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BackgroundClassic theories posit that depression is driven by a negative learning bias. Most studies supporting this proposition used small and selected samples, excluding patients with comorbidities. However, comorbidity between psychiatric disorders occurs in up to 70% of the population. Therefore, the generalizability of the negative bias hypothesis to a naturalistic psychiatric sample as well as the specificity of the bias to depression, remain unclear. In the present study, we tested the negative learning bias hypothesis in a large naturalistic sample of psychiatric patients, including depression, anxiety, addiction, attention-deficit/hyperactivity disorder, and/or autism. First, we assessed whether the negative bias hypothesis of depression generalized to a heterogeneous (and hence more naturalistic) depression sample compared with controls. Second, we assessed whether negative bias extends to other psychiatric disorders. Third, we adopted a dimensional approach, by using symptom severity as a way to assess associations across the sample.MethodsWe administered a probabilistic reversal learning task to 217 patients and 81 healthy controls. According to the negative bias hypothesis, participants with depression should exhibit enhanced learning and flexibility based on punishment v. reward. We combined analyses of traditional measures with more sensitive computational modeling.ResultsIn contrast to previous findings, this sample of depressed patients with psychiatric comorbidities did not show a negative learning bias.ConclusionsThese results speak against the generalizability of the negative learning bias hypothesis to depressed patients with comorbidities. This study highlights the importance of investigating unselected samples of psychiatric patients, which represent the vast majority of the psychiatric population.

BackgroundIt is widely acknowledged that comorbidity between psychiatric disorders is common. Shared and diverse underpinnings of psychiatric disorders cannot be systematically understood on the basis of symptom-based categories of mental disorders, which map poorly onto pathophysiological mechanisms. In the MIND-Set study, we make use of current concepts of comorbidity that transcend the current diagnostic categories. We test this approach to psychiatric problems in patients with frequently occurring psychiatric disorders and their comorbidities (excluding psychosis). The main objective of the MIND-Set project is to determine the shared and specific mechanisms of neurodevelopmental and stress-related psychiatric disorders at different observational levels.MethodsThis is an observational, cross-sectional study. Data from different observational levels as defined in the research domain criteria (RDoC; genetics, physiology, neuropsychology, system level neuroimaging, behavior, self-report and experimental neurocognitive paradigms) are collected over four time points. Included are adult (≥ 18 years), non-psychotic, psychiatric patients with a clinical diagnosis of a stress-related disorder (mood disorder, anxiety disorder and/or addiction disorder) and/or a neurodevelopmental disorder (ASD and/or ADHD). Individuals with no current or past psychiatric diagnosis are included as controls. Data collection started in June 2016 with the aim to include a total of 650 patients and 150 healthy controls by 2021. The data collection procedure includes online questionnaires and three subsequent sessions with 1) Standardized clinical examination, physical examination, and blood sampling; 2) Psychological constructs, neuropsychological tests, and biological marker sampling; 3) Neuroimaging measures.DiscussionThe MIND-Set study enables us to investigate the mechanistic underpinnings of non-psychotic psychiatric disorders transdiagnostically. We will identify both shared and disorder-specific markers at different observational levels that can be used as targets for future diagnostic and treatment approaches.

Background Prior work has proposed that major depressive disorder (MDD) is associated with a specific cognitive bias: patients with depression seem to learn more from punishment than from reward. This learning bias has been associated with blunting of reward-related neural responses in the striatum. A key question is whether negative learning bias is also present in patients with MDD and comorbid disorders and whether this bias is specific to depression or shared across disorders. Methods We employed a transdiagnostic approach assessing a heterogeneous group of (nonpsychotic) psychiatric patients from the MIND-Set (Measuring Integrated Novel Dimensions in Neurodevelopmental and Stress-Related Mental Disorders) cohort with and without MDD but also with anxiety, attention-deficit/hyperactivity disorder, and/or autism (n = 66) and healthy control subjects (n = 24). To investigate reward and punishment learning, we employed a deterministic reversal learning task with functional magnetic resonance imaging. Results In contrast to previous studies, patients with MDD did not exhibit impaired reward learning or reduced reward-related neural activity anywhere in the brain. Interestingly, we observed consistently increased neural responses in the bilateral lateral prefrontal cortex of patients when they received a surprising reward. This increase was not specific to MDD, but generalized to anxiety, attention-deficit/hyperactivity disorder, and autism. Critically, increased prefrontal activity to surprising reward scaled with transdiagnostic symptom severity, particularly that associated with concentration and attention, as well as the number of diagnoses; patients with more comorbidities showed a stronger prefrontal response to surprising reward. Conclusions Prefrontal enhancement may reflect compensatory working memory recruitment, possibly to counteract the inability to swiftly update reward expectations. This neural mechanism may provide a candidate transdiagnostic index of psychiatric severity.