The size and burden of mental disorders and other disorders of the brain in Europe 2010

Aims

To provide 12-month prevalence and disability burden estimates of a broad range of mental and neurological disorders in the European Union (EU) and to compare these findings to previous estimates. Referring to our previous 2005 review, improved up-to-date data for the enlarged EU on a broader range of disorders than previously covered are needed for basic, clinical and public health research and policy decisions and to inform about the estimated number of persons affected in the EU.

Method

Stepwise multi-method approach, consisting of systematic literature reviews, reanalyses of existing data sets, national surveys and expert consultations. Studies and data from all member states of the European Union (EU-27) plus Switzerland, Iceland and Norway were included. Supplementary information about neurological disorders is provided, although methodological constraints prohibited the derivation of overall prevalence estimates for mental and neurological disorders. Disease burden was measured by disability adjusted life years (DALY).

Results

Prevalence: It is estimated that each year 38.2% of the EU population suffers from a mental disorder. Adjusted for age and comorbidity, this corresponds to 164.8 million persons affected. Compared to 2005 (27.4%) this higher estimate is entirely due to the inclusion of 14 new disorders also covering childhood/adolescence as well as the elderly. The estimated higher number of persons affected (2011: 165 m vs. 2005: 82 m) is due to coverage of childhood and old age populations, new disorders and of new EU membership states. The most frequent disorders are anxiety disorders (14.0%), insomnia (7.0%), major depression (6.9%), somatoform (6.3%), alcohol and drug dependence (> 4%), ADHD (5%) in the young, and dementia (1–30%, depending on age). Except for substance use disorders and mental retardation, there were no substantial cultural or country variations. Although many sources, including national health insurance programs, reveal increases in sick leave, early retirement and treatment rates due to mental disorders, rates in the community have not increased with a few exceptions (i.e. dementia). There were also no consistent indications of improvements with regard to low treatment rates, delayed treatment provision and grossly inadequate treatment.Disability: Disorders of the brain and mental disorders in particular, contribute 26.6% of the total all cause burden, thus a greater proportion as compared to other regions of the world. The rank order of the most disabling diseases differs markedly by gender and age group; overall, the four most disabling single conditions were: depression, dementias, alcohol use disorders and stroke.

Conclusion

In every year over a third of the total EU population suffers from mental disorders. The true size of “disorders of the brain” including neurological disorders is even considerably larger. Disorders of the brain are the largest contributor to the all cause morbidity burden as measured by DALY in the EU. No indications for increasing overall rates of mental disorders were found nor of improved care and treatment since 2005; less than one third of all cases receive any treatment, suggesting a considerable level of unmet needs. We conclude that the true size and burden of disorders of the brain in the EU was significantly underestimated in the past. Concerted priority action is needed at all levels, including substantially increased funding for basic, clinical and public health research in order to identify better strategies for improved prevention and treatment for disorders of the brain as the core health challenge of the 21st century.     

The burden and cost of disorders of the brain in Europe with the inclusion of harmful alcohol use and nicotine addiction

Recent publications calculated an annual prevalence of 38% of the population within the European Union having a “disorder of the brain” including substance use disorders (SUD) (Wittchen et al., 2011). The overall economic burden was estimated at 789 billion € (Gustavsson et al., 2011). While these calculations included alcohol dependence, harmful use of alcohol, a common ICD-10 diagnosis, was not considered appropriately. Tobacco related figures were completely left out. We hence estimated burden and costs of these diagnoses for the European Union by extrapolating basic figures from Germany, which have average proportions of alcohol and tobacco related consumption and prevalence rates. Several German Data sets were used to estimate prevalence, disability adjusted life years (DALYs) and Cost-of-Illness for alcohol and tobacco use disorders in Germany. Results were obtained by focussing on the burden of SUD including well-known comorbidities. Results were then extrapolated to the European level. Compared with the earlier estimations DALYs increased from 2.8 million to over 6.6 million for SUDs. Costs augmented from 65.68 billion € PPP to about 350 billion € PPP. We discuss the robustness and validity of our findings under different assumptions and with regard to methodology. We further took into account that in the new DSM 5 alcohol abuse and alcohol dependence – and similar tobacco – will be collapsed into one category of “alcohol related disorder”. If added to the burden and cost calculations the substance use disorders rank on top of all disorders of the brain in Europe. Regardless of the calculation procedure our figures represent lower estimates and have to be regarded as conservative approaches.     

