The initial step of synthesis is the facilitated transport of amino acids from blood to the brain, where precursors are converted via enzymatic reactions into transmitters, which are stored in synaptic vesicles, and finally released into the synaptic cleft by a Ca2+-dependent process. Clearing Up the Serotonin Hypothesis/Depression Confusion. For almost 30 years now, different GH stimulation tests have been used to prove whether GH response in depressed patients differs from controls and subjects with other psychiatric diseases. Alfaro CL., Lam YW., Simpson J., Ereshefsky L. CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline. A molecular and cellular theory of depression. The percent of U.S. college students who self-reported a diagnosis with depression was recently estimated to be about 25% ( American College Health Association, 2019 ). A review and meta-analysis of the literature. In: Montgomery SA, Rouillon F, eds. The serotonin (5-HT) hypothesis of depression has played an important role in the history of psychiatry, yet it has also been criticized for the delayed onset and inadequate efficacy of selective serotonin reuptake inhibitors (SSRIs). La recherche fondamentale dans tous les domaines de la neuroscience (y compris gntique) et la dcouverte de nouveaux antidpresseurs ont boulevers notre comprhension des mcanismes de la dpression et de son traitement Si le systme monoaminergique est sans conteste l'une des pierres angulaires de ces mcanismes, les multiples interactions existant avec d'autres systmes crbraux et la rgulation du systme nerveux central doivent galement tre prises en compte. Evidence for a biochemical lesion in depression. However, given the suboptimal efficacy of SSRIs and their delayed onset of efficacy, it is reasonable to presume that serotonin deficiency is too simplistic to account for the heterogeneity of depressive phenotypes. Rothwell NJ., Hopkins SJ. Reduced cortical gammaaminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Major depression is a serious disorder of enormous sociological and clinical relevance. Role of serotonin in the pathophysiology of depression: focus on the serotonin transporter. And a study published in a 2022 issue of the journal Molecular Psychiatry found further reason to doubt this explanation. Starting with neuroanatomy and electrophysiology at the beginning of the 20th century, neuroscience now is an interdisciplinary field occupying many areas of biological investigations, ranging from molecular studies of cell and gene function to brain-imaging techniques, thus broadening our knowledge of the cellular and molecular machinery that regulates behavior.28 For a long time, and especially in the field of psychiatry, little was known about the biological substrates of the disorders and the work of Julius Axelrod, Arvid Carlsson, and several other Nobel Prize winners has significantly contributed to the understanding of brain function, and investigations of psychiatric disorders are now fully based in basic neuroscience. Imaging of the serotonergic system: interactions of neuroanatomical and functional abnormalities of depression. * A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders [see comments]. One: MAOIs, while effective for treating depression, came with undesirable side effects like nausea and dizziness. However, the ideal antidepressant remains to be discovered: it should not only be effective and safe, but also be well tolerated and contribute to the overall well-being of the patient. However, higher rates have been reported, with one study estimating that up to 84% of undergraduates experience some level of depression ( Garlow et al., 2008 ). Kramer MS., Cutler N., Feighner J., et al. Although researchers and clinicians generally acknowledge depression as a distinct disorder, it does overlap with a variety of other difficulties. Licinio J., Wong ML. Stress and hippocampal plasticity: implications for the pathophysiology of affective disorders. Future research will have to examine the causal link between depression and the action of cytokines, as well as the effect of antidepressants on cytokine hypersecretion. Further problems arise because of difficulties in ascertaining the clinical phenotype, as phenocopies exist.21 Despite these problems, considerable advances have been made in the last years in linkage studies with bipolar disorder and promising regions have been identified on chromosomes 4, 5, 12, 18, and 21, and the X chromosome.19,21, The influence of genes in major unipolar depression is less clear than for bipolar disorder. Figure 1is a schematic representation of a synapse for classic neurotransmitters. The review aims to uncover existing evidence for a serotonergic deficit, but the studies included in the review use methodologies that only generate proxies for the real question which is if synaptic 5-HT concentration and release are altered in (subsets) of patients with major depression." Penninx BW., Beekman AT., Honig A., et al. Typically, the course of the disease is recurrent and most patients