olanzapine and Neurodegenerative-Diseases

Regulators of G protein signaling (RGS) are a family of proteins classically known to accelerate the intrinsic GTPase activity of G proteins, which results in accelerated inactivation of heterotrimeric G proteins and inhibition of G protein coupled receptor signaling. RGS proteins play major roles in essential cellular processes, and dysregulation of RGS protein expression is implicated in multiple diseases, including cancer, cardiovascular and neurodegenerative diseases. The expression of RGS proteins is highly dynamic and is regulated by epigenetic, transcriptional and post-translational mechanisms. This review summarizes studies that report dysregulation of RGS protein expression in disease states, and presents examples of drugs that regulate RGS protein expression. Additionally, this review discusses, in detail, the transcriptional and post-transcriptional mechanisms regulating RGS protein expression, and further assesses the therapeutic potential of targeting these mechanisms. Understanding the molecular mechanisms controlling the expression of RGS proteins is essential for the development of therapeutics that indirectly modulate G protein signaling by regulating expression of RGS proteins.

Topics: Animals; Azacitidine; Benzodiazepines; Cardiovascular Diseases; Drugs, Investigational; Epigenesis, Genetic; GTP-Binding Proteins; Humans; Hydroxamic Acids; Neoplasms; Neurodegenerative Diseases; Olanzapine; Protein Processing, Post-Translational; RGS Proteins; Signal Transduction; Vorinostat

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Antipsychotic Agents; Benzodiazepines; Benzothiazoles; Brain; Clonazepam; Desipramine; Dibenzothiazepines; Dopamine Agonists; Humans; Lithium Carbonate; Maprotiline; Melatonin; Neurodegenerative Diseases; Neuroprotective Agents; Olanzapine; Parkinson Disease; Pramipexole; Quetiapine Fumarate; Selective Serotonin Reuptake Inhibitors; Valproic Acid

Fahr disease, also known as familial idiopathic basal ganglia calcification, is a rare neurodegenerative disorder, the etiology of which remains unknown. Given its various presentations, Fahr disease is presumed to be underdiagnosed and its prevalence underestimated. We present a case of Fahr disease that presented mainly with pure psychiatric symptoms. Isolated psychiatric symptoms without neurological manifestations are rarely seen in patients diagnosed with Fahr disease. Psychiatrists should consider Fahr disease as a differential diagnosis in the evaluation of psychiatric illness.

Topics: Basal Ganglia; Basal Ganglia Diseases; Calcinosis; Depression; Diagnosis, Differential; Female; Humans; Mental Disorders; Middle Aged; Neurodegenerative Diseases; Olanzapine; Paroxetine; Psychiatric Status Rating Scales; Psychotropic Drugs; Tomography, X-Ray Computed; Treatment Outcome

Schizophrenia is a neurodevelopmental disorder associated with persistent symptomatology, severe functional disability, and residual morbidity characteristic of neurodegenerative brain diseases. The illness begins with genetic susceptibility and generally expresses itself after puberty through subtle changes that begin during the prodromal stage. Symptoms get progressively worse and tend to become more resistant to treatment with each relapse. Evidence for a neuroprotective effect of some forms of early treatment is beginning to emerge. While the underlying mechanisms remain uncertain, atypical antipsychotics may counteract some of the progressive deteriorative effects by enhancing synaptic plasticity and cellular resilience. However, identifying and treating patients in the earliest disease states presents methodological challenges as there is no consensus on the best methods of intervention and differences in at-risk children are not readily detectable or substantial enough to predict which ones will develop schizophrenia. In this expert roundtable supplement, Jeffrey A. Lieberman, MD, reviews the historical context of progressive deterioration in schizophrenia. Next, Diana O. Perkins, MD, MPH, reviews some of the challenges to early identification of illness as well as the impact of early versus delayed treatment. Finally, L. Fredrik Jarskog, MD, focuses on the neurobiology of functional progression in schizophrenia as well as pharmacology and the potential for neuroprotection.

Topics: Adolescent; Adult; Antipsychotic Agents; Atrophy; Benzodiazepines; Cerebral Cortex; Child; Cognition Disorders; Disease Progression; Haloperidol; Humans; Image Processing, Computer-Assisted; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Neurodegenerative Diseases; Neuroprotective Agents; Neuropsychological Tests; Olanzapine; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Schizotypal Personality Disorder