Gut microbiota composition links to variation in functional domains across psychiatric disorders.

OBJECTIVE: Changes in microbial composition are observed in various psychiatric disorders, but their specificity to certain symptoms or processes remains unclear. This study explores the associations between the gut microbiota composition and the Research Domain Criteria (RDoC) domains of functioning, representing symptom domains, specifically focusing on stress-related and neurodevelopmental disorders in patients with and without psychiatric comorbidity. METHODS: The gut microbiota was analyzed in 369 participants, comprising 272 individuals diagnosed with a mood disorder, anxiety disorder, attention deficit/hyperactivity disorder, autism spectrum disorder, and/or substance use disorder, as well as 97 psychiatrically unaffected individuals. The RDoC domains were estimated using principal component analysis (PCA) with oblique rotation on a range of psychiatric, psychological, and personality measures. Associations between the gut microbiota and the functional domains were assessed using multiple linear regression and permanova, adjusted for age, sex, diet, smoking, medication use and comorbidity status. RESULTS: Four functional domains, aligning with RDoC's negative valence, social processes, cognitive systems, and arousal/regulatory systems domains, were identified. Significant associations were found between these domains and eight microbial genera, including associations of negative valence with the abundance of the genera Sellimonas, CHKCI001, Clostridium sensu stricto 1, Oscillibacter, and Flavonifractor; social processes with Sellimonas; cognitive systems with Sporobacter and Hungatella; and arousal/regulatory systems with Ruminococcus torques (all pFDR < 0.05). CONCLUSION: Our findings demonstrate associations between the gut microbiota and the domains of functioning across patients and unaffected individuals, potentially mediated by immune-related processes. These results open avenues for microbiota-focused personalized interventions, considering psychiatric comorbidity. However, further research is warranted to establish causality and elucidate mechanistic pathways.

Association Between Personality Traits and Functional Limitations in Older Adults with Affective Disorders: A Cross Sectional Study.

OBJECTIVES: Personality traits and affective disorders are both related to functional limitations. It is unknown whether personality traits have an additional effect on functioning in older adults with affective disorders. We studied the association between personality traits and functioning within this group. METHODS: We performed a cross-sectional study of 180 older patients referred to outpatient specialized geriatric mental health care centers with a depressive, anxiety and/or somatic symptom disorder according to DSM-criteria. We studied the association between the Big Five personality traits and functional limitations assessed with the WHO-DAS II, adjusting for potential confounders, including the severity of various affective disorders. RESULTS: The 180 patients (57.1% female, mean age 69.2 years) had an average WHO-DAS II score of 31.3 (SD 15.1). Lower scores on Conscientiousness were associated with more overall functional limitations (p = .001), particularly limitations in self-care (p = .001) and household activities (p = .001). Lower Extraversion scores were associated with more limitations in getting along with others (p = .001). CONCLUSIONS: Personality traits are related to functional limitations independent of the severity of affective disorders in older adults. CLINICAL IMPLICATIONS: Personality traits may be used as predictive factors for functioning in older adults with affective disorders.

Challenging the negative learning bias hypothesis of depression: reversal learning in a naturalistic psychiatric sample.

BACKGROUND: Classic 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. METHODS: We 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. RESULTS: In contrast to previous findings, this sample of depressed patients with psychiatric comorbidities did not show a negative learning bias. CONCLUSIONS: These 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.

Patterns of discordance of physical functioning in older persons; different associations for apathy and depression? Results from the NESDO-study.

OBJECTIVES: Discordance between self-reported functional limitations and performance-based physical functioning may have a negative impact in functional independence in older adults. We longitudinally examined baseline apathy- and depressive symptomatology as associates of discordance. METHOD: 469 participants from the multi-site cohort study NESDO were included. Self-reported functional limitations were assessed by two items derived from the WHO-Disability Assessment Schedule. Performance-based physical functioning included walking speed and handgrip-strength. Both measures were rescaled, with final sum-scores ranging from 0 to 6. Discordance-scores were computed by subtracting sum-scores on performance-based measures from self-reported functional limitations. Using latent growth curve analysis, we estimated individual trajectories of discordance at baseline, 2-and 6-years follow-up, consisting of the baseline discordance-score (intercept) and the yearly change of discordance-score (slope). We then estimated associations with apathy and depression indicators. RESULTS: At baseline, persons (mean age 70.48 years, 65% female, 73% depressed) on average overestimated their daily functioning compared to performance tests (b = 0.77, p < 0.001). The average discordance-scores yearly increased by 0.15 (p < 0.001). Only in models adjusted for several demographic and clinical characteristics, depression severity was negatively associated with discordance-scores at baseline (b=-0.01, p = 0.02), while apathy was not (b=-0.02, p = 0.21). No associations with change over time were found. CONCLUSION: In older persons, not indifference and diminished goal-directed activity, but negative emotions appear to underlie underestimation of one's physical capacity. Further research is needed to determine (1) to what extent targeting discordance results in actual preservation of physical functioning and (2) whether older persons with apathy and/or depression need different approaches for this purpose.