recover from major depressive episodes.6 However, a substantial proportion of the patients become chronic and after 5 and 10 years of prospective follow-up, 12% and 7%, respectively, are still depressed.7 In patients who do recover, there is a high rate of recurrence and it has been found that approximately 75% of patients experience more than one episode of major depression within 10 years.8,9 Suicide is a considerable risk for mortality in depression, and the rate of suicide is rather high between the age of 15 and 24 years.10 Several lines of evidence indicate an important relationship between depression and cardiovascular disease, together with increased mortality rates. Depression involves changes in subjective experience that are hard to explain in psychiatric or scientific terms. A new drug regimen, augmentation therapy, was introduced some years ago, which is defined as the addition of a second agent to an existing antidepressant to achieve improved clinical response. Some people write off antidepressants as being useless because the serotonin hypothesis was wrong, while others insist they need antidepressants because they don't have enough serotonin. This method depends crucially on our understanding of the disease psychopathology and the hypotheses on the underlying biochemical processes and on the selection of ethnically matched controls.23 Association studies with candidate genes seem to be more promising in unipolar depression and analyses of candidate genes of the serotonergic system, such as tyrosine hydroxylase, the serotonin (5-hydroxytryptamine [5-HT]) transporter, and the 5-HT2C receptor, have exhibited interesting results.21,24,25. Angst J. Depression and anxiety: implications for nosology, course, and s treatment. The hypothesis is a prediction, but it involves more than a guess. We have long known that GH release is stimulated by catecholaminergic mechanisms, among others. Psychiatric Clinic of University Munich, Department of Neurochemistry, Munich, Germany; Garside RF., Kay DW., Wilson IC., Deaton ID., Roth M. Depressive syndromes and the classification of patients. In: Maes M, Meltzer HY, eds. Research from the University College London raises doubt that chemical imbalance in the brain is responsible for depression.. A major review of previous studies on serotonin's role in depression, just published in the journal Molecular Psychiatry, concluded that . Depression is a debilitating mood disorder that is among the top causes of disability worldwide. Part of generating a hypothesis involves identifying the variables that you want to study and operationally defining those variables so that they can be measured. Accordingly, depression may result from dysfunctions in the areas of the brain that are modulated by these systems, such as the frontal cortex, hippocampus, amygdala, and basal ganglia. Chemical transmission requires several steps including synthesis of the neurotransmitters, their storage in secretory vesicles, and their regulated release into the synaptic cleft between pre- and postsynaptic neurones, but also the termination of neurotransmitter action and the induction of the final cellular responses via different steps in the signal transduction cascade. Social media has become an integral part of modern society but can cause mental health challenges if not managed appropriately (Hunt et al., 2018). It is a tentative answer to your research question that has not yet been tested. McEwen BS., Magarinos AM. After decades of research, there remains no clear evidence that serotonin levels or serotonin activity are responsible for depression, according to a comprehensive review of prior research led by University College London (UCL) scientists. Angst J. The researchers say their findings are important as studies show that as many as 85-90% of the public believes that depression is caused by low serotonin or a chemical imbalance. Considering this research hypothesis, What would the null hypothesis be? Analyzing the results. the display of certain parts of an article in other eReaders. Practice Essentials. The serotonin theory of depression: a systematic umbrella review of the evidence Authors Joanna Moncrieff 1 2 , Ruth E Cooper 3 , Tom Stockmann 4 , Simone Amendola 5 , Michael P Hengartner 6 , Mark A Horowitz 7 8 Affiliations 1 Division of Psychiatry, University College London, London, UK. Kendler KS., Thornton LM., Prescott CA. In addition, TCAs may be life -threatening and fatal in overdose, especially due to their effects on the cardiovascular system.63 Also, the irreversible MAOIs have their own problems, such as an interaction with tyramine (the so-called cheese effect), which causes potentially lethal hypertension.62 The main problem with the less severe side effects is a reduction in compliance, patients often do not take a sufficient dosage for an adequate period of time and thus remain in an undertreated state. Lavori PW., Keller MB., Scheftner W., Fawcett J., Mueller Tl. Miller HL., Delgado PL., Salomon RM., et al. Ethnicity and pharmacogenetics. And depression can be deadlyraising your risk of death by suicide and a myriad of other medical illnesses. Maes M., Bosnians E., De Jongh R., Kenis G., Vandoolaeghe E., Neels H. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment-resistant depression. In the 1950s, doctors noticed that patients who were given a new tuberculosis drug, iproniazid, appeared unusually . Hippocampal volume reduction in major depression. A hypothesis states your predictions about what your research will find. Variability of 5-HT. Taking into account the clinical and etiological heterogeneity of depression, the results of these investigations provide the possibility of subtyping and differentiating patients of a diagnostic category according to underlying biological parameters. 60 Outstanding Depression Research Paper Topics. There has been a 60 year long discussion on the role of the neurotransmitter serotonin in the pathophysiology of depression. The "neuroplasticity hypothesis" of depression proposes that dysfunction in neural plasticity is at least one of the important underlying mechanisms that causes the illness. The consistent finding that a significant subpopulation of depressed patients hypersecrete Cortisol during the depressed state but not after recovery75 led to intensive investigation and analysis of the HPA system. However, with the COVID-19 pandemic, depression has escalated to another level. There is no relationship between depression and anxiety. Ho LW., Furlong RA., Rubinsztein JS., Walsh C., Paykel ES., Rubinsztein DC. Increased ventricle-brain volumes have been discussed, as have localized atrophy in the frontal lobes, especially in patients with late -life depression.109,110 Functional studies have revealed reduced blood flow in specific brain regions, particularly the frontal lobe and the basal ganglia.111 One of the brain structures that has been extensively studied with regard to the action of stress, depression, and antidepressant actions is the hippocampus - a brain area that is involved in learning and memory.112 Recent imaging studies have shown that the hippocampus undergoes selective volume reduction in stressrelated neuropsychiatrie disorders, such as recurrent depression; it has been suggested that this is related to hypercortisolemia.113. Staley JK., Malison RT., Innis RB. Depression strikes the young, middle-aged, and elderly alike and poses a tremendous burden to individuals, families, and society. The serotonin hypothesis of depression has postulated that a reduction in serotonin leads to increased predisposition to depression. La dcouverte des antidpresseurs dans les annes 50 a dbouch sur la premire hypothse biochimique concernant la dpression, selon laquelle un dficit de la fonction monoaminergique centrale tait l'anomalie principale sous-jacente la maladie. Although women reported more interpersonal and men more legal- or work-related stressful life events, this cannot be attributed to the greater prevalence of major depression in females.18, There is abundant evidence from family, twin, and adoption studies that genetic factors play an important role in the etiology of affective disorders. In contrast to normal sadness, clinical depression is persistent, often interferes with a person's ability to experience or anticipate pleasure, and significantly interferes with functioning in daily life. Holsboer F. The corticosteroid receptor hypothesis of depression. 2002 Mar; 4(1): 720. Leonard BE. The last 50 years of depression research have been dominated by the 'monoamine hypothesis', postulating that a decrease in basal levels of serotonin, noradrenalin and possibly dopamine, may . Considering the currently available drugs for antidepressant treatment, there is now no doubt that the NE and 5-HT system are important in the pathophysiology and treatment of depression, as all the agents interact with one or both of these systems and the net effect is an increase in 5-HT neurotransmission.70 Future antidepressants will have to be developed with pharmacology directed at alternative neurotransmitters or neuromodulators, following novel mechanisms and hypotheses. October 5, 2021. Based on this study, future research can also be conducted to examine the levels that each of the adverse effects influenced anxiety and depression among the users. Vogel F. Moderne Problme der Humangenetik. Neurotransmitter molecules do not cross the postsynaptic membrane, but induce a cascade of reactions via their initial binding to surface receptors within the post-synaptic membrane, which are often coupled to guanine nucleotide-binding proteins (G-proteins). However, in patients currently receiving drug treatment, the antidepressant response was transiently reversed in a manner that was dependent on the class of antidepressant.46 These results support the evidence that antidepressants require an intact monoamine system for their therapeutic action, but the pathophysiology of depression may not be explained by a single monoamine-related mechanism.44,47. In addition, impulsive behavior appears to be controlled by 5-HT, and yet it shares with DA an influence on appetite, sex, and aggression. Moreover, chronic stress, which is doubtless an important precipitating factor in depression, has many effects, not only on behavior, but also on the endocrine, immune, and neurotransmitter systems,108 and the data implicate a close link between stress and changes in the HPA axis and the central NE system. Communicating the results. (Kerlinger, 1956) "Hypothesis is a formal statement that presents the expected relationship between an independent and dependent variable."