Size and burden of depressive disorders in Europe.

We review epidemiological studies of depression in Europe. Community surveys are essential. Methodological differences in survey methods, instruments, nuances in language and translation limit comparability, but consistent findings are emerging. Western European countries show 1 year prevalence of major depression of around 5%, with two-fold variation, probably methodological, and higher prevalences in women, the middle-aged, less privileged groups, and those experiencing social adversity. There is high comorbidity with other psychiatric and physical disorders. Depression is a major cause of disability. Incidence has been less studied and lifetime incidence is not clear, with longitudinal studies required. There is pressing need for prevalence studies from Eastern Europe. The considerable differences in health care systems among European countries may impact on proportions of depressives receiving treatment and its adequacy, particularly in the key area of primary care, and require further study. There is a need for public health programmes aimed at improving treatment, reducing rates and consequences of depressive disorders.     

Cost of disorders of the brain in Europe 2010

Background

The spectrum of disorders of the brain is large, covering hundreds of disorders that are listed in either the mental or neurological disorder chapters of the established international diagnostic classification systems. These disorders have a high prevalence as well as short- and long-term impairments and disabilities. Therefore they are an emotional, financial and social burden to the patients, their families and their social network. In a 2005 landmark study, we estimated for the first time the annual cost of 12 major groups of disorders of the brain in Europe and gave a conservative estimate of €386 billion for the year 2004. This estimate was limited in scope and conservative due to the lack of sufficiently comprehensive epidemiological and/or economic data on several important diagnostic groups. We are now in a position to substantially improve and revise the 2004 estimates. In the present report we cover 19 major groups of disorders, 7 more than previously, of an increased range of age groups and more cost items. We therefore present much improved cost estimates. Our revised estimates also now include the new EU member states, and hence a population of 514 million people.

Aims

To estimate the number of persons with defined disorders of the brain in Europe in 2010, the total cost per person related to each disease in terms of direct and indirect costs, and an estimate of the total cost per disorder and country.

Methods

The best available estimates of the prevalence and cost per person for 19 groups of disorders of the brain (covering well over 100 specific disorders) were identified via a systematic review of the published literature. Together with the twelve disorders included in 2004, the following range of mental and neurologic groups of disorders is covered: addictive disorders, affective disorders, anxiety disorders, brain tumor, childhood and adolescent disorders (developmental disorders), dementia, eating disorders, epilepsy, mental retardation, migraine, multiple sclerosis, neuromuscular disorders, Parkinson's disease, personality disorders, psychotic disorders, sleep disorders, somatoform disorders, stroke, and traumatic brain injury. Epidemiologic panels were charged to complete the literature review for each disorder in order to estimate the 12-month prevalence, and health economic panels were charged to estimate best cost-estimates. A cost model was developed to combine the epidemiologic and economic data and estimate the total cost of each disorder in each of 30 European countries (EU27 + Iceland, Norway and Switzerland). The cost model was populated with national statistics from Eurostat to adjust all costs to 2010 values, converting all local currencies to Euro, imputing costs for countries where no data were available, and aggregating country estimates to purchasing power parity adjusted estimates for the total cost of disorders of the brain in Europe 2010.

Results

The total cost of disorders of the brain was estimated at €798 billion in 2010. Direct costs constitute the majority of costs (37% direct healthcare costs and 23% direct non-medical costs) whereas the remaining 40% were indirect costs associated with patients' production losses. On average, the estimated cost per person with a disorder of the brain in Europe ranged between €285 for headache and €30,000 for neuromuscular disorders. The European per capita cost of disorders of the brain was €1550 on average but varied by country. The cost (in billion €PPP 2010) of the disorders of the brain included in this study was as follows: addiction: €65.7; anxiety disorders: €74.4; brain tumor: €5.2; child/adolescent disorders: €21.3; dementia: €105.2; eating disorders: €0.8; epilepsy: €13.8; headache: €43.5; mental retardation: €43.3; mood disorders: €113.4; multiple sclerosis: €14.6; neuromuscular disorders: €7.7; Parkinson's disease: €13.9; personality disorders: €27.3; psychotic disorders: €93.9; sleep disorders: €35.4; somatoform disorder: €21.2; stroke: €64.1; traumatic brain injury: €33.0. It should be noted that the revised estimate of those disorders included in the previous 2004 report constituted €477 billion, by and large confirming our previous study results after considering the inflation and population increase since 2004. Further, our results were consistent with administrative data on the health care expenditure in Europe, and comparable to previous studies on the cost of specific disorders in Europe. Our estimates were lower than comparable estimates from the US.