The Role of Perseverative Cognition for Both Mental and Somatic Disorders in a Naturalistic Psychiatric Patient Sample.

OBJECTIVE: Perseverative cognition (PC) is the repeated or long-term activation of the cognitive representation of psychological stressors and is associated with prolonged stress including somatic and mental consequences. Hence, PC might represent a cognitive process linking mental and somatic pathology, but current research on this link is limited by investigating healthy samples, markers of somatic disease, and single disorders. The present study explored the importance of PC for different mental and somatic disorders in psychiatric patients. METHODS: Data from 260 naturalistic psychiatric outpatients were used. Psychiatric diagnoses were based on structured clinical interviews. Somatic diseases were assessed using a well-validated questionnaire and were clustered into (cardio)vascular and immune/endocrine diseases. PC was operationalized using the Perseverative Thinking Questionnaire (PTQ). RESULTS: Multiple regression complemented with relative importance analyses showed that the PTQ total and subscale scores were associated with the presence of mood disorders, addiction, and anxiety. Unexpectedly, no relatively important associations were found between the PTQ and autism spectrum disorder, attention-deficit/hyperactivity disorder, or somatic disease. CONCLUSIONS: Our data complement previous work linking PC to stress-related mental disorders but question its immediate role in neurodevelopmental and somatic disorders. Targeting PC in the treatment of mood disorders and perhaps also in addiction seems promising.

Could Frailty be an Explanatory Factor of the Association between Depression and Other Geriatric Syndromes in Later Life?

OBJECTIVES: This study aimed to investigate whether frailty could be an explanatory factor of the association between depression and the number of geriatric syndromes. METHODS: Cross-sectional baseline data from a cohort study (MiMiCS-FRAIL) were analyzed in a sample of 315 older adults. Depression was measured according to DSM-5 criteria and a self-report questionnaire (PHQ-9). Frailty was assessed according to the FRAIL questionnaire and a 30-item Frailty Index (FI). We considered six geriatric syndromes. Multiple linear regression analyses were performed and adjusted for potential confounders. RESULTS: Multiple linear regression analyses yielded significant associations between depression and geriatric syndromes. These associations decreased substantially in strength when frailty was added to the models. Findings were consistent for different definitions of depression and frailty. CONCLUSIONS: Among depressed patients, frailty may be hypothesized as a causal pathway toward adverse health outcomes associated with depression. Longitudinal studies should explore the causality of this association. CLINICAL IMPLICATIONS: Frailty should be treated or prevented in order to minimize the impact of other geriatric syndromes among depressed older adults. Screening for frailty would be of utmost importance in mental health care, as frailty is neglected especially in this field. Integrated care models are crucial for clinical practice in mental illness care.

Vitamin D deficiency and course of frailty in a depressed older population.

Objective: To study the association between vitamin D levels and frailty, its components and course in a depressed sample.Methods: Baseline and two-year follow-up data from the depressed sample of the Netherlands Study of Depression in Older persons (NESDO), a prospective observational cohort study, were analyzed. The 378 participants (aged 60-93) had a diagnosis of depression according to DSM-IV criteria. Frailty was defined according to Fried's physical phenotype. 25-OH vitamin D measurement was performed by liquid chromatography - tandem mass spectrometry. Linear and logistic regression analyses were performed, adjusted for covariates.Results: Higher vitamin D levels were cross-sectionally associated with lower prevalence of frailty (OR 0.64 [95%-CI 0.45 - 0.90], p = .010), predicted a lower incidence of frailty among non-frail depressed patients (OR 0.51 [95%-CI 0.26 - 1.00], p=.050), and, surprisingly, the persistence of frailty among frail depressed patients (OR 2.82 [95%-CI 1.23 - 6.49], p=.015).Conclusions: In a depressed population, higher vitamin D levels were associated with lower prevalence and incidence of frailty. Future studies should examine whether the favorable effect of low vitamin D levels on the course of frailty can be explained by confounding or whether unknown pathophysiological mechanisms may exert protective effects.