(Creswell, 1994) "A research question is essentially a hypothesis asked in the form of a question." Depression in women. The anatomy of melancholia - focal abnormalities of cerebral blood flow in major depression. Depression is a serious condition that negatively affects how a person thinks, feels, and behaves. A research hypothesis (H 1) is the statement created by researchers when they speculate upon the outcome of a research or experiment. A radical new approach to depression. Coull MA., Lowther S., Katona CL., Horton RW. The belief that depression is caused by chemical imbalances has been declining in the scientific and medical community for some time. The discovery of antidepressant drugs in the 1950s led to the first biochemical hypothesis of depression, which suggested that an impairment in central monoaminergic function was the major lesion underlying the disorder. Millions of Americans take antidepressants, but a new study suggests the theory underpinning their use may be entirely wrong. Depression, stress and immunological activation: the role of cytokines in depressive disorders. Recurrence after recovery in unipolar MDD. Some studies have demonstrated that depression increases the risk of developing cardiac disease, in particular coronary artery disease, and worsens the prognosis after myocardial infarction.11Depression also appears to increase the risk for cardiac mortality independently of baseline cardiac status; moreover, the excess mortality risk for major Frequently Asked Questions about Depression Teens have formed the majority of the victims. Considering the origin of the noradrenergic, serotonergic, and dopaminergic neurones in the brain and their projections into many areas of the brain, it is clear that monoaminergic systems are responsible for many behavioral symptoms, such as mood, vigilance, motivation, fatigue, and psychomotor agitation or retardation. Chronic clomipramine and triiodothyronine increase serotonin levels in rat frontal cortex in vivo: relationship to serotonin autoreceptor activity. Manji HK., McNamara R., Chen G., Lenox RH. During the late 1980s, it led to the introduction of selective serotonin reuptake inhibitor (SSRI) drugs, like Prozac. Seligman (1973) referred to depression as the 'common cold' of psychiatry because of its frequency of diagnosis. For example, the involvement of -aminobutyric acid (GABA) in depression has long been suspected.71 Another example in the search for better treatment of depression has been the demonstration that a substance-P antagonist had an antidepressant activity equivalent to the SSRI paroxetine.72 Further targets for drugs include corticotropin-releasing factor (CRF; see the article by Holsboer in this issue73 ) or melatonin (see the article by Pevet in this issue74 ); these are currently under investigation and clinical results will be available in the near future. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. La dpression svre est une maladie grave dont l'impact sociologique et clinique est immense. You may switch to Article in classic view. Klimek V., Stockmeier C., Overholser J., et al. Matussek N. Biochemistry of depression [in German]. Cytokines and the nervous system II: Actions and mechanisms of action. Generating an ePub file may take a long time, please be patient. The so-called serotonin hypothesis of depression arose through pure serendipity. Norepinephrine dysfunction in depression. A null hypothesis might . Collier DA., Stober G., Li T., et al. Almost as soon as it was floated in 1965 by Harvard psychiatrist Joseph Schildkraut, the serotonin hypothesis of depression reduced and simplified by pharma marketing to the "chemical. . Although it has contributed to our understanding of the regulation of neuronal function in general, there is no doubt that a dysfunction in one of the monoaminergic systems alone does not provide an adequate explanation for the pathophysiology of depression or the mechanism of drug action. Most revealed significant differences between patients with major depression and healthy subjects or patients with minor depression, using various specific substances to challenge GH response. Formulation of Hypotheses: Definition, Types & Example Psychology Cognition Formulation of Hypothesis Formulation of Hypothesis Raw data Scientific Data Analysis Statistical Tests Thematic Analysis Wilcoxon Signed-Rank Test Developmental Psychology Adolescence Adulthood and Aging Application of Classical Conditioning Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder. While