Alec Roy

Primary depression can be associated with substantial hypercortisolism, thus prompting some researchers to suggest that depression shares pathophysiologic features with Cushing's disease. Clinically, depression can be difficult or impossible to distinguish from mild or early Cushing's disease that is associated with depressive features. The purpose of this study was to evaluate whether the pituitary-adrenal responses to ovine corticotropin-releasing hormone could help to clarify the mechanism of hypercortisolism in depression and in Cushing's disease and to assist in the differential diagnosis of these disorders. As compared with controls (n = 34), depressed patients (n = 30) had basal hypercortisolism (P less than 0.001) that was associated with attenuated plasma ACTH responses to ovine corticotropin-releasing hormone (P less than 0.001). This indicates that in patients with depression, the corticotroph cell in the pituitary responds appropriately to the negative feedback of high cortisol levels. In contrast, patients with Cushing's disease (n = 29) had plasma ACTH hyperresponsiveness to ovine corticotropin-releasing hormone (P less than 0.001), despite basal hypercortisolism (P less than 0.001), which indicates a gross impairment of the mechanism by which cortisol exerts negative feedback on the pituitary. Less than 25 percent of the patients with depression or Cushing's disease had peak ACTH responses that overlapped. We conclude that the pathophysiologic features of hypercortisolism in depression and Cushing's disease are distinct in each of the disorders and that the ovine corticotropin-releasing hormone stimulation test can be helpful in their differential diagnosis.

Corticotropin-releasing factor (CRF) is a newly sequenced neuropeptide thought to be a principal stimulus to pituitary corticotropin (ACTH) secretion. Evidence obtained from laboratory animals and primates is reviewed which indicates that CRF not only stimulates the pituitary-adrenal axis but also influences several aspects of CNS function which may be of relevance to psychiatric illness. Clinically, experience in administering ovine CRF to more than 150 individuals shows that CRF can be helpful in resolving differential diagnostic dilemmas in patients with various disorders of the hypothalamic-pituitary-adrenal axis and in furthering an understanding of the pathophysiology of conditions such as Cushing's disease and depression.

CONTEXT: Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood. OBJECTIVES: To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects. DESIGN: Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction. SETTING: Academic medical center. PATIENTS OR OTHER PARTICIPANTS: Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity. MAIN OUTCOME MEASURES: The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area. RESULTS: Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P < .001). Most of the CpG sites lying in the -300/+500 region, on both strands, had low or no methylation, with the exception of a few sites located near the transcriptional start site that had differential methylation, while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels. CONCLUSIONS: BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.

A matched controlled study of 30 chronic schizophrenic suicides is presented. Eighty per cent were male and committed suicide at a mean age of 25.8 years after a mean duration of illness of 4.8 years. Significantly more of the suicides had a chronic relapsing schizophrenic illness; 23.3 per cent committed suicide while in-patients, and 50 per cent of the out-patients committed suicide within three months of discharge from in-patient care. Significantly more of the suicides had a past history of depression (56.6 per cent), were depressed in the last episode of contract (53.3 per cent), had their last admission for depression or suicidal ideation (55.2 per cent) and were unemployed (80 per cent).

In a matched controlled study of 90 psychiatric patient suicides, I found that significantly more of the suicides suffered from chronic schizophrenia (33.3%) or recurrent affective disorder (18.8%) and had made a previous suicide attempt (46.6%). The suicides were young and significantly more were unmarried (84.5%), unemployed (66%), living alone, (55.5%) and depressed (65.5%), and 44.4% had a primary diagnosis of depressive disorder. Of the 75 outpatient suicides, 58% had seen a psychiatrist within the previous week, 61 of the 75 (81.3%) had been admitted in their last episode of contact, and 44% of these suicided within a month of discharge.