Psilocybin for dementia prevention? The potential role of psilocybin to alter mechanisms associated with major depression and neurodegenerative diseases.

Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases. Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.

Risk assessment of psychiatric complications in infectious diseases: CALCulation of prognostic indices on example of COVID-19.

Introduction: Factors such as coronavirus neurotropism, which is associated with a massive increase in pro-inflammatory molecules and neuroglial reactivity, along with experiences of intensive therapy wards, fears of pandemic, and social restrictions, are pointed out to contribute to the occurrence of neuropsychiatric conditions. Aim: The aim of this study is to evaluate the role of COVID-19 inflammation-related indices as potential markers predicting psychiatric complications in COVID-19. Methods: A total of 177 individuals were examined, with 117 patients from a temporary infectious disease ward hospitalized due to COVID-19 forming the experimental group and 60 patients from the outpatient department showing signs of acute respiratory viral infection comprising the validation group. The PLR index (platelet-to-lymphocyte ratio) and the CALC index (comorbidity + age + lymphocyte + C-reactive protein) were calculated. Present State Examination 10, Hospital Anxiety and Depression Scale, and Montreal Cognitive Assessment were used to assess psychopathology in the sample. Regression and Receiver operating characteristic (ROC) analysis, establishment of cutoff values for the COVID-19 prognosis indices, contingency tables, and comparison of means were used. Results: The presence of multiple concurrent groups of psychopathological symptoms in the experimental group was associated (R² = 0.28, F = 5.63, p < 0.001) with a decrease in the PLR index and a simultaneous increase in CALC. The Area Under Curve (AUC) for the cutoff value of PLR was 0.384 (unsatisfactory). For CALC, the cutoff value associated with an increased risk of more psychopathological domains was seven points (sensitivity = 79.0%, specificity = 69.4%, AUC = 0.719). Those with CALC > 7 were more likely to have disturbances in orientation (χ² = 13.6; p < 0.001), thinking (χ² = 7.07; p = 0.008), planning ability (χ² = 3.91; p = 0.048). In the validation group, an association (R²McF = 0.0775; p = 0.041) between CALC values exceeding seven points and the concurrent presence of pronounced anxiety, depression, and cognitive impairments was demonstrated (OR = 1.52; p = 0.038; AUC = 0.66). Discussion: In patients with COVID-19, the CALC index may be used for the risk assessment of primary developed mental disturbances in the context of the underlying disease with a diagnostic threshold of seven points.

Has the sun set for seasonal affective disorder and HPA axis studies? A systematic review and future prospects.

OBJECTIVE: Seasonal Affective Disorder (SAD) is a form of cyclic mood disorder that tends to manifest as winter depression. SAD has anecdotally been described as a hypocortisolemic condition. However, there are no systematic reviews on SAD and Hypothalamic-Pituitary-Adrenal (HPA) axis function. This review intends to summarize these findings. METHODS: Using the PRISMA (2009) guideline recommendations we searched for relevant articles indexed in databases including MEDLINE, EMBASE, PsycINFO, and PsychArticles. The following keywords were used: "Seasonal affective disorder", OR "Winter Depression", OR "Seasonal depression" associated with: "HPA Axis" OR "cortisol" OR "CRH" OR "ACTH". RESULTS: Thirteen papers were included for qualitative analysis. Studies used both heterogeneous methods and populations. The best evidence comes from a recent study showing that SAD patients tend to demonstrate an attenuated Cortisol Awakening Response (CAR) in winter, but not in summer, compared to controls. Dexamethasone Suppression Test (DST) studies suggest SAD patients have normal suppression of the HPA axis. CONCLUSION: There is still insufficient evidence to classify SAD as a hypocortisolemic condition when compared to controls. Heterogeneous methods and samples did not allow replication of results. We discuss the limitations of these studies and provide new methods and targets to probe HPA axis function in this population. SAD can provide a unique window of opportunity to study HPA axis in affective disorders, since it is highly predictable and can be followed before, during and after episodes subsides.

Atypical depression and non-atypical depression: Is HPA axis function a biomarker? A systematic review.

BACKGROUND: The link between the abnormalities of the Hypothalamic-pituitary-adrenal (HPA) axis and depression has been one of the most consistently reported findings in psychiatry. At the same time, multiple studies have demonstrated a stronger association between the increased activation of HPA-axis and melancholic, or endogenous depression subtype. This association has not been confirmed for the atypical subtype, and some researchers have suggested that as an antinomic depressive subtype, it may be associated with the opposite type, i.e. hypo-function, of the HPA-axis, similarly to PTSD. The purpose of this systematic review is to summarise existing studies addressing the abnormalities of the HPA-axis in melancholic and/or atypical depression. METHOD: We conducted a systematic review in the literature by searching MEDLINE, PsycINFO, OvidSP and Embase databases until June 2017. The following search items were used: "hypothalamic-pituitary-adrenal" OR "HPA" OR "cortisol" OR "corticotropin releasing hormone" OR "corticotropin releasing factor" OR "glucocorticoid*" OR "adrenocorticotropic hormone" OR "ACTH" AND "atypical depression" OR "non-atypical depression" OR "melancholic depression" OR "non-melancholic depression" OR "endogenous depression" OR "endogenomorphic depression" OR "non-endogenous depression". Search limits were set to include papers in English or German language published in peer-reviewed journals at any period. All studies were scrutinized to determine the main methodological characteristics, and particularly possible sources of bias influencing the results reported. RESULTS: We selected 48 relevant studies. Detailed analysis of the methodologies used in the studies revealed significant variability especially regarding the samples' definition comparing the HPA axis activity of melancholic patients to atypical depression, including healthy controls. The results were subdivided into 4 sections: (1) 27 studies which compared melancholic OR endogenous depression vs. non-melancholic or non-endogenous depression or controls; (2) 9 studies which compared atypical depression or atypical traits vs. non-atypical depression or controls; (3) 7 studies which compared melancholic or endogenous and atypical depression subtypes and (4) 5 studies which used a longitudinal design, comparing the measures of HPA-axis across two or more time points. While the majority of studies did confirm the association between melancholic depression and increased post-challenge cortisol levels, the association with increases in basal cortisol and basal ACTH were less consistent. Some studies, particularly those focusing on reversed vegetative symptoms, demonstrated a decrease in the activity of the HPA axis in atypical depression compared to controls, but the majority did not distinguish it from healthy controls. CONCLUSIONS: In conclusion, our findings indicate that there is a difference in the activity of the HPA-axis between melancholic and atypical depressive subtypes. However, these are more likely explained by hypercortisolism in melancholia; and most often normal than decreased function in atypical depression. Further research should seek to distinguish a particular subtype of depression linked to HPA-axis abnormalities, based on symptom profile, with a focus on vegetative symptoms, neuroendocrine probes, and the history of adverse childhood events. New insights into the dichotomy addressed in this review might be obtained from genetic and epigenetic studies of HPA-axis related genes in both subtypes, with an emphasis on the presence of vegetative symptoms.