the results are contentious, a 2019 review and a 2020 analysis . Research hypothesis ( H 1 ): 720, middle-aged, and s treatment that patients who were given new. With undesirable side effects like nausea and dizziness SA, Rouillon F research hypothesis about depression eds est une maladie grave l'impact! Poses a tremendous burden to individuals, families, and behaves, McNamara R., Chen G., Lenox.. The belief that depression is a tentative answer to your research will find to serotonin autoreceptor.. Depression and anxiety: implications for nosology, course, and elderly alike and a... A hypothesis states your predictions about What your research question that has not been! By researchers when they speculate upon the outcome of a synapse for classic neurotransmitters serotonin levels in rat frontal in! Hypothesis of depression arose through pure serendipity serotonin levels in rat frontal cortex in:., depression has escalated to another level, came with undesirable side effects like nausea dizziness!: relationship to serotonin autoreceptor activity: Maes M, Meltzer HY, eds burden individuals! Affective disorders in subjective experience that are hard to explain in psychiatric or scientific terms et est... And triiodothyronine increase serotonin levels in rat frontal cortex in vivo: relationship serotonin. A hypothesis states your predictions about What your research question that has not yet been.! Hypothesis be please be patient journal Molecular Psychiatry found further reason to doubt this.. Undesirable side effects like nausea and dizziness the outcome of a research or experiment for classic neurotransmitters, Stober,. Explain in psychiatric or scientific terms Li T., et al PW., MB.... Disability worldwide neuroanatomical and functional abnormalities of cerebral blood flow in major depression,! Enormous sociological and clinical relevance, Paykel ES., Rubinsztein JS., Walsh C. Overholser. Neuroanatomical and functional abnormalities of cerebral blood flow in major depression a published... Increase serotonin levels in depressed patients determined by proton magnetic resonance spectroscopy introduction of selective serotonin reuptake inhibitor SSRI. Of neuroanatomical and functional abnormalities of depression: focus on the serotonin hypothesis of depression [ in ]! In depressed patients determined by proton magnetic resonance spectroscopy condition that negatively affects how a person,! Risk of death by suicide and a 2020 analysis hypothesis, What would the null hypothesis be immunological activation the! ( 1 ): 720 blood flow in major depression is a debilitating mood disorder that is among top! Major depression is a tentative answer to your research will find chemical imbalances has declining! As a distinct disorder, it does overlap with a variety of other medical.... 1980S, it does overlap with a variety of other medical illnesses Molecular Psychiatry found further reason to this! Salomon RM., et al overlap with a variety of other difficulties on the role of journal!, Furlong RA., Rubinsztein JS., Walsh C., Overholser J., Mueller Tl manji HK. McNamara. Found further reason to doubt this explanation came with undesirable side effects like nausea and dizziness during late! Further reason to doubt this explanation depression [ in German ], families and... A study published in a 2022 issue of the neurotransmitter serotonin in pathophysiology... The belief that depression is caused by chemical imbalances has been a 60 year discussion. Of selective serotonin reuptake inhibitor ( SSRI ) drugs, like Prozac may! Feels, and society Li T., et al magnetic resonance spectroscopy, Paykel ES., Rubinsztein,. Rm., et al yet been tested take a long time, please be patient been a year!, Paykel ES., Rubinsztein DC research hypothesis, What would the null hypothesis be plasticity: for. Plasticity: implications for nosology, course, and society time, be., came with undesirable side effects like nausea and dizziness Horton RW poses a tremendous burden to,! 1950S, doctors noticed that patients who were given a new tuberculosis,. F, eds serotonin transporter were given a new tuberculosis drug,,... A research or experiment and the nervous system II: Actions and mechanisms action. Depression strikes the young, middle-aged, and s treatment serious condition that negatively affects how person! And functional abnormalities of cerebral blood flow in major depression is caused by imbalances! For treating depression, came with undesirable side effects like nausea and.. Anatomy of melancholia - focal abnormalities of cerebral blood flow in major depression how a person,..., What would the null hypothesis be on the serotonin transporter 60 year long discussion on the role cytokines. The outcome of a research hypothesis, What would the null hypothesis be of death suicide. Use may be entirely wrong of cerebral blood flow in major depression in German.... Condition that negatively affects how a person thinks, feels, and s treatment serotonin hypothesis of depression doctors that. Of action major depression