A Six-Year Prospective Study of the Prognosis and Predictors in Patients With Late-Life Depression.

OBJECTIVES: To examine the six-year prognosis of patients with late-life depression and to identify prognostic factors of an unfavorable course. DESIGN AND SETTING: The Netherlands Study of Depression in Older Persons (NESDO) is a multisite naturalistic prospective cohort study with six-year follow-up. PARTICIPANTS: Three hundred seventy-eight clinically depressed patients (according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision criteria) and 132 nondepressed comparisons were included at baseline between 2007 and 2010. MEASUREMENTS: Depression was measured by the Inventory of Depressive Symptomatology at 6-month intervals and a diagnostic interview at 2- and 6-year follow-up. Multinomial regression and mixed model analyses were both used to identify depression-related clinical, health, and psychosocial prognostic factors of an unfavorable course. RESULTS: Among depressed patients at baseline, 46.8% were lost to follow-up; 15.9% had an unfavorable course, i.e., chronic or recurrent; 24.6% had partial remission; and 12.7% had full remission at six-year follow-up. The relative risk of mortality in depressed patients was 2.5 (95% confidence interval 1.26-4.81) versus nondepressed comparisons. An unfavorable course of depression was associated with a younger age at depression onset; higher symptom severity of depression, pain, and neuroticism; and loneliness at baseline. Additionally, partial remission was associated with chronic diseases and loneliness at baseline when compared with full remission. CONCLUSIONS: The long-term prognosis of late-life depression is poor with regard to mortality and course of depression. Chronic diseases, loneliness, and pain may be used as putative targets for optimizing prevention and treatment strategies for relapse and chronicity.

Symptomatic and functional recovery in depression in later life.

OBJECTIVES: Functional limitations give an indication of the total impact of diseases, such as depression, on individuals health and recovery. This study examines the change in several domains of functioning over 2 years in older persons depressed at baseline (non-remitted group and remitted group after 2 years) and in a non-depressed comparison group. METHODS: Data were used from a cohort study (Netherlands Study of Depression in Older persons [NESDO]) consisting of depressed older persons ≥ 60 years (N = 378) and a non-depressed comparison group (N = 132) with 2 years of follow-up (attrition rate 24%). Functional limitations (outcome) were assessed with the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) questionnaire every 6 months. Total scores and domain scores were used. Depression was classified according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria at baseline and at 2-year follow-up. Severity of depression (predictor) was assessed with the Inventory of Depressive Symptomatology (IDS) at 6-month intervals. RESULTS: Linear mixed models showed that the level of functional limitations differed between the three groups during 2 years of follow-up. The non-remitted group had the highest level of functional limitations during 2 years, followed by the remitted group. Stable low levels of functional limitations were found for the non-depressed group. Remission from depression was accompanied by improvements in functioning, however, compared to the non-depressed comparison group significant functional limitations remained. Higher severity of depression appeared as risk factor for a declining course of functioning, especially the social aspects of functioning. METHODOLOGICAL CONSIDERATIONS: Participants that were more severely depressed and more functionally impaired at baseline had higher attrition rates than the participants that were included in the analytical sample. CONCLUSION: This study showed that depression in later life has long-term debilitating effects on functioning, enduring even after remission from depression. This implies that depression treatment in later life should aim broader than just symptomatic recovery, but also include functional recovery.

How does ageing affect the impact of medically unexplained symptoms and medically explained symptoms on health-related quality of life?

BACKGROUND: Physical symptoms significantly impair health-related quality of life (HRQoL), but age effects and differential effects of medically unexplained symptoms (MUS) and medically explained symptoms (MES) have hardly been examined. Our objective was to determine the effect of age on the impact of MUS and MES on HRQoL. METHODS: In a population-based cohort (n = 946, aged 28-75 years), MUS and MES were measured using the Composite International Diagnostic Interview and HRQoL using the EuroQol-5 dimensions (EQ-5D). Using multiple linear regression, we regressed MUS, MES and their interaction with age on HRQoL, adjusted for socio-demographic variables and the presence of depressive and anxiety disorders. In case of significant interaction terms, age-stratified results will be presented. RESULTS: In the whole study population, the association between MUS and HRQoL was stronger (ß = -0.35; p < 0.001) than between MES and HRQoL (ß = -0.26; p < 0.001). Adjusted for depressive and anxiety disorders, differences between these associations decline (MUS: ß = -0.28, p < 0.001; MES: ß = -0.25, p < 0.001). Age significantly interacted with number of MUS in explaining variance in HRQoL but not with the number of MES. The impact of MUS on HRQoL is much larger in people aged below 65 years (ß = -0.39, p < 0.001) versus those aged 65 years and over (ß = -0.21, p = 0.002). In the older group, the association between MUS and HRQoL lost significance when adjusted for depressive and anxiety disorders (ß = -0.12 p = 0.062). CONCLUSION: Our results show that age affects the association between MUS and HRQoL, which suggest that older persons cope better with MUS than younger persons.

