Background A dysregulated stress response, including exaggerated affective reactivity and abnormal hypothalamic-pituitary-adrenal axis responsivity, has been implicated in the etiology, maintenance, and relapse of major depressive disorder (MDD). Among adolescents, discordant affective and physiological stress response profiles have been linked to negative affective outcomes and increased risk for psychopathology. Whether these findings extend to adults with varying degree of MDD risk is unclear, as are possible links to various risk factors. Methods We used a person-centered, multisystem approach in a sample of 119 unmedicated adults with current or remitted MDD and individuals without past MDD to evaluate psychobiological stress response profiles. Multitrajectory modeling was applied to positive affect, negative affect, and salivary cortisol (CORT) levels in response to the Maastricht Acute Stress Test. Results Analyses identified 4 within-person profiles, 1 typical, termed normative (n = 32, 26.9%) and 3 atypical: CORT hyperreactivity affective stability (n = 17, 14.3%), CORT hyporeactivity affective reactivity 1 (n = 45, 37.8%), and CORT hyporeactivity affective reactivity 2 (n = 25, 21.0%). While validating the assumption of a normative profile and increased risk for psychopathology in non-normative stress response profiles, coherent associations emerged between stress response profiles and clinical status, depression severity, anhedonia, perceived stress, childhood adversity, and reports of well-being, suggesting increased risk for psychopathology for individuals with a hyperreactive or discordant hyporeactive stress response profile. Conclusions This work advances our understanding of stress response mechanisms in MDD and underscores the potential of targeted interventions to enhance resilience and reduce psychopathology based on individual stress response profiles.

The neurobiological mechanisms underlying the placebo phenomenon in patients with major depressive disorder (MDD) remain largely unknown. The progressive rise in rates of placebo responses within clinical trials over the past two decades may impede the detection of a true signal and thus present a major obstacle in new treatment development. Understanding the mechanisms would have several important implications, including (1) identifying biomarkers of placebo responders (thereby identifying those individuals who could benefit therapeutically from such interventions), (2) opening new avenues for manipulating such mechanisms to maximize symptom reduction, and (3) refining treatments with approaches that decrease (in clinical trials) or increase (in clinical practice) the placebo response. Here we investigated the research question: is the dopaminergic system one of the neurobiological underpinnings of the placebo response within MDD? Inspired by preclinical and clinical findings that have implicated dopamine in the occurrence, prediction, and expectation of reward, we hypothesized that dopaminergic activity in the mesolimbic system is a critical mediator of placebo response in MDD. To test this hypothesis, we designed a double-blind, placebo-controlled, sequential parallel comparison design clinical trial aimed at maximizing placebo antidepressant response. We integrated behavioral, imaging, and hemodynamic probes of mesocorticolimbic dopaminergic pathways within the context of manipulations of psychological constructs previously linked to placebo responses (e.g., expectation of improvement). The aim of this manuscript is to present the rationale of the study design and to demonstrate how a cross-modal methodology may be utilized to investigate the role of reward circuitry in placebo response in MDD.

The Probabilistic Reward Task (PRT) is widely used to investigate the impact of Major Depressive Disorder (MDD) on reinforcement learning (RL), and recent studies have used it to provide insight into decision-making mechanisms affected by MDD. The current project used PRT data from unmedicated, treatment-seeking adults with MDD to extend these efforts by: (1) providing a more detailed analysis of standard PRT metrics—response bias and discriminability—to better understand how the task is performed; (2) analyzing the data with two computational models and providing psychometric analyses of both; and (3) determining whether response bias, discriminability, or model parameters predicted responses to treatment with placebo or the atypical antidepressant bupropion. Analysis of standard metrics replicated recent work by demonstrating a dependency between response bias and response time (RT), and by showing that reward totals in the PRT are governed by discriminability. Behavior was well-captured by the Hierarchical Drift Diffusion Model (HDDM), which models decision-making processes; the HDDM showed excellent internal consistency and acceptable retest reliability. A separate “belief” model reproduced the evolution of response bias over time better than the HDDM, but its psychometric properties were weaker. Finally, the predictive utility of the PRT was limited by small samples; nevertheless, depressed adults who responded to bupropion showed larger pre-treatment starting point biases in the HDDM than non-responders, indicating greater sensitivity to the PRT’s asymmetric reinforcement contingencies. Together, these findings enhance our understanding of reward and decision-making mechanisms that are implicated in MDD and probed by the PRT.

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced.

Research on cognitive functions in obsessive-compulsive disorder (OCD) is notoriously heterogeneous with no moderators identified that account for this variability. OCD severity is the primary potential moderator of interest given the longstanding trait versus state debate. Nevertheless, severity has been previously assessed exclusively as a moderator and was not directly and systematically investigated. To address this gap in the literature, the aim of this study was to conduct a systematic meta-analytic review of correlations between cognitive function and symptom severity in OCD samples. Thirty-eight studies were included, allowing for analysis of 132 effects and meta-regression analyses for potential moderators. Small effects were found for the association between cognitive function and symptom severity on major neuropsychological domains, and some subdomains exhibited medium effects for this association. However, several significant methodological and conceptual problems were identified, including the use of the Yale-Brown Obsessive-Compulsive Scale that assesses severity in the past week and not at time of testing, a tendency to not report non-significant correlations, and problematic ecological validity of neuropsychological tests in OCD. In conclusion, we found a small-to-moderate degree of association between OCD symptom severity and cognitive function, but results should be interpreted cautiously given the limitations identified. We offer recommendations that will facilitate future research into this association and move the field beyond the largely stagnant debate about the state versus trait nature of cognitive functioning in OCD, and across disorders.

BackgroundRecent studies suggest that yoga practice may improve cognitive functioning. Although preliminary data indicate that yoga improves working memory (WM), high-resolution information about the type of WM subconstructs, namely maintenance and manipulation, is not available. Furthermore, the association between cognitive enhancement and improved mindfulness as a result of yoga practice requires empirical examination. The aim of the present study is to assess the impact of a brief yoga program on WM maintenance, WM manipulation and attentive mindfulness.MethodsMeasures of WM(Digit Span Forward, Backward, and Sequencing, and Letter-Number Sequencing) were administered prior to and following 6 sessions of yoga (N = 43). Additionally, the Mindfulness Attention Awareness Scale was administered to examine the potential impact of yoga practice on mindfulness, as well as the relationships among changes in WM and mindfulness.ResultsAnalyses revealed significant improvement from pre- to post- training assessment on both maintenance WM (Digit Span Forward) and manipulation WM(Digit Span Backward and Letter-Number Sequencing). No change was found on Digit Span Sequencing. Improvement was also found on mindfulness scores. However, no correlation was observed between mindfulness and WM measures.ConclusionsA 6-session yoga program was associated with improvement on manipulation and maintenance WM measures as well as enhanced mindfulness scores. Additional research is needed to understand the extent of yoga-related cognitive enhancement and mechanisms by which yoga may enhance cognition, ideally by utilizing randomized controlled trials and more comprehensive neuropsychological batteries.