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      Clinical role of brexpiprazole in depression and schizophrenia

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          Abstract

          Brexpiprazole, a serotonin–dopamine activity modulator, is the second D 2 partial agonist to come to market and has been approved for the treatment of schizophrenia and as an adjunctive treatment in major depressive disorder. With less intrinsic activity than aripiprazole at the D 2 receptor and higher potency at 5-HT 2A, 5-HT 1A, and α1 B receptors, the pharmacological properties of brexpiprazole suggest a more tolerable side effect profile with regard to akathisia, extrapyramidal dysfunction, and sedation. While no head-to-head data are currently available, double-blind placebo-controlled studies show favorable results, with the number needed to treat (NNT) vs placebo of 6–15 for response in acute schizophrenia treatment and 4 for maintenance. NNT is 12 for response and 17–31 for remission vs placebo in major depression. In schizophrenia trials, treatment-emergent adverse effects (TEAEs) and discontinuation rates due to TEAEs were lower in treatment groups vs placebo (7.1%–9.2% vs 14.7%, respectively). Meanwhile, discontinuation rates due to TEAEs in depression studies were higher in treatment groups vs placebo (1.3%–3.5% vs 0–1.4%, respectively) and appeared dose dependent. Rates of akathisia are lower compared to those with aripiprazole and cariprazine, weight gain is more prominent than with aripiprazole, cariprazine, or ziprasidone, and sedation is less than with aripiprazole but more than with cariprazine. Brexpiprazole target dosing is 2–4 mg in schizophrenia and 2 mg in depression augmentation. Dose adjustments should be considered in hepatic or renal dysfunction and/or in poor cytochrome P450 2D6 metabolizers. While brexpiprazole represents an exciting second entry for D 2 partial agonists with positive studies thus far, direct head-to-head comparisons will shed more light on the efficacy and side effect profile of brexpiprazole.

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          Most cited references 29

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          Burden of depressive disorders by country, sex, age, and year: findings from the global burden of disease study 2010.

          Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease. Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders. Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%-10.8%) of global YLDs and dysthymia for 1.4% (0.9%-2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%-3.2%) of global DALYs and dysthymia for 0.5% (0.3%-0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%-3.8%) to 3.8% (3.0%-4.7%) of global DALYs. GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden. Please see later in the article for the Editors' Summary.
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            Depression: The Disorder and the Burden

