Abstract
Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world’s population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in schizophrenic patients and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of the schizophrenic brain. While current antipsychotic medications—typically dopamine D2 antagonists—adequately address positive symptoms of the disease, such as the acute hallucinations and delusions, they fail to substantially improve negative features, such as social isolation, and can further compromise poor cognitive function in schizophrenic patients. In fact, cognitive impairment is a core feature of schizophrenia. The treatment of cognitive impairment and other residual symptoms associated with schizophrenia, therefore, remains a significant unmet medical need. With current cell-surface receptor-based pharmacology falling short of addressing these core symptoms associated with schizophrenia, more recent approaches to treatment development have focused on processes within the cell. In this review, we discuss the importance of a number of intracellular targets, including cyclic nucleotide phosphodiestereases, and non-phosphodiesterase approaches such as ITI-007, which have been proposed to regulate hyperdopaminergic function, hypoglutamatergic function and/or the delicate balance of the two associated with cognitive deficits in schizophrenia. We also discuss the challenge facing those developing drugs to target specific pathways involved in psychopathology without involving other systems that produce concomitant side effects.
Keywords: Antipsychotic, phosphodiesterase, cyclic AMP, dopamine, cyclic GMP, glutamate, cognition.ne, cyclic GMP, glutamate, cognition
Current Pharmaceutical Design
Title:Intracellular Signaling and Approaches to the Treatment of Schizophrenia and Associated Cognitive Impairment
Volume: 20 Issue: 31
Author(s): Gretchen L. Snyder and Kimberly E. Vanover
Affiliation:
Keywords: Antipsychotic, phosphodiesterase, cyclic AMP, dopamine, cyclic GMP, glutamate, cognition.ne, cyclic GMP, glutamate, cognition
Abstract: Schizophrenia is a pervasive neuropsychiatric disorder affecting over 1% of the world’s population. Dopamine system dysfunction is strongly implicated in the etiology of schizophrenia. Data support the long-standing concept of schizophrenia as a disease characterized by hyperactivity within midbrain (striatal D2) dopamine systems. In addition, there is now considerable evidence that glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in schizophrenic patients and that hypoactivity in cortical dopamine and glutamate pathways is a key feature of the schizophrenic brain. While current antipsychotic medications—typically dopamine D2 antagonists—adequately address positive symptoms of the disease, such as the acute hallucinations and delusions, they fail to substantially improve negative features, such as social isolation, and can further compromise poor cognitive function in schizophrenic patients. In fact, cognitive impairment is a core feature of schizophrenia. The treatment of cognitive impairment and other residual symptoms associated with schizophrenia, therefore, remains a significant unmet medical need. With current cell-surface receptor-based pharmacology falling short of addressing these core symptoms associated with schizophrenia, more recent approaches to treatment development have focused on processes within the cell. In this review, we discuss the importance of a number of intracellular targets, including cyclic nucleotide phosphodiestereases, and non-phosphodiesterase approaches such as ITI-007, which have been proposed to regulate hyperdopaminergic function, hypoglutamatergic function and/or the delicate balance of the two associated with cognitive deficits in schizophrenia. We also discuss the challenge facing those developing drugs to target specific pathways involved in psychopathology without involving other systems that produce concomitant side effects.
Export Options
About this article
Cite this article as:
Snyder L. Gretchen and Vanover E. Kimberly, Intracellular Signaling and Approaches to the Treatment of Schizophrenia and Associated Cognitive Impairment, Current Pharmaceutical Design 2014; 20 (31) . https://dx.doi.org/10.2174/1381612819666131216115417
DOI https://dx.doi.org/10.2174/1381612819666131216115417 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Melatonin, a Potential Therapeutic Agent for Smooth Muscle-Related Pathological Conditions and Aging
Current Medicinal Chemistry Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches
Current Pediatric Reviews Inflammation, Oxidation, Caloric Expenditure and Cognitive Impairment in Brazilian Elderly Assisted at Primary Care
Current Alzheimer Research Cytosolic Phospholipase A2 Inhibitors as Therapeutic Agents for Neural Cell Injury
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Therapeutic Approach for Neuronal Disease by Regulating Reninangiotensin System
Current Hypertension Reviews Clinical and Pharmacological Aspects of Inflammatory Demyelinating Diseases in Childhood: An Update
Current Neuropharmacology Lead Finding for Acetyl Cholinesterase Inhibitors from Natural Origin: Structure Activity Relationship and Scope
Mini-Reviews in Medicinal Chemistry Editorial (Thematic Issue: Translational Alzheimer’s Disease Research)
Current Alzheimer Research Editorial (Thematic Issue: Molecular Imaging in Dementia: From the State of the Art to the New Perspectives)
Current Alzheimer Research Prevention of Macrovascular Disease in Type 2 Diabetic Patients: Blockade of the Renin-Angiotensin-Aldosterone System
Current Diabetes Reviews Clinical Evidence of Herb-Drug Interactions: A Systematic Review by the Natural Standard Research Collaboration
Current Drug Metabolism The NGF Metabolic Pathway in the CNS and its Dysregulation in Down Syndrome and Alzheimer’s Disease
Current Alzheimer Research Transgenic Mouse Models of Parkinsons Disease and Huntingtons Disease
CNS & Neurological Disorders - Drug Targets MicroRNAs in Cardiovascular Therapeutics
Current Topics in Medicinal Chemistry Long-Term Follow-Up of Patients Immunized with AN1792: Reduced Functional Decline in Antibody Responders
Current Alzheimer Research Clinical Trajectories and Biological Features of Primary Progressive Aphasia (PPA)
Current Alzheimer Research Implication of Rho GTPases in Neurodegenerative Diseases
Current Drug Targets Measuring Morphological and Cellular Changes in Alzheimers Dementia: A Review Emphasizing Stereology
Current Alzheimer Research Melatonin Role in Experimental Arthritis
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Synthesis and Antiacetylcholinesterase Activity Evaluation of New 2-aryl Benzofuran Derivatives
Letters in Drug Design & Discovery