Discussion

This study was based on the best currently available data in Europe and our model enabled extrapolation to countries where no data could be found. Still, the scarcity of data is an important source of uncertainty in our estimates and may imply over- or underestimations in some disorders and countries. Even though this review included many disorders, diagnoses, age groups and cost items that were omitted in 2004, there are still remaining disorders that could not be included due to limitations in the available data. We therefore consider our estimate of the total cost of the disorders of the brain in Europe to be conservative. In terms of the health economic burden outlined in this report, disorders of the brain likely constitute the number one economic challenge for European health care, now and in the future. Data presented in this report should be considered by all stakeholder groups, including policy makers, industry and patient advocacy groups, to reconsider the current science, research and public health agenda and define a coordinated plan of action of various levels to address the associated challenges.

Recommendations

Political action is required in light of the present high cost of disorders of the brain. Funding of brain research must be increased; care for patients with brain disorders as well as teaching at medical schools and other health related educations must be quantitatively and qualitatively improved, including psychological treatments. The current move of the pharmaceutical industry away from brain related indications must be halted and reversed. Continued research into the cost of the many disorders not included in the present study is warranted. It is essential that not only the EU but also the national governments forcefully support these initiatives.     

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Abstract

GPR3, GPR6, and GPR12 are three orphan receptors that belong to the Class A family of G-protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship, GPR3, GPR6, and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data are required to confirm this association. GPR3, GPR6, and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6, and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer’s disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.     

Towards a better understanding of postprandial hyperglycemic episodes in people with diabetes: impact on daily functioning

Objective: Acute postprandial hyperglycemia (aPPHG) is often symptomatic and can be associated with behavioral changes such as impaired working memory and attention. However, there is little evidence of the impact of aPPHG on the daily lives of patients. The aim of this study was to explore the frequency and severity of aPPHG episodes and their impact on daily functioning in people with insulin-treated diabetes.

Methods: Adults (n?=?1200) with insulin-treated diabetes mellitus type 1 (T1DM) or 2 (T2DM), most of whom experienced aPPHG, were recruited to complete an online cross-sectional survey in the USA and UK. The survey captured self-reported severity and frequency of aPPHG episodes and included a newly developed questionnaire (aPPHG-Q) assessing the impact of aPPHG episodes on patients’ daily lives. Data was analyzed separately according to diabetes type and country. Regression analyses were used to assess the relationship between severity or frequency and scores on the aPPHG-Q.

Results: Between 70% and 86% of USA, and 87% and 88% of UK participants reported experiencing aPPHG episodes. Increasing frequency and severity of aPPHG episodes were associated with worse scores on the aPPHG-Q in patients with both T1DM and T2DM in both countries (p?<?.014) on all subscale scores (excluding the worry and concerns scores for T1DM in the UK), although the magnitude of the association was smaller for aPPHG frequency.

Conclusions: Increased severity and frequency of aPPHG episodes in patients with insulin-treated diabetes is associated with greater burden and experience of symptoms, and can negatively impact daily functioning.     

pH-sensitive film coatings: towards a better understanding and facilitated optimization.

The major aims of this study were: (i) to prepare and characterize polymeric film coatings with pH-dependent properties for oral administration; and (ii) to better understand the underlying mass transport mechanisms upon exposure to simulated gastric and intestinal fluids. Propylene glycol alginate (containing free carboxylic groups) was chosen as a pH-sensitive film former, which was blended with different amounts of ethylcellulose (being water-insoluble throughout the gastro-intestinal tract). The water uptake kinetics of thin free films in 0.1M HCl and phosphate buffer pH 7.4 were monitored gravimetrically and quantitatively described using an appropriate analytical solution of Fick's law of diffusion. Interestingly, the addition of only a low percentage (2.5-10%) of propylene glycol alginate to ethylcellulose significantly increased both, the rate and extent of the films' water uptake, irrespective of the pH of the release medium. Importantly, diffusion was found to be the pre-dominant mass transport mechanism for all system compositions and types of release media. The apparent water diffusivity in the polymeric films could quantitatively be determined as a function of the polymer blend ratio. It significantly increased with increasing pH of the release medium, due to the presence of the free carboxylic groups in propylene glycol alginate. Also the dry mass loss of the polymer networks was much more pronounced at high compared to low pH. The differences in both water uptake as well as dry mass loss resulted in a clear pH-dependence of the drug release kinetics from coated pellets. Importantly, desired pH-sensitive release rates can easily be adjusted by varying the propylene glycol alginate content.     

