Absence of default mode downregulation in response to a mild psychological stressor marks stress-vulnerability across diverse psychiatric disorders

•Maladaptation to acute stress constitutes an important vulnerability and maintenance factor for psychiatric disorders.•We show transdiagnostic and disorder specific aspects of the brain's acute stress response.•Our results mainly suggest shared, transdiagnostic aspects of a maladaptive stress response.•Patients show relatively decreased frontoparietal network connectivity under stress.•Absence of default mode network downregulation marks a maladaptive stress response across disorders. Clinically, it is well-established that vulnerability to stress is a common feature across a broad spectrum of psychiatric disorders. However, this link has been mechanistically studied almost exclusively in patients with so-called stress-related disorders such as depression and anxiety. To probe transdiagnostic mechanisms, we set out to study the acute stress response across a broader range of psychiatric disorders taking a large-scale brain network perspective. We investigated the brain's response to a mild, experimentally well-controlled psychological stressor in the form of an aversive movie. We studied 168 patients with stress-related and/or neurodevelopmental disorders (including comorbidity) and 46 control subjects. We focused on three networks that have a central role in the brain's stress response and are affected in a wide range of psychiatric disorders: the salience network (SN), default mode network (DMN) and frontoparietal network (FPN). Our results support an increased vulnerability to stress across all patients, indicated by a higher subjective stress level at baseline and follow-up compared to matched controls. At the brain systems level, the stress response was characterized by a relatively decreased FPN connectivity and an absence of a decrease in the within DMN connectivity across all disorders compared to controls. At the neurocognitive level, these findings may reflect a diminished top-down control and a tendency to more pronounced (negative) self-referential processing. Besides these shared aspects of the maladaptive stress response, we also discuss indications for disorder-specific aspects. Taken together, our results emphasize the importance of investigating the mechanistic underpinnings of psychiatric disorders transdiagnostically as recently done in neurogenetics.