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Drugs and the Brain: The Challenge of Schizophrenia

Drugs and the Brain: The Challenge of Schizophrenia. David A. Lewis, MD Translational Neuroscience Program Department of Psychiatry Center for the Neuroscience of Mental Disorders University of Pittsburgh. Leading Causes of Disability: Market Economies, 1990. The Burden of Schizophrenia.

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Drugs and the Brain: The Challenge of Schizophrenia

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  1. Drugs and the Brain:The Challenge of Schizophrenia David A. Lewis, MD Translational Neuroscience Program Department of Psychiatry Center for the Neuroscience of Mental Disorders University of Pittsburgh

  2. Leading Causes of Disability: Market Economies, 1990

  3. The Burden of Schizophrenia • Common: ~1% of population • Chronic: Affected individuals typically ill from adolescence or early adulthood • Co-morbidity: Depression, substance abuse, suicide (10%)

  4. Suicide • ~40,000 deaths by suicide in US annually. • 95% of people who commit suicide are suffering from a diagnosable psychiatric illness. • Common diagnoses in suicide: major depression, alcoholism, schizophrenia. • 2/3 communicate their intent and 50% have consulted a physician within the month prior to death.

  5. Schizophrenia:Historical Perspectives 1 • 1893 Kraepelin distinguished “dementia praecox” from manic-depressive psychosis • Emphasized course and prognosis • Early onset • Deteriorating course • Dementia as the end state • An “organic” brain disorder

  6. Schizophrenia:Historical Perspectives 2 • 1911 Bleuler coins “schizophrenia” in reference to the splitting of mental functions • Emphasized psychological mechanisms • Four fundamental features (“the 4 A’s”) • Loosening of Associations • Autistic behavior and thought • Disturbance in Affect • Ambivalence • Psychosis = Accessory Symptoms

  7. Schizophrenia:Historical Perspectives 3 • 1939 Schneider emphasized diagnostic reliability • Described “first rank symptoms” • Audible thoughts • Voices arguing or commenting • Thought insertion, withdrawal or broadcasting • Made impulses, feelings or will • Very common in schizophrenia but not specific to this diagnosis

  8. Auditory hallucinations Paranoid delusions Thought disorder Tangential associations Blocking Perseveration Echolalia Clanging Alogia Poverty of speech Poverty of speech content Avolition-apathy Affective flattening Poor eye contact Paucity of expressive gestures Inappropriate affect Motor disturbances Posturing Akathisia (drug-induced restlessness) Depressed mood/suicidal ideation Lack of insight Video Interview

  9. Schizophrenia as a Genetic Disorder • The morbid risk of schizophrenia increases in relation to the percentage of genes shared with an affected individual.

  10. Schizophrenia and Genetic Risk

  11. The familial nature of schizophrenia is NOT due simply to a shared environment • The risk of schizophrenia is ~17% for fraternal twins and ~48% for identical twins. • The risk for adopted-away biological children of individuals with schizophrenia… • is elevated as expected for first-degree relatives. • higher than rates of schizophrenia present in their adoptive families. • higher than rates of schizophrenia in the adopted-away offspring of unaffected parents.

  12. Inheritance is not sufficient for the development of schizophrenia • Conordance for schizophrenia in monozygotic twins is only ~ 50%. • ~ 60% of individuals with schizophrenia have neither a 1st nor 2nd degree relative with the disorder. • Patterns of inheritance do not fit single gene, Mendelian models, but suggest the influence of multiple susceptibility genes, each of small effect.

  13. Schizophrenia as an Environmental Disorder • A variety of “environmental” events appear to increase the risk for schizophrenia: • Pregnancy and labor/delivery complications • Late winter/early spring births • Urban place of birth and rearing • Advanced paternal age • However, the predictive value of all of these risk factors is low.

  14. Schizophrenia as a Neurodevelopmental Disorder • During childhood and adolescence, individuals who subsequently manifest schizophrenia may exhibit… • Motor abnormalities • Social abnormalities • Impairments in IQ and school performance

  15. Schizophrenia as a Neurodevelopmental Disorder • Early model:Brain lesion from early in life remains clinically silent until normal developmental processes during adolescence bring the structures affected by the lesion “on line.” • Late model:Brain dysfunction arises as a result of altered brain development (e.g., synaptic pruning) during adolescence.

  16. The Disease Process of Schizophrenia Pathophysiology Pathogenesis Pathological Entity Clinical Syndrome Etiology Adapted from Paul R. McHugh, M.D.

  17. The Neurobiological Challenges of Schizophrenia • The apparent absence of neuropathological abnormalities. • The complexity of the brain systems that are dysfunctional.

  18. Alzheimer’s Disease 1906 clinical description 1906 neuritic plaques (NP) and neurofibrillary tangles 1984 amyloid protein in NP 1987 gene for beta-amyloid protein (BAP) 1990’s molecular mechanisms underlying BAP deposition 1990’s genes for rare familial forms and susceptibility genes for common forms Schizophrenia 1895 clinical description 1979 enlarged ventricles 2000 alterations in thalamo-cortical-striatal circuitry 2002 first compelling risk genes identified Neuropathological Markers: A Tale of Two Disorders

  19. Biological Complexity of the Clinical Features of Schizophrenia • Disturbances in Vision • Visual field defects vs. visual hallucinations

  20. Sensory-Motor vs. Cognitive Circuits • The activities of encoding sensory information and commanding movements occupy only about 20% of the volume of the cerebral cortex. • The remaining association cortices are concerned with attending to and recognizing complex stimuli, and to storing (both short and long term) such information in order to plan appropriate responses. Such abilities are termed cognitive processes.

  21. Neuroscience, Purves et al

  22. Fig 12.8 Neuroscience, Purves. P260.

  23. Fig 2 Cerebral Cortex, VanEssen. 1991.

  24. Fig 4 Cerebral Cortex, Van Essen. 1991.

  25. The Disease Process of Schizophrenia Pathophysiology Pathogenesis Pathological Entity Clinical Syndrome Etiology Adapted from Paul R. McHugh, M.D.

  26. Schizophrenia affects multiple complex brain systems as evidenced by the range of clinical features • Positivesymptoms: Delusions, hallucinations, thought disorder • Negative symptoms: Decreased motivation, diminished emotional expression • Cognitive deficits:Impairments in attention, executive function, certain types of memory • Sensory abnormalities:“Gating” disturbances • Sensorimotor abnormalities:Eye tracking disturbances • Motorabnormalities:Posturing, impaired coordination

  27. Cognitive Deficits in Schizophrenia: Core Features of the Illness • Present in individuals at high risk • Premorbid and prodromal phase marker • Persistent (progressive?) during illness • Predictor of long-term outcome

  28. Cognitive Deficits in Schizophrenia • Include impaired working memory, the ability to keep in mind briefly a bit of information in order to guide subsequent behavior. • Working memory deficits are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC).

  29. DLPFC Activation as a Function of Working Memory Load in Schizophrenia R DLPFC (BA46) Controls .30 Patients .20 % fMRI Signal Change .10 n = 16 per group 0 0-back 1-back 2-back +28 mm WM Load Courtesy of Dr. Cameron Carter

  30. Cognitive Deficits in Schizophrenia • Working memory requires an intact dopamine innervation of the dorsolateral prefrontal cortex. • Dopamine-containing axons project from the ventral mesencephalon (VTA) to the cerebral cortex.

  31. Catechol-O-methyltransferase (COMT) • Enzyme involved in the metabolic degradation of dopamine. • COMT appears to be the major contributor to the termination of dopamine action in the prefrontal cortex due to low levels of the dopamine transporter. • Single guanine to adenine transition (common) changes val to met at codon 108. • Val-COMT has 4-fold greater activity than met-COMT, leading to decreased prefrontal dopamine levels. • Schizophrenic individuals with val/val COMT show greater impairments on working memory tasks.

  32. Deficits in Prefrontal Cortical Dopamine Neurotransmission in Schizophrenia • Normal function of the DLPFC depends upon appropriate stimulation of dopamine D1 receptors • Individuals with schizophrenia may have • Decreased dopamine axons in the DLPFC • Increased levels of D1 receptors in the DLPFC • Improvement in DLPFC function with dopamine agonists

  33. But, Schizophrenia Also Appears to be Associated with an Excess of Dopamine Neurotransmission • Amphetamines can induce psychotic symptoms. • All antipsychotic drugs share antagonism of the dopamine D2 receptor. • Subjects with schizophrenia show excess release of dopamine in the striatum.

  34. Dopamine Neurotransmission in Schizophrenia • The cognitive symptoms of schizophrenia may be associated with a functional deficit of dopamine at D1 receptors in the prefrontal cortex. • The psychotic features of schizophrenia may be associated with a functional excess of dopamine at D2 receptors in the striatum (caudate/putamen).

  35. Structural Brain Abnormalities in Schizophrenia • ~40% increase in 3rd and lateral ventricular volumes • Associated with more neuropsychological impairments and negative symptoms • More prominent in males • 3-4% decrease in whole brain volume

  36. Structural Brain Abnormalities in Schizophrenia • Hippocampus and Association Cortices • Decreased gray matter volume • No cell loss • Reductions in pre- and post-synaptic markers

  37. Basic Neurochemistry, 1994

  38. Structural Brain Abnormalities in Schizophrenia • Mediodorsal thalamic nucleus • Decreased volume • ~30% Decrease in neuronal number

  39. Structural Brain Abnormalities in Schizophrenia • Convergent lines of evidence indicate that schizophrenia is associated with • A reduction in synaptic connections in the hippocampus and cerebral cortex. • Fewer neurons in the mediodorsal thalamus. • Which neurotransmitter systems are involved in these abnormalities?

  40. Altered Glutamate Neurotransmission - 1 • Phencyclidine (PCP) and ketamine, non-competitive antagonists of the NMDA subtype of glutamate receptors… • Exacerbate clinical features of schizophrenia. • May induce transiently some positive, negative and cognitive symptoms resembling those of schizophrenia in normal adults. • Rarely cause such symptoms in children.

  41. Altered Glutamate Neurotransmission - