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.

/pdf/molecular-mechanisms-of-depression-perspectives-on-new-51kg9254ke.pdf

Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies

Context Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. Objective To determine whether a rapid antidepressant effect can be achieved with an antagonist at theN-methyl-D-aspartate receptor in subjects with major depression. Design A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005. Setting Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects withDSM-IVmajor depression (treatment resistant). Interventions After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale. Results Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Conclusions Robust and rapid antidepressant effects resulted from a single intravenous dose of anN-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Trial Registration clinicaltrials.gov Identifier:NCT00088699.

/pdf/a-randomized-trial-of-an-n-methyl-d-aspartate-antagonist-in-4j85ht0xbk.pdf

A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression

Pathological disturbances of mood may follow a 'bipolar' course, in which normal moods alternate with both depression and mania, or a 'unipolar' course, in which only depression occurs. Both bipolar and unipolar disorders can be heritable illnesses associated with neurochemical, neuroendocrine and autonomic abnormalities. The neurobiological basis for these abnormalities has not been established. Using positron emission tomographic (PET) images of cerebral blood flow and rate of glucose metabolism to measure brain activity, we have now localized an area of abnormally decreased activity in the prefrontal cortex ventral to the genu of the corpus callosum in both familial bipolar depressives and familial unipolar depressives. This decrement in activity was at least partly explained by a corresponding reduction in cortical volume, as magnetic resonance imaging (MRI) demonstrated reductions in the mean grey matter volume in the same area of 39 and 48% in the bipolar and unipolar samples, respectively. This region has previously been implicated in the mediation of emotional and autonomic responses to socially significant or provocative stimuli, and in the modulation of the neurotransmitter systems targeted by antidepressant drugs.

Subgenual prefrontal cortex abnormalities in mood disorders

The estimated lifetime prevalence of bipolar disorder (BPD) in population surveys using structured diagnostic interviews and standardized criteria averages approximately 0.8% for BP-I and 1.1% for BP-II.1-8 Despite this comparatively low prevalence, BPD is a leading cause of premature mortality due to suicide and associated medical conditions such as diabetes and cardiovascular disease.9, 10 BPD also causes widespread role impairment.11, 12 The recurrent nature of manic and depressive episodes often leads to high direct as well as high indirect health care costs.13, 14

BPD might be even more burdensome from a societal perspective due to the fact that sub-threshold bipolar spectrum disorder has seldom been taken into consideration in examining the epidemiology of BPD. Bipolar spectrum disorder includes hypomania without major depression and hypomania of lesser severity or briefer duration than specified in the DSM and ICD criteria. Although the precise definitions are as yet unclear, recent studies suggest that bipolar spectrum disorder might affect as many as 6% of the general population.15, 16 However, bipolar spectrum disorder has not been studied previously in a nationally representative survey of the US. The purpose of the current report is to present the results of such a study based on analysis of the National Comorbidity Survey Replication (NCS-R).17 We estimate prevalence and clinical features of sub-threshold BPD in comparison to BP-I and BP-II.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/482285/yoa60082_543_552.pdf

Lifetime and 12-Month Prevalence of Bipolar Spectrum Disorder in the National Comorbidity Survey Replication

Context There is limited information on the prevalence and correlates of bipolar spectrum disorder in international population-based studies using common methods. Objectives To describe the prevalence, impact, patterns of comorbidity, and patterns of service utilization for bipolar spectrum disorder (BPS) in the World Health Organization World Mental Health Survey Initiative. Design, Setting, and Participants Cross-sectional, face-to-face, household surveys of 61 392 community adults in 11 countries in the Americas, Europe, and Asia assessed with the World Mental Health version of the World Health Organization Composite International Diagnostic Interview, version 3.0, a fully structured, lay-administered psychiatric diagnostic interview. Main Outcome Measures Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) disorders, severity, and treatment. Results The aggregate lifetime prevalences were 0.6% for bipolar type I disorder (BP-I), 0.4% for BP-II, 1.4% for subthreshold BP, and 2.4% for BPS. Twelve-month prevalences were 0.4% for BP-I, 0.3% for BP-II, 0.8% for subthreshold BP, and 1.5% for BPS. Severity of both manic and depressive symptoms as well as suicidal behavior increased monotonically from subthreshold BP to BP-I. By contrast, role impairment was similar across BP subtypes. Symptom severity was greater for depressive episodes than manic episodes, with approximately 74.0% of respondents with depression and 50.9% of respondents with mania reporting severe role impairment. Three-quarters of those with BPS met criteria for at least 1 other disorder, with anxiety disorders (particularly panic attacks) being the most common comorbid condition. Less than half of those with lifetime BPS received mental health treatment, particularly in low-income countries, where only 25.2% reported contact with the mental health system. Conclusions Despite cross-site variation in the prevalence rates of BPS, the severity, impact, and patterns of comorbidity were remarkably similar internationally. The uniform increases in clinical correlates, suicidal behavior, and comorbidity across each diagnostic category provide evidence for the validity of the concept of BPS. Treatment needs for BPS are often unmet, particularly in low-income countries.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/211192/yoa05088_241_251.pdf

Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative.

An eleven item clinician-administered Mania Rating Scale (MRS) is introduced, and its reliability, validity and sensitivity are examined. There was a high correlation between the scores of two independent clinicians on both the total score (0.93) and the individual item scores (0.66 to 0.92). The MRS score correlated highly with an independent global rating, and with scores of two other mania rating scales administered concurrently. The score also correlated with the number of days of subsequent stay in hospital. It was able to differentiate statistically patients before and after two weeks of treatment and to distinguish levels of severity based on the global rating.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/34DE3C8ED1EB65C54E87970C87BC0528/S0007125000198551a.pdf/div-class-title-a-rating-scale-for-mania-reliability-validity-and-sensitivity-div.pdf

A rating scale for mania: reliability, validity and sensitivity.

Young Mania Rating Scale

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A rating scale for mania: reliability, validity and sensitivity.

Young Mania Rating Scale