Cortisol Reactivity to Stress and Its Association With White Matter Integrity in Adults With Schizophrenia.

OBJECTIVES: Although acute hypothalamic-pituitary-adrenal axis response to stress is often adaptive, prolonged responses may have detrimental effects. Many components of white matter structures are sensitive to prolonged cortisol exposure. We aimed to identify a behavioral laboratory assay for cortisol response related to brain pathophysiology in schizophrenia. We hypothesized that an abnormally prolonged cortisol response to stress may be linked to abnormal white matter integrity in patients with schizophrenia. METHODS: Acute and prolonged salivary cortisol response was measured outside the scanner at pretest and then at 0, 20, and 40 minutes after a psychological stress task in patients with schizophrenia (n = 45) and controls (n = 53). Tract-averaged white matter was measured by 64-direction diffusion tensor imaging in a subset of patients (n = 30) and controls (n = 33). RESULTS: Patients who did not tolerate the psychological stress task and quit had greater acute (t = 2.52 [p = .016] and t = 3.51 [p = .001] at 0 and 20 minutes) and prolonged (t = 3.62 [p = .001] at 40 minutes) cortisol reactivity compared with patients who finished the task. Abnormally prolonged cortisol reactivity in patients was significantly associated with reduced white matter integrity (r = -0.468, p = .009). Regardless of task completion status, acute cortisol response was not related to the white matter measures in patients or controls. CONCLUSIONS: This paradigm was successful at identifying a subset of patients whose cortisol response was associated with brain pathophysiology. Abnormal cortisol response may adversely affect white matter integrity, partly explaining this pathology observed in schizophrenia. Prolonged stress responses may be targeted for intervention to test for protective effects against white matter damages.

Assessment of trait and state aspects of depression in schizophrenia.

Depression and negative symptoms can be difficult to distinguish in schizophrenia. Assessments for negative symptoms usually account for the longitudinal nature of these symptoms, whereas instruments available to measure depression mainly assess current or recent symptoms. This construct difference may confound comparison of depressive and negative symptoms in schizophrenia because both domains may have trait-like aspects. We developed an instrument to measure both longitudinal "trait" as well as recent "state" symptoms of depression and tested this instrument (Maryland Trait and State Depression [MTSD] scale) in a sample of 98 individuals with schizophrenia or schizoaffective disorder and 115 community participants without psychotic illness. Exploratory factor analysis of the MTSD revealed 2 factors accounting for 73.4% of the variance; these 2 factors corresponded with "trait" and "state" depression inventory items. Neither MTSD-state nor MTSD-trait was correlated with negative symptoms as measured with the Brief Negative Symptom Scale (r = .07 and -.06, respectively) in schizophrenia patients. MTSD state and trait scores were significantly correlated with the Brief Psychiatric Rating Scale depression subscale (r = .58 and .53, respectively) as well as the Profile of Mood States depression subscale (r = .57 and .44). Persons with schizophrenia had significantly greater trait depressive symptoms than controls (P = .031). Individuals with schizoaffective disorder had significantly higher trait depression (P = .001), but not state depression (P = .146), compared with schizophrenia patients. Trait depressive symptoms are prominent in schizophrenia and are distinct from negative symptoms.

Testing trait depression as a potential clinical domain in schizophrenia.

The DSM-5 includes depression as a dimension of psychosis. We tested whether persistent experience of depression, called 'trait depression', is a clinical feature separate from psychosis and several well-known, trait-like deficits of schizophrenia. 126 individuals with schizophrenia and 151 control participants completed the Maryland Trait and State Depression questionnaire, with a subset completing measures of cognition and functional capacity, and diffusion tensor imaging (n=73 patients and 102 controls for imaging analysis). Subjectively experienced, longitudinal trait depression is significantly higher in patients with schizophrenia compared with controls. Higher trait depression scores were associated with more severe psychosis. Surprisingly, individuals with higher trait depression manifested less cognitive and global functioning deficits. In addition, trait depression scores were positively associated with fractional anisotropy of white matter. Trait depression appears to be a highly relevant clinical domain in the care of patients with schizophrenia that also has distinct relationships with some other known traits of the disease. Trait depression may be an important contributor to the clinical heterogeneity of schizophrenia.