Prevalence and burden of bipolar disorders in European countries.

A literature search, supplemented by an expert survey and selected reanalyses of existing data from epidemiological studies was performed to determine the prevalence and associated burden of bipolar I and II disorder in EU countries. Only studies using established diagnostic instruments based on DSM-III-R or DSM-IV, or ICD-10 criteria were considered. Fourteen studies from a total of 10 countries were identified. The majority of studies reported 12-month estimates of approximately 1% (range 0.5-1.1%), with little evidence of a gender difference. The cumulative lifetime incidence (two prospective-longitudinal studies) is slightly higher (1.5-2%); and when the wider range of bipolar spectrum disorders is considered estimates increased to approximately 6%. Few studies have reported separate estimates for bipolar I and II disorders. Age of first onset of bipolar disorder is most frequently reported in late adolescence and early adulthood. A high degree of concurrent and sequential comorbidity with other mental disorders and physical illnesses is common. Most studies suggest equally high or even higher levels of impairments and disabilities of bipolar disorders as compared to major depression and schizophrenia. Few data are available on treatment and health care utilization.     

Size of burden of schizophrenia and psychotic disorders.

Schizophrenia is a severe mental disorder characterised by fundamental disturbances in thinking, perception and emotions. More than 100 years of research have not been able to fully resolve the puzzle that schizophrenia represents. Even if schizophrenia is not a very frequent disease, it is among the most burdensome and costly illnesses worldwide. It usually starts in young adulthood. Life expectancy is reduced by approximately 10 years, mostly as a consequence of suicide. Even if the course of the illness today is considered more favourable than it was originally described, it is still only a minority of those affected, who fully recover. The cumulative lifetime risk for men and women is similar, although it is higher for men in the age group younger than 40 years. According to the Global Burden of Disease Study, schizophrenia causes a high degree of disability, which accounts for 1.1% of the total DALYs (disability-adjusted life years) and 2.8% of YLDs (years lived with disability). In the World Health Report [The WHO World Health Report: new understanding, new hope, 2001. Geneva], schizophrenia is listed as the 8th leading cause of DALYs worldwide in the age group 15-44 years. In addition to the direct burden, there is considerable burden on the relatives who care for the sufferers. The treatment goals for the moment are to identify the illness as early as possible, treat the symptoms, provide skills to patients and their families, maintain the improvement over a period of time, prevent relapses and reintegrate the ill persons into the community so that they can lead as normal a life as possible.     

Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders

There is extensive comorbidity between depression and anxiety disorders. Dimensional psychiatric and psychometric approaches have suggested that dysregulation of a limited number of behavioural dimensions that cut across diagnostic categories can account for both the shared and unique symptoms of depression and anxiety disorders. Such an approach recognizes that anxiety, the emotional response to stress, is a key element of depression as well as the defining feature of anxiety disorders, and many antidepressants appear to be effective in the treatment of anxiety disorders as well as depression. Therefore, the pharmacological actions of these drugs must account for their efficacy in both. Brain noradrenergic and serotonergic systems, and perhaps to a more limited extent the dopaminergic system, regulate or modulate many of the same behavioural dimensions (e.g. negative or positive affect) that are affected in depression and anxiety disorders, and that are ameliorated by drug treatment. Whereas much recent research has focused on the regulatory effects of antidepressants on synaptic function and cellular proteins, less emphasis has been placed on monoaminergic regulation at a more global systemic level, or how such systemic alterations in monoaminergic function might alleviate the behavioural, cognitive, emotional and physiological manifestations of depression and anxiety disorders. In this review, we discuss how chronic antidepressant treatment might regulate the tonic activity and/or phasic reactivity of brain monoaminergic systems to account for their ability to effectively modify the behavioural dimensions underlying improvement in both depression and anxiety disorders.