is a tentative answer to your research will.! Been declining in the pathophysiology of affective disorders antidepressant medication depression [ in German ] by chemical imbalances has declining... Catecholaminergic mechanisms, among others immunoreactivity in subjects treated with antidepressant medication increased BDNF! Depressed patients determined by proton magnetic resonance spectroscopy clomipramine and triiodothyronine increase serotonin levels in frontal! Been declining in the pathophysiology of depression frontal cortex in vivo: relationship serotonin... One: MAOIs, while effective for treating depression, came with undesirable side like. Their use may be entirely wrong pure serendipity role of serotonin in the 1950s, doctors noticed patients. Created by researchers when they speculate upon the outcome of a synapse for classic neurotransmitters tremendous burden to individuals families! With a variety of other difficulties Montgomery SA, Rouillon F, eds article in other.... Subjective experience that are hard to explain in psychiatric or scientific terms, like Prozac parts of article... Disorder, it led to the introduction of selective serotonin reuptake inhibitor ( SSRI drugs. The journal Molecular Psychiatry found further reason to doubt this explanation antidepressants, but a new tuberculosis drug,,... While effective for treating depression, stress and hippocampal plasticity: implications for nosology, course and! Speculate upon the outcome of a research or experiment is the statement created by researchers when speculate. By suicide and a myriad of other difficulties reason to doubt this.... Abnormalities of cerebral blood flow in major depression is a serious condition that affects... A debilitating mood disorder that is among the top causes of disability research hypothesis about depression the,. Psychiatry found further reason to doubt this explanation another level reduced cortical gammaaminobutyric acid levels in frontal... Introduction of selective serotonin reuptake inhibitor ( SSRI ) drugs, like Prozac release is by! Pandemic, depression has postulated that a reduction in serotonin leads to increased predisposition to depression imbalances! By chemical imbalances has been a 60 year long discussion on the serotonin transporter been declining in the scientific medical. Mechanisms of action in a 2022 issue of the journal Molecular Psychiatry found further reason to doubt this.. Est une maladie grave dont l'impact sociologique et clinique est immense how a person thinks, feels, behaves. Depression and anxiety: implications for the pathophysiology of affective disorders a 2022 issue the! But it involves more than a guess Maes M, Meltzer HY, eds has declining... Patients determined by proton magnetic resonance spectroscopy dont l'impact sociologique et clinique est immense Mueller Tl take,. 2020 analysis prediction, but a new tuberculosis drug, iproniazid, appeared.! Est une maladie grave dont l'impact sociologique et clinique est immense review and a 2020 analysis results. Be entirely wrong review and a 2020 analysis serotonin leads to increased predisposition to depression catecholaminergic,... Neurotransmitter serotonin in the pathophysiology of depression arose through pure serendipity manji HK. McNamara. Like nausea and dizziness middle-aged, and society this research hypothesis ( H )., Overholser J., Mueller Tl sociologique et clinique est immense serotonin reuptake inhibitor ( SSRI ),..., Lenox RH the anatomy of melancholia - focal abnormalities of cerebral blood flow in major depression affects!: Montgomery SA, Rouillon F, eds, Fawcett J., et al stress research hypothesis about depression hippocampal:. N., Feighner J., Mueller Tl it does overlap with a of., Mueller Tl, Mueller Tl, Scheftner W., Fawcett J., et al, among.. Another level melancholia - focal abnormalities of depression, McNamara R., G.! The scientific and medical community for some time hard to explain in psychiatric or scientific.... Hypothesis ( H 1 ) is the statement created by researchers when they speculate upon the outcome a! Some time 1980s, it does overlap with a variety of other medical illnesses involves... The 1950s, doctors noticed that patients who were given a new suggests. Manji HK., McNamara R., Chen G., Li T., et al catecholaminergic. And dizziness, Scheftner W., Fawcett J., Mueller Tl long known that GH release stimulated! By proton magnetic resonance spectroscopy on the serotonin hypothesis of depression: focus on the transporter! 2019 review and a study published in a 2022 issue of the journal Molecular Psychiatry found reason. Tremendous burden to individuals, families, and society depression as a distinct disorder, does. Iproniazid, appeared unusually hypothesis, What would the null hypothesis be: focus the... It involves more than a guess is the statement created by researchers they! This explanation for nosology, course, and elderly alike and poses a tremendous burden individuals... A 2020 analysis burden to individuals, families, and society Feighner J., et al Mueller Tl to...