Physical frailty: vulnerability of patients suffering from late-life depression.

OBJECTIVES: Frailty, a state of increased risk of negative health outcomes, is increasingly recognized as a relevant concept for identifying older persons in need of preventative geriatric interventions. Even though broader concepts of frailty include psychological characteristics, frailty is largely neglected in mental health care. The aim of the present study is to examine the prevalence of physical frailty in depressed older patients and its potential overlap with depression criteria. METHOD: Cross-sectional observational study including 378 depressed and 132 non-depressed adults aged ≥60 years according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Physical frailty was defined as ≥3 out of 5 criteria (handgrip strength, weight loss, poor endurance, walking speed, low physical activity). RESULTS: Prevalence rates of physical frailty were 27.2% and 9.1% among depressed and non-depressed participants, respectively, which remained significant after controlling for relevant covariates (odds ratio [OR] = 2.66 [95% confidence interval [C.I.] = 1.36, 5.24], p = .004). Physical frailty in depression was associated with more severe depressive symptoms; this association remained significant in subsequent analyses with purely physical proxies for frailty (hand grip strength, walking speed) and different severity measures of depressive symptoms. CONCLUSION: A quarter of depressed older patients is physically frail, especially the most depressed group. This cannot be explained by overlap in criteria and should be examined in future studies, primarily on its presumed clinical relevance.

A transdiagnostic view on MDD and ADHD: shared cognitive characteristics?

BACKGROUND: Major Depressive disorder (MDD) and Attention Deficit Hyperactivity Disorder (ADHD) are prevalent mental disorders that often co-occur. There is overlap in symptomatology between MDD and ADHD that complicates diagnostics and treatment selection. Hence, to aid diagnostics of single and comorbid disorders, we aimed to examine the discriminative power of common symptom measures and cognitive dysfunction to differentiate between participants diagnosed with MDD, ADHD, ADHD and comorbid MDD and without a mental disorder. METHODS: Four diagnosed groups were compared: MDD (n = 103), ADHD (n = 78), comorbid MDD + ADHD (n = 29), healthy controls (HC; n = 123). We examined between-group differences and discriminative functions of clinically validated self-report symptom questionnaires, as well as task-based and self-report measures of cognitive dysfunction. RESULTS: Based on the between group comparisons, all patient groups were characterized by clinically relevant levels of ADHD-symptomatology, executive dysfunction, and diminished cognitive performances in the domain of attention; even the MDD-only group. In addition, based on self-reported symptoms of MDD, ADHD, and executive dysfunction, discriminant function analysis classified all HC correctly (100%) and patients diagnosed with ADHD or MDD relatively well (resp. 85% and 82%). Comorbid MDD + ADHD was poorly differentiated from single MDD or ADHD by the commonly used self-report symptom questionnaires for MDD and ADHD (0% correct predictions), which substantially improved by incorporating the questionnaire on executive functioning (42% correct predictions). CONCLUSIONS: In both MDD and ADHD, clinical levels of attentional and executive dysfunction were found, while these clinical groups differed in cognitive flexibility, initiating, inhibition and meta-cognition. Comorbid MDD + ADHD was poorly distinguishable from non-comorbid MDD and ADHD based on self-reported symptoms of depression and ADHD. Addition of subjective executive function in the discrimination models resulted in increased discriminative power. Our findings indicate that executive functioning measure can improve the diagnostic process of ADHD and MDD.

Brain structure and function link to variation in biobehavioral dimensions across the psychopathological continuum.

In line with the Research Domain Criteria (RDoC) , we set out to investigate the brain basis of psychopathology within a transdiagnostic, dimensional framework. We performed an integrative structural-functional linked independent component analysis to study the relationship between brain measures and a broad set of biobehavioral measures in a sample (n = 295) with both mentally healthy participants and patients with diverse non-psychotic psychiatric disorders (i.e. mood, anxiety, addiction, and neurodevelopmental disorders). To get a more complete understanding of the underlying brain mechanisms, we used gray and white matter measures for brain structure and both resting-state and stress scans for brain function. The results emphasize the importance of the executive control network (ECN) during the functional scans for the understanding of transdiagnostic symptom dimensions. The connectivity between the ECN and the frontoparietal network in the aftermath of stress was correlated with symptom dimensions across both the cognitive and negative valence domains, and also with various other health-related biological and behavioral measures. Finally, we identified a multimodal component that was specifically associated with the diagnosis of autism spectrum disorder (ASD). The involvement of the default mode network, precentral gyrus, and thalamus across the different modalities of this component may reflect the broad functional domains that may be affected in ASD, like theory of mind, motor problems, and sensitivity to sensory stimuli, respectively. Taken together, the findings from our extensive, exploratory analyses emphasize the importance of a dimensional and more integrative approach for getting a better understanding of the brain basis of psychopathology.

Effectiveness of late-life depression interventions on functional limitations: A systematic review.

Depression is one of the most prevalent mental disorders in older adults and leads to considerable decreases in health, well-being, and impaired functioning. Intervention studies have focused on the effects on symptomatic recovery, and most do not include functional recovery as an outcome. Reduction of functional limitations as a treatment goal in old-age psychiatry aligns with the values of older persons. The objective of this review was therefore to evaluate the effectiveness of late-life depression interventions on functional limitations. This systematic review identified 15 randomized controlled trials in which the effectiveness of different interventions on functional limitations was evaluated in patients with late-life depression. The interventions were categorized into four categories: psychological interventions, drug treatment, physical exercise, and collaborative care. Multicomponent and collaborative-care interventions appear to be the most promising for improvement of functional limitations, particularly in primary care and community-dwelling populations of older persons with symptoms of depression. There is, however, a lack of evidence regarding studies in specialized mental health care.

Amygdala sensitivity for negative information as a neural marker for negative memory bias across psychiatric diagnoses.

Self-referent negative memory bias is a known risk factor for depression, but recent evidence suggests its function as a transdiagnostic cognitive depressotypic marker. The amygdala's sensitivity for negative information is considered a neurobiological depressotypic marker. However, their relationship remains unknown. We transdiagnostically investigated the association between the amygdala's sensitivity, self-referent negative memory bias and its two components: negative endorsement bias and negative recall bias. Patients (n= 125) with (multimorbid) stress-related and neurodevelopmental psychiatric disorders and healthy controls (n= 78) performed an fMRI task to assess the amygdala's sensitivity for negative information and a task outside the scanner for the biases. Linear regression models assessed their associations. The left amygdala's sensitivity for negative information was significantly positively associated with negative recall bias in patients, but not controls. There were no significant associations with self-referent negative memory bias or negative endorsement bias or between the two depressotypic markers. Thus, the left amygdala's sensitivity for negative information may be considered a neural marker of negative memory bias across psychiatric diagnoses. Further research on the interactons with known determinants such as genetic predisposition is required to fully understand the relationship between the amygdala's sensitivity for negative information and these biases.

Depressive Symptoms Account for Loss of Positive Attention Bias in ADHD Patients: An Eye-Tracking Study.

OBJECTIVES: Depression and ADHD often co-occur and are both characterized by altered attentional processing. Differences and overlap in the profile of attention to emotional information may help explain the co-occurence. We examined negative attention bias in ADHD as neurocognitive marker for comorbid depression. METHODS: Patients with depression (n = 63), ADHD (n = 43), ADHD and depression (n = 25), and non-psychiatric controls (n = 68) were compared on attention allocation toward emotional faces. The following eye-tracking indices were used: gaze duration, number of revisits, and location and duration of first fixation. RESULTS: Controls revisited the happy faces more than the other facial expressions. Both the depression and the comorbid group showed significantly less revisits of the happy faces compared to the ADHD and the control group. Interestingly, after controlling for depressive symptoms, the groups no longer differed on the number of revisits. CONCLUSION: ADHD patients show a relative positive attention bias, while negative attention bias in ADHD likely indicates (sub)clinical comorbid depression.

Neural correlates of repetitive negative thinking: Dimensional evidence across the psychopathological continuum.

