to onset of hypomanic/manic versus major depressive episodes. In a longitudinal study, we tested the hypothesis that aggression would prospectively predict a shorter time to the onset of hypomanic/manic episodes and a longer time to the onset of major depressive episodes, based on the behavioral approach system theory of BSDs. Young adults (N = 120) diagnosed with cyclothymia, bipolar II disorder, or bipolar disorder not otherwise specified were followed every 4 months for an average of 3.55 years. Participants completed measures of depressive and manic symptoms, family history of mood disorder, impulsivity, and aggression at baseline and were followed prospectively with semistructured diagnostic interview assessments of hypomanic/manic and major depressive episodes and treatment seeking for mood problems. Cox proportional hazard regression analyses indicated that overall, physical, and verbal aggression predicted a longer time to major depressive episode onset, even after controlling for baseline depressive and manic symptoms, family history of mood disorder, treatment seeking for mood problems, and impulsivity. Aggression, however, did not significantly predict time to onset of hypomanic/manic episodes, controlling for the same covariates. The findings suggest that approach-related behaviors may be utilized to delay the onset of major depressive episodes among people with BSDs.

Anhedonia as a clinical correlate of inflammation in adolescents across psychiatric conditions

Abstract Objectives: Peripheral inflammation has been associated with multiple psychiatric disorders, particularly with depression. However, findings remain inconsistent and unreproducible, most likely due to the disorder’s heterogeneity in phenotypic presentation. Therefore, in the present study, in an effort to account for inter-individual differences in symptom severity, we utilised a dimensional approach to assess the relationships between a broad panel of inflammatory cytokines and key psychiatric symptoms (i.e. depression, anhedonia, anxiety, fatigue and suicidality) in adolescents across psychiatric disorders. We hypothesised that only anhedonia (reflecting deficits of reward function) will be associated with inflammation. Methods: Participants were 54 psychotropic medication-free adolescents with diverse psychiatric conditions and 22 healthy control (HC) adolescents, aged 12–20. We measured 41 cytokines after in vitro lipopolysaccharide stimulation. Mann-Whitney U and Spearman correlation tests examined group comparison and associations, respectively, while accounting for multiple comparisons and confounds, including depression severity adolescent. Results: There were no group differences in cytokine levels. However, as hypothesised, within the psychiatric group, only anhedonia was associated with 19 cytokines, including haematopoietic growth factors, chemokines, pro-inflammatory cytokines, and anti-inflammatory cytokines. Conclusions: Our findings suggest that general inflammation may induce reward dysfunction, which plays a salient role across psychiatric conditions, rather than be specific to one categorical psychiatric disorder.

A Double-Blind Placebo-Controlled Trial of Omega-3 Fatty Acids as a Monotherapy for Adolescent Depression

OBJECTIVE Reports are mixed on the efficacy of omega-3 fatty acids (O3FA) for the treatment of major depressive disorder (MDD), with only limited data in adolescents. The present trial aimed to investigate systematically the efficacy of O3FA as a monotherapy, compared to a placebo, in adolescents with MDD. Secondarily, we explored O3FA effects on anhedonia, irritability, and suicidality-all key features of adolescent MDD. METHODS Fifty-one psychotropic medication-free adolescents with DSM-IV-TR diagnoses of MDD (aged 12-19 years; 57% female) were randomized to receive O3FA or a placebo for 10 weeks. Data were collected between January 2006 and June 2013. O3FA and a placebo were administered on a fixed-flexible dose titration schedule based on clinical response and side effects. The initial dose of 1.2 g/d was increased 0.6 g/d every 2 weeks, up to a maximum of 3.6 g/d. Clinician-rated and self-rated depression severity, along with treatment response, served as primary outcome measures. Additionally, we examined O3FA effects on depression-related symptoms, including anhedonia, irritability, and suicidality. Treatment differences were analyzed via intent-to-treat analyses. RESULTS O3FA were not superior to a placebo on any clinical feature, including depression severity and levels of anhedonia, irritability, or suicidality. Additionally, response rates were comparable between treatment groups. Within-treatment analyses indicated that both treatments were associated with significant improvement in depression severity on self- (O3FA: t = -4.38, P < .001; placebo: t = -3.52, P = .002) and clinician (O3FA: t = -6.47, P < .001; placebo: t = -8.10, P < .001) ratings. CONCLUSIONS In adolescents with MDD, O3FA do not appear to be superior to placebo. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00962598.

The role of lifetime anxiety history in the course of bipolar spectrum disorders

Individuals with bipolar spectrum disorder (BSD) frequently meet criteria for comorbid anxiety disorders, and anxiety may be an important factor in the etiology and course of BSDs. The current study examined the association of lifetime anxiety disorders with prospective manic/hypomanic versus major depressive episodes. Participants were 244 young adults (aged 17-26) with milder forms of BSDs (i.e., bipolar-II, cyclothymia, BD-NOS). First, bivariate analyses assessed differences in baseline clinical characteristics between participants with and without DSM-IV anxiety diagnoses. Second, negative binomial regression analyses tested whether lifetime anxiety predicted number of manic/hypomanic or major depressive episodes developed during the study. Third, survival analyses evaluated whether lifetime anxiety predicted time to onset of manic/hypomanic and major depressive episodes. Results indicated that anxiety history was associated with greater illness severity at baseline. Over follow-up, anxiety history predicted fewer manic/hypomanic episodes, but did not predict number of major depressive episodes. Anxiety history also was associated with longer time to onset of manic/hypomanic episodes, but shorter time to onset of depressive episodes. Findings corroborate past studies implicating anxiety disorders as salient influences on the course of BSDs. Moreover, results extend prior research by indicating that anxiety disorders may be linked with reduced manic/hypomanic phases of illness.

A pilot study of cortical glutathione in youth with depression

AIM This study used proton magnetic resonance spectroscopy (1H MRS) to measure in vivo brain glutathione (GSH) in adolescents with major depressive disorder (MDD), and explored the relationship between GSH and illness severity and chronicity. Secondarily, associations between GSH and anhedonia, a key symptom of MDD in adolescents, were investigated. METHODS Occipital cortex GSH levels were obtained in 19 psychotropic medication-free adolescents with MDD (ages 12-21) and compared to those in eight healthy control adolescents. Correlations between GSH levels and anhedonia severity were examined both in the full participant sample and within the MDD group. Within the MDD group, correlations between GSH levels and illness severity and chronicity were assessed. RESULTS Occipital GSH levels were lower in adolescents with MDD compared to controls, but did not correlate with anhedonia (either within the MDD group or the full sample), MDD severity, or onset. There were also no group differences in levels of total choline, creatine, and N-acetylaspartate - all neurometabolites that were simultaneously detected with 1H MRS. CONCLUSIONS Although preliminary, findings add new data to support the role of oxidative stress in MDD and suggest that lower GSH may be a potential marker of MDD early on in the course of illness.