             M. Reddy (2010)
            Depression, the common psychological disorder, affects about 121 million people worldwide. World Health Organization (WHO) states that depression is the leading cause of disability as measured by Years Lived with Disability (YLDs) and the fourth leading contributor to the global burden of disease. By the year 2020, depression is projected to reach second place in the ranking of Disability Adjusted Life Years (DALY) calculated for all ages. Today, depression already is the second cause of DALYs in the age category 15-44 years. BURDEN OF DISEASE An estimated 3-4% of India's 100 crore plus population suffers from major mental disorders and about 7-10% of the population suffers from minor depressive disorders. In the southeast Asian region, 11% of DALYs and 27% of YLDs are attributed to neuropsychiatric disease. A review of eight epidemiological studies on depression in South Asia shows that the prevalence in primary care was 26.3%. In the Goa study, the rate of depressive disorders was 46.5% in adult primary care attendees. The above table 1 shows that disability due to depression exceeds disability due to all forms of cancer and diabetes mellitus combined, as well as exceeding the disability due to strokes and hypertensive heart diseases. Table 1 Age-standardized DALYs per 100,000 population 2004 WHO figures for India The Global Burden of Disease (GBD) study (GBD 1990 Study) launched by the WHO in the 1990s showed that Depressive disorders account for 3.7% of total DALYs and 10.7% of total YLDs. GBD 2000 study (WHO 2001) showed that depression accounts for 4.46% of total DALYs and 12.1% of total YLDs. This clearly highlights a trend of increasing burden of disability secondary to depression. SUICIDALITY Depression is associated with high suicidality. About 50% of individuals who have committed suicide carried a primary diagnosis of depression. Because mood disorders underlie 50-70% of all suicides, effective treatment of these disorders on a national level should, in principle, drastically reduce this major complication of mood disorders. Indian union health ministry estimates state that 120,000 people commit suicide every year in India. Also over 400,000 people attempt suicide. A significant percentage of people who commit suicide in India (37.8%) are below 30 years of age. Ministry officials state that majority of those committing suicide suffer from depression or mental disorders. MORBIDITY Exactly 23% of depressed patients report health difficulties severe enough to keep them bedridden. A community sample of patients with MDD demonstrated increased health care utilization in comparison to patients in the general medical setting. Depression is associated with more impairment in occupational and interpersonal functioning in comparison to several common medical illnesses. The cost of depression, particularly the cost in lost work days, is as great as or greater than the cost of many other common medical illnesses. MATERNAL AND CHILD HEALTH Depression also has a large impact on maternal and child well being. A series of studies from South Asia have demonstrated that early childhood failure to thrive, as indicated by undernutrition and stunting of growth in babies under 1 year, is independently associated with depression in mothers. A study from Pakistan shows that babies of mothers who were depressed during pregnancy and in the postnatal period were more than five times at greater risk for being underweight and stunted at 6 months than babies of non-depressed mothers, even after adjustment for other confounding factors like socioeconomic status. Childhood failure to thrive is a major risk factor for child mortality. Depressed mothers are more likely to cease breastfeeding. Depression during pregnancy is strongly associated with low birth weight. TREATMENT The outcome of depression can be significantly improved by early detection. A wide range of highly effective treatments including antidepressant medications (at a cheaper cost), somatic therapies and psychotherapeutic interventions is available for the treatment of depression. Antidepressant medications and supportive psychological interventions are effective in about 80% of patients. But the number of trained professionals (Psychiatrists, Psychologists, Psychiatric nurses) in our country is very limited and spread out only in urban/semiurban areas. THE PROBLEM OF AWARENESS Less than 25% of those affected (in some estimates less than 10%) by depression receive treatment. Barriers to effective care include the lack of resources, lack of trained providers, and the stigma. Nearly half of the patients with depression, as in diabetes, remain undiagnosed for years or inadequately treated. Large numbers of patients from rural areas remain under care of religious healers and may never receive correct treatment. Special diets, tonics, appetite stimulants and energy pills dominate the prescriptions. Stigma still is a significant barrier. The majority of patients do not receive evidence-based treatments. NEED FOR PRIMARY CARE INVOLVEMENT Despite the fact that many patients with depressive disorders seek help in primary care, general practitioners have difficulties in diagnosing and treating depression. The point prevalence of major depressive disorder in general hospital setting care is higher than 10%. Concomitant depression increases the morbidity and mortality from concurrent medical illness. Depression increases the risk for cardiac illness, diabetes, hypertension, etc. Depressed patients have three times higher risk of developing MI compared to people not having depression. Mood disorders, as highly prevalent and lethal disorders, must command a greater share in the clinical curriculum. Depressive disorders can be easily diagnosed at the primary care level and do not require any special investigations or hi-tech equipment. They can be detected early and managed very effectively by a primary care doctor, with a wide array of effective and safe medications available at reasonable cost. The challenge is to provide all primary care physicians with the requisite hands-on experience in this prevalent group of disorders. Emphasis on training in psychiatry during undergraduate medical training remains an issue of immediate attention. It is highly imperative that Depressive Disorder be considered an issue of public health importance to provide effective treatment to the patients and to reduce the burden of disease on the nation.
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              Epidemiology of schizophrenia: the global burden of disease and disability.

               A Jablensky (1999)
              Evidence from nearly a century of epidemiological research indicates that schizophrenia occurs in all populations with a prevalence in the range of 1.4 to 4.6 per 1000 and incidence rates in the range of 0.16-0.42 per 1000 population. Multi-centre studies conducted by the World Health Organization have highlighted important differences between 'Western' and 'Third World' populations as regards the course and outcome of the disorder, with a significantly better prognosis in the developing countries. The factors underlying the better outcome of schizophrenia in developing countries remain essentially unknown but are likely to involve interactions between genetic variation and specific aspects of the environment. These features place schizophrenia, along with diabetes, cancer and hypertension, into the group of genetically complex diseases which are characterised by polygenic transmission, locus heterogeneity and environmental contribution to causation. The emerging pattern of risk factors and antecedents of schizophrenia suggests multiple, mainly quantitative deviations from the average developmental trajectory, primarily in the areas of early neurodevelopment, cognitive ability and social behaviour. These deviations are compatible with the notion of non-specific background factors facilitating the operation of genetically determined causal pathways. Research likely to result in new insights should focus on the population distribution and behavioural effects of potential risk factors and markers suggested by biological and genetic research.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2017
                10 March 2017
                : 13
                : 299-306
                Affiliations
                Psychiatry and Neurobehavioral Sciences, University of Virginia School of Medicine, Charlottesville, VA, USA
                Author notes
                Correspondence: Anita H Clayton, Psychiatry and Neurobehavioral Sciences, University of Virginia School of Medicine, PO Box 800623, Charlottesville, VA 22908 USA, Email ahc8v@ 123456virginia.edu
                Article
                tcrm-13-299
                10.2147/TCRM.S94060
                5354524
                © 2017 Parikh 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.

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