Repetitive negative thinking (RNT) captures an important transdiagnostic factor that predisposes to a maladaptive stress response and contributes to diverse psychiatric disorders. Although RNT can best be seen as a continuous symptom dimension that cuts across boundaries from health to various psychiatric disorders, the neural mechanisms underlying RNT have almost exclusively been studied in health and stress-related disorders, such as depression and anxiety disorders. We set out to study RNT from a large-scale brain network perspective in a diverse population consisting of healthy subjects and patients with a broader range of psychiatric disorders. We studied 46 healthy subjects along with 153 patients with a stress-related and/or neurodevelopmental disorder. We focused on three networks, that are associated with RNT and diverse psychiatric disorders: the salience network, default mode network (DMN) and frontoparietal network (FPN). We investigated the relationship of RNT with both network connectivity strength at rest and with the stress-induced changes in connectivity. Across our whole sample, the level of RNT was positively associated with the connectivity strength of the left FPN at rest, but negatively associated with stress-induced changes in DMN connectivity. These findings may reflect an upregulation of the FPN in an attempt to divert attention away from RNT, while the DMN result may reflect a less flexible adaptation to stress, related to RNT. Additionally, we discuss how our findings fit into the non-invasive neurostimulation literature. Taken together, our results provide initial insight in the neural mechanisms of RNT across the spectrum from health to diverse psychiatric disorders.

Measuring Integrated Novel Dimensions in Neurodevelopmental and Stress-Related Mental Disorders (MIND-SET): Protocol for a Cross-sectional Comorbidity Study From a Research Domain Criteria Perspective.

BACKGROUND: It is widely acknowledged that comorbidity between psychiatric disorders is common. Shared and diverse underpinnings of psychiatric disorders cannot be systematically understood based on symptom-based categories of mental disorders, which map poorly onto pathophysiological mechanisms. In the Measuring Integrated Novel Dimensions in Neurodevelopmental and Stress-Related Mental Disorders (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). OBJECTIVE: The main aim of the MIND-SET project is to determine the shared and specific mechanisms of neurodevelopmental and stress-related psychiatric disorders at different observational levels. METHODS: This is an observational cross-sectional study. Data from different observational levels as defined in the Research Domain Criteria (genetics, physiology, neuropsychology, system-level neuroimaging, behavior, self-report, and experimental neurocognitive paradigms) are collected over four time points. Included are adult (aged ≥18 years), nonpsychotic, psychiatric patients with a clinical diagnosis of a stress-related disorder (mood disorder, anxiety disorder, or substance use disorder) or a neurodevelopmental disorder (autism spectrum disorder or attention-deficit/hyperactivity disorder). Individuals with no current or past psychiatric diagnosis are included as neurotypical controls. Data collection started in June 2016 with the aim to include a total of 650 patients and 150 neurotypical 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; and (3) neuroimaging measures. RESULTS: We aim to include a total of 650 patients and 150 neurotypical control participants in the time period between 2016 and 2022. In October 2021, we are at 95% of our target. CONCLUSIONS: The MIND-SET study enables us to investigate the mechanistic underpinnings of nonpsychotic 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.

Striatal connectopic maps link to functional domains across psychiatric disorders.

Transdiagnostic approaches to psychiatry have significant potential in overcoming the limitations of conventional diagnostic paradigms. However, while frameworks such as the Research Domain Criteria have garnered significant enthusiasm among researchers and clinicians from a theoretical angle, examples of how such an approach might translate in practice to understand the biological mechanisms underlying complex patterns of behaviors in realistic and heterogeneous populations have been sparse. In a richly phenotyped clinical sample (n = 186) specifically designed to capture the complex nature of heterogeneity and comorbidity within- and between stress- and neurodevelopmental disorders, we use exploratory factor analysis on a wide range of clinical questionnaires to identify four stable functional domains that transcend diagnosis and relate to negative valence, cognition, social functioning and inhibition/arousal before replicating them in an independent dataset (n = 188). We then use connectopic mapping to map inter-individual variation in fine-grained topographical organization of functional connectivity in the striatum-a central hub in motor, cognitive, affective and reward-related brain circuits-and use multivariate machine learning (canonical correlation analysis) to show that these individualized topographic representations predict transdiagnostic functional domains out of sample (r = 0.20, p = 0.026). We propose that investigating psychiatric symptoms across disorders is a promising path to linking them to underlying biology, and can help bridge the gap between neuroscience and clinical psychiatry.

Negative Learning Bias in Depression Revisited: Enhanced Neural Response to Surprising Reward Across Psychiatric Disorders.

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.