The Economic Burden of Schizophrenia in the United States in 2002

Wu, Eric Q.; Birnbaum, Howard G.; Shi, Lizheng; Ball, Douglas E.; Kessler, Ronald C.; Moulis, M; Aggarwal, Jyoti

doi:10.4088/jcp.v66n0906

Cited by 506 publications

(340 citation statements)

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“…Most people know someone or have a family member, however distant, with this diagnosis. The direct costs of this illness are high (Wu et al, 2005). More hospital beds are occupied by persons with schizophrenia than all other psychiatric illnesses combined (Buchanan and Carpenter, 2000).…”

Section: Introduction: the Problem Of Schizophreniamentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

103

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We propose that postmortem tissue is an underutilized substrate that may be used to translate genetic and/or preclinical studies, particularly for neuropsychiatric illnesses with complex etiologies. Postmortem brain tissues from subjects with schizophrenia have been extensively studied, and thus serve as a useful vehicle for illustrating the challenges associated with this biological substrate. Schizophrenia is likely caused by a combination of genetic risk and environmental factors that combine to create a disease phenotype that is typically not apparent until late adolescence. The complexity of this illness creates challenges for hypothesis testing aimed at understanding the pathophysiology of the illness, as postmortem brain tissues collected from individuals with schizophrenia reflect neuroplastic changes from a lifetime of severe mental illness, as well as treatment with antipsychotic medications. While there are significant challenges with studying postmortem brain, such as the postmortem interval, it confers a translational element that is difficult to recapitulate in animal models. On the other hand, data derived from animal models typically provide specific mechanistic and behavioral measures that cannot be generated using human subjects. Convergence of these two approaches has led to important insights for understanding molecular deficits and their causes in this illness. In this review, we discuss the problem of schizophrenia, review the common challenges related to postmortem studies, discuss the application of biochemical approaches to this substrate, and present examples of postmortem schizophrenia studies that illustrate the role of the postmortem approach for generating important new leads for understanding the pathophysiology of severe mental illness.

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Section: Introduction: the Problem Of Schizophreniamentioning

confidence: 99%

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

McCullumsmith

Hammond

Shan

et al. 2013

Neuropsychopharmacol

103

View full text Add to dashboard Cite

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“…The first outward symptoms of schizophrenia often initiate in early adulthood, requiring lifelong daily maintenance therapy at an annual cost to the United States of $68 billion (both direct and indirect, 2002 data), a figure which is second to Alzheimer's disease and nearly the same as stroke and congestive heart failure combined. 30 Current treatments have been in existence since the 1950s and include both typical and atypical antipsychotics. These agents rely on D 2 antagonism as the major biological mechanism of action and have been elegantly shown to correlate with clinical efficacy in treating the positive symptoms of the disorder.…”

Section: Schizophrenia and First Generation Mglu 5 Pamsmentioning

confidence: 99%

Progress toward Positive Allosteric Modulators of the Metabotropic Glutamate Receptor Subtype 5 (mGlu₅)

Stauffer

2011

ACS Chem. Neurosci.

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ABSTRACT:This Review describes recent trends in the development of small molecule mGlu 5 positive allosteric modulators (PAMs). A large body of pharmacological, genetic, electrophysiological, and in vivo behavioral evidence has accumulated over the past decade which continues to support the hypothesis and rationale for the activation of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) as a viable and promising target for the development of novel antipsychotics. Until recently, functionally efficacious and potent mGlu 5 PAMs have been somewhat structurally limited in scope and slow to emerge. This Review will discuss efforts since late 2008 which have provided novel mGlu 5 PAM chemotypes, offering ligands with a diverse range of pharmacological, physicochemical, and DMPK properties that were previously unavailable. In addition, significant biological studies of importance in the past few years using the well established PAMs known as DFB, CPPHA, CDPPB, and ADX-47273 will be discussed. KEYWORDS:Metabotropic, mGlu 5 , schizophrenia, allosteric, positive allosteric modulator, DFB, CPPHA, CDPPB, ADX-47273, glutamate G lutamate is the single most important excitatory neurotransmitter in the mammalian central nervous system (CNS). 1 The concentration of glutamate within the cytoplasm of glutamatergic neurons is several times more than that of any other amino acid, approximately 5À10 mM, and within synaptic vesicles glutamate reserves can be significantly higher. The two major receptor classes that are known to be modulated by glutamate include ionotropic glutamate receptors (iGlus), which are multimeric glutamate-gated cation channels, and metabotropic glutamate receptors (mGlus), which are seven transmembrane heptahelical (7TM) spanning proteins coupled to effector G-proteins. 2 Ionotropic glutamate receptors are responsible for fast acting glutaminergic transmission in the CNS and are mediated by the three subclasses of iGlus: the R-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) receptors. All three iGlu channels undergo a conformational change and open in response to glutamate binding and induce excitatory post synaptic current, with the NMDA receptor perhaps best characterized and central to many hypotheses of CNS pathologies. A wide range of neurological disorders including chronic pain, schizophrenia, Alzheimer's disease, epilepsy, drug addiction, and fragile X syndrome have been associated with dysfunction of glutamatergic systems. 1,3 In contrast to ionotropic glutamate receptors, metabotropic glutamate receptors bind glutamate to modulate either presynaptic neurotransmitter release or postsynaptic excitatory neurotransmission.Allosteric modulation of metabotropic glutamate receptors as a glutamate-based approach for therapeutic intervention, either via enhancing or inhibiting endogenous agonist responses, is a highly active area of research and drug development. 3À7 Allosteric mechanisms of receptor modulation provide several potential advantages o...

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“…Schizophrenia is the psychiatric disorder associated with the largest health care use [2]. In Sweden, a recent study showed that in schizophrenia life expectancy is reduced by 19 years for men and 17 years for women compared to the population [3].…”

Section: Introductionmentioning

confidence: 99%