Stefan Borgwardt

Depression is a multicausal disorder and has been associated with the risk to develop cancer, dementia, diabetes, epilepsy and stroke. As a metabolic disorder depression has been associated with obesity, diabetes, insulin sensitivity, neuropeptide Y, glucose regulation, poor glycemic control, glucagone-like peptide-1, cholezystokinin, ghrelin, leptin, the endocannabinoid system, insulin-like growth factor and gastrin-releasing peptide. As a cardiovascular disease a close relationship exists between depression and blood pressure, heart rate, norepinephrine, sympathetic tone, vascular resistance, blood viscosity, plasma volume, intima thickness and atherosclerosis. Additionally blood coagulation, fibrinolysis, D-dimers, plasminogen activator inhibitor-1 protein, platelet activation, VEGF, plasma nitric oxide and its synthase are changed in depressed patients. As an endocrinological and stress disorder depression has been connected with the concentration of free T4, TSH, CRH, arginine vasopressin, corticotrophin, corticosteroid release and ACTH. Depression as an inflammatory disorder is mediated by pro-inflammatory cytokines, interleukin-1, interleukin-6, TNF-alpha, soluble interleukin-2 receptors, interferon-alpha, interleukin 8, interleukin-10, hs-CRP, acute phase proteins, haptoglobin, toll like receptor 4, interleukin-1beta, mammalian target of rapamycin pathway, substance P, cyclooxygenase-2, prostaglandin-E2, lipid peroxidation levels and acid sphingomyelinase. Nutritional factors might influence depression risk, i.e. the consumption of folate, omega-3 fatty acids, monounsaturated fatty acids, olive oil, fish, fruits, vegetables, nuts, legumes, vitamin B6 and vitamin B12. The neurodegenerative hypothesis of depression explains decreased hippocampal volumes in depressed patients and changes of neurotrophic support by BDNF, erythropoietin, GDNF, FGF-2, NT3, NGF and growth hormone. In this context, a fast neuroprotective and antidepressant effect has also been observed by ketamine, which acts via the glutamatergic system. Hence, GABA, AMPA, EAAT, NMDA- and metabotropic glutamate receptors (mGluR1 to mGluR8) have gained interest in depression recently. Alternative, causative or also easy available treatment strategies beyond serotonin and noradrenaline reuptake inhibition might be a major topic of future psychiatric care. In this review, an attempt is made to overview concepts of the disease and search for perspectives on antidepressant treatment strategies beyond approved medications.

CONTEXT: During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. OBJECTIVE: To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. DATA SOURCES: Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. STUDY SELECTION AND DATA EXTRACTION: Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. DATA SYNTHESIS: Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. CONCLUSIONS: The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.

CONTEXT: A substantial proportion of people at clinical high risk (HR) of psychosis will develop a psychotic disorder over time. Cognitive deficits may predate the onset of psychosis and may be useful as markers of increased vulnerability to illness. OBJECTIVE: To quantitatively examine the cognitive functioning in subjects at HR in the literature to date. DATA SOURCES: Electronic databases were searched until January 2011. All studies reporting cognitive performance in HR subjects were retrieved. STUDY SELECTION: Nineteen studies met the inclusion criteria, comprising a total of 1188 HR subjects and 1029 controls. DATA EXTRACTION: Neurocognitive functioning and social cognition as well as demographic, clinical, and methodological variables were extracted from each publication or obtained directly from its authors. DATA SYNTHESIS: Subjects at HR were impaired relative to controls on tests of general intelligence, executive function, verbal and visual memory, verbal fluency, attention and working memory, and social cognition. Processing speed domain was also affected, although the difference was not statistically significant. Later transition to psychosis was associated with even more marked deficits in the verbal fluency and memory domains. The studies included reported relatively homogeneous findings. There was no publication bias and a sensitivity analysis confirmed the robustness of the core results. CONCLUSIONS: The HR state for psychosis is associated with significant and widespread impairments in neurocognitive functioning and social cognition. Subsequent transition to psychosis is particularly associated with deficits in verbal fluency and memory functioning.