Serotonin modulates an inhibitory input to the central amygdala from the ventral periaqueductal gray.

Fear is an adaptive state that drives defensive behavioral responses to specific and imminent threats. The central nucleus of the amygdala (CeA) is a critical site of adaptations that are required for the acquisition and expression of fear, in part due to alterations in the activity of inputs to the CeA. Here, we characterize a novel GABAergic input to the CeA from the ventral periaqueductal gray (vPAG) using fiber photometry and ex vivo whole-cell slice electrophysiology combined with optogenetics and pharmacology. GABA transmission from this ascending vPAG-CeA input was enhanced by serotonin via activation of serotonin type 2 C (5HT2C) receptors. Results suggest that these receptors are presynaptic. Interestingly, we found that GABA release from the vPAG-CeA input is enhanced following fear learning via activation of 5HT2C receptors and that this pathway is dynamically engaged in response to aversive stimuli. Additionally, we characterized serotonin release in the CeA during fear learning and recall for the first time using fiber photometry coupled to a serotonin biosensor. Together, these findings describe a mechanism by which serotonin modulates GABA release from ascending vPAG GABA inputs to the CeA and characterize a role for this pathway in fear.

Mental Disorders, Substance Use Disorders, and Psychotropic Medication Use Among Sudden-Death Victims.

OBJECTIVE: The authors sought to estimate the prevalence of mental and substance use disorders and psychotropic medication prescriptions among working-age sudden-death victims. METHODS: Using a written protocol, the authors screened for sudden deaths attended by emergency medical services (EMS) in a large metropolitan county in North Carolina from March 1, 2013, to February 28, 2015. Sudden-death cases were adjudicated by three cardiologists. Mental health and chronic disease diagnoses and treatments were abstracted from EMS, medical examiner, toxicology, and autopsy reports and from clinical records for the past 5 years before death. RESULTS: Sudden death was identified for 399 adults ages 18-64 years, 270 of whom had available medical records. Most sudden-death victims were White (63%) and male (65%), had a comorbid condition such as hypertension or respiratory disease, and had a mean±SD age of death of 53.6±8.8 years. Most victims (59%) had at least one mental health or substance use disorder documented in a recent medical record; 76%-78% of victims with a mental disorder had a documented psychotropic medication prescription. However, fewer than one-half (41%) had a documented referral to a mental health professional. The most common diagnostic categories were depressive, anxiety, and alcohol-related disorders. Almost one-half (46%) of the victims had a recent psychotropic prescription, most commonly antidepressants (29%) and benzodiazepines (19%). CONCLUSIONS: Mental illness, substance use disorders, and psychotropic medication prescriptions were prevalent among sudden-death victims. The health care needs of these individuals may be better addressed by collaborative care for general medical and mental disorders.

Fear of Cancer Recurrence and Death Anxiety: Unaddressed Concerns for Adult Neuro-oncology Patients.

Primary brain tumor (PBT) patients may experience existential distress; however, few studies have examined this issue. The objectives of this study were to (1) systematically review PBT representation in psycho-oncology literature regarding fear/anxiety related to progression, recurrence, and death and (2) preliminarily assess the prevalence of fear of dying in a sample of PBT patients. Systematic searching of three databases yielded 1555 articles for review. Of these, 327 studies met inclusion criteria (patient sample N = 132,951). Only eight studies (0.18% of the participants) included patients with a PBT diagnosis, potentially due to exclusion criteria such as cognitive impairment or specific treatment parameters which may prohibit PBT patient participation. Review of the results from the eight included studies revealed mixed methods and limited demographic analyses; existential distress was correlated with heightened depression and anxiety, and overall worsened quality of life. From the original data collection, approximately one-third of PBT patients endorsed fear of dying, which was positively related to depression severity. Taken together, results suggest that PBT patients are considerably underrepresented in existential psycho-oncology literature, despite preliminary findings suggesting prevalence of these concerns. Future research on existential distress in neuro-oncology is warranted.

Death anxiety in patients with primary brain tumor: Measurement, prevalence, and determinants.

OBJECTIVE: This study investigated death anxiety in patients with primary brain tumor (PBT). We examined the psychometric properties of two validated death anxiety measures and determined the prevalence and possible determinants of death anxiety in this often-overlooked population. METHODS: Two cross-sectional studies in neuro-oncology were conducted. In Study 1, 81 patients with PBT completed psychological questionnaires, including the Templer Death Anxiety Scale (DAS). In Study 2, 109 patients with PBT completed similar questionnaires, including the Death and Dying Distress Scale (DADDS). Medical and disease-specific variables were collected across participants in both studies. Psychometric properties, including construct validity, internal consistency, and concurrent validity, were investigated. Levels of distress were analyzed using frequencies, and determinants of death anxiety were identified using logistic regression. RESULTS: The DADDS was more psychometrically sound than the DAS in patients with PBT. Overall, 66% of PBT patients endorsed at least one symptom of distress about death and dying, with 48% experiencing moderate-severe death anxiety. Generalized anxiety symptoms and the fear of recurrence significantly predicted death anxiety. SIGNIFICANCE OF RESULTS: The DADDS is a more appropriate instrument than the DAS to assess death anxiety in neuro-oncology. The proportion of patients with PBT who experience death anxiety appears to be higher than in other advanced cancer populations. Death anxiety is a highly distressing symptom, especially when coupled with generalized anxiety and fears of disease progression, which appears to be the case in patients with PBT. Our findings call for routine monitoring and the treatment of death anxiety in neuro-oncology.

Death-related distress in adult primary brain tumor patients.

BACKGROUND: A diagnosis of cancer may increase mortality salience and provoke death-related distress. Primary brain tumor (PBT) patients may be at particular risk for such distress given the certainty of tumor progression, lack of curative treatments, and poor survival rates. This study is the first to examine the prevalence of death-related distress and its correlates in PBT patients. METHODS: Adult PBT patients (N = 105) enrolled in this cross-sectional study and completed the Death Distress Scale (subscales: Death Depression, Death Anxiety, Death Obsession), Generalized Anxiety Disorder-7, and Patient Health Questionnaire-9. Prevalence and predictors of death-related distress, and the relationships of demographic variables to clusters of distress, were explored. RESULTS: The majority of PBT patients endorsed clinically significant death-related distress in at least one domain. Death anxiety was endorsed by 81%, death depression by 12.5%, and death obsession by 10.5%. Generalized anxiety was the only factor associated with global death-related distress. Cluster analysis yielded 4 profiles: global distress, emotional distress, resilience, and existential distress. Participants in the resilience cluster were significantly further out from diagnosis than those in the existential distress cluster. There were no differences in cluster membership based on age, sex, or tumor grade. CONCLUSIONS: PBT patients appear to have a high prevalence of death-related distress, particularly death anxiety. Further, 4 distinct profiles of distress were identified, supporting the need for tailored approaches to addressing death-related distress. A shift in clusters of distress based on time since diagnosis also suggest the need for future longitudinal assessment.