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      Spotlight on Pimavanserin Tartrate and Its Therapeutic Potential in the Treatment of Major Depressive Disorder: The Evidence to Date

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          Abstract

          Major depressive disorder (MDD) is widely prevalent and one of the leading causes of disability. Treatment outcomes remain suboptimal with 1 in 3 patients with MDD responding inadequately to commonly used antidepressants. Pimavanserin, an atypical antipsychotic that modulates serotonergic neurotransmission by selectively binding to serotonin receptor (2A and 2C) subtypes and without dopaminergic activity, may have the potential as an adjunctive treatment for MDD. In a phase 2 trial (n=203), addition of pimavanserin, as compared to placebo, to stable treatment with antidepressants was associated with greater reduction in 17-item Hamilton Depression Rating Scale score [HAMD, least square means (95% confidence interval) of −1.7 (−0.03, −3.37), p=0.039]. Furthermore, treatment with pimavanserin was associated with significantly greater improvement in specific symptoms associated with depression such as impaired sexual function, anxiety, sleepiness, and irritability. However, the availability of pimavanserin for clinical care of patients with MDD remains uncertain. Top-line results of phase 3 studies (n=298) that were announced by the sponsor found similar reductions in HAMD (mean baseline-to-week-5 reduction of 9.0 and 8.1, p=0.296) and rates of adverse events (58.1% and 54.7%) with addition of pimavanserin and placebo respectively to stable treatment with antidepressants. Given the potential benefit for specific symptoms such as impaired sexual function, anxiety and sleep/wakefulness disturbances, future studies that enrich for these symptoms may be needed to clarify the utility of adjunctive pimavanserin in treatment of patients with MDD.

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          Most cited references 46

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          Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

          Summary Background As mortality rates decline, life expectancy increases, and populations age, non-fatal outcomes of diseases and injuries are becoming a larger component of the global burden of disease. The Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) provides a comprehensive assessment of prevalence, incidence, and years lived with disability (YLDs) for 328 causes in 195 countries and territories from 1990 to 2016. Methods We estimated prevalence and incidence for 328 diseases and injuries and 2982 sequelae, their non-fatal consequences. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between incidence, prevalence, remission, and cause of death rates for each condition. For some causes, we used alternative modelling strategies if incidence or prevalence needed to be derived from other data. YLDs were estimated as the product of prevalence and a disability weight for all mutually exclusive sequelae, corrected for comorbidity and aggregated to cause level. We updated the Socio-demographic Index (SDI), a summary indicator of income per capita, years of schooling, and total fertility rate. GBD 2016 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, low back pain, migraine, age-related and other hearing loss, iron-deficiency anaemia, and major depressive disorder were the five leading causes of YLDs in 2016, contributing 57·6 million (95% uncertainty interval [UI] 40·8–75·9 million [7·2%, 6·0–8·3]), 45·1 million (29·0–62·8 million [5·6%, 4·0–7·2]), 36·3 million (25·3–50·9 million [4·5%, 3·8–5·3]), 34·7 million (23·0–49·6 million [4·3%, 3·5–5·2]), and 34·1 million (23·5–46·0 million [4·2%, 3·2–5·3]) of total YLDs, respectively. Age-standardised rates of YLDs for all causes combined decreased between 1990 and 2016 by 2·7% (95% UI 2·3–3·1). Despite mostly stagnant age-standardised rates, the absolute number of YLDs from non-communicable diseases has been growing rapidly across all SDI quintiles, partly because of population growth, but also the ageing of populations. The largest absolute increases in total numbers of YLDs globally were between the ages of 40 and 69 years. Age-standardised YLD rates for all conditions combined were 10·4% (95% UI 9·0–11·8) higher in women than in men. Iron-deficiency anaemia, migraine, Alzheimer’s disease and other dementias, major depressive disorder, anxiety, and all musculoskeletal disorders apart from gout were the main conditions contributing to higher YLD rates in women. Men had higher age-standardised rates of substance use disorders, diabetes, cardiovascular diseases, cancers, and all injuries apart from sexual violence. Globally, we noted much less geographical variation in disability than has been documented for premature mortality. In 2016, there was a less than two times difference in age-standardised YLD rates for all causes between the location with the lowest rate (China, 9201 YLDs per 100 000, 95% UI 6862–11943) and highest rate (Yemen, 14 774 YLDs per 100 000, 11 018–19 228). Interpretation The decrease in death rates since 1990 for most causes has not been matched by a similar decline in age-standardised YLD rates. For many large causes, YLD rates have either been stagnant or have increased for some causes, such as diabetes. As populations are ageing, and the prevalence of disabling disease generally increases steeply with age, health systems will face increasing demand for services that are generally costlier than the interventions that have led to declines in mortality in childhood or for the major causes of mortality in adults. Up-to-date information about the trends of disease and how this varies between countries is essential to plan for an adequate health-system response.
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            The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults.

            Research on suicide prevention and interventions requires a standard method for assessing both suicidal ideation and behavior to identify those at risk and to track treatment response. The Columbia-Suicide Severity Rating Scale (C-SSRS) was designed to quantify the severity of suicidal ideation and behavior. The authors examined the psychometric properties of the scale. The C-SSRS's validity relative to other measures of suicidal ideation and behavior and the internal consistency of its intensity of ideation subscale were analyzed in three multisite studies: a treatment study of adolescent suicide attempters (N=124); a medication efficacy trial with depressed adolescents (N=312); and a study of adults presenting to an emergency department for psychiatric reasons (N=237). The C-SSRS demonstrated good convergent and divergent validity with other multi-informant suicidal ideation and behavior scales and had high sensitivity and specificity for suicidal behavior classifications compared with another behavior scale and an independent suicide evaluation board. Both the ideation and behavior subscales were sensitive to change over time. The intensity of ideation subscale demonstrated moderate to strong internal consistency. In the adolescent suicide attempters study, worst-point lifetime suicidal ideation on the C-SSRS predicted suicide attempts during the study, whereas the Scale for Suicide Ideation did not. Participants with the two highest levels of ideation severity (intent or intent with plan) at baseline had higher odds for attempting suicide during the study. These findings suggest that the C-SSRS is suitable for assessment of suicidal ideation and behavior in clinical and research settings.
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              Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                13 January 2021
                2021
                : 15
                : 151-157
                Affiliations
                [1 ]Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [2 ]Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                Author notes
                Correspondence: Manish Kumar Jha Depression and Anxiety Center for Discovery and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai , 1 Gustave L. Levy Place, New York, NY10029, USATel +1 212-585-4636 Email manish.jha@mssm.edu
                [*]

                These authors contributed equally to this work

                Article
                240862
                10.2147/DDDT.S240862
                7812044
                33469267
                © 2021 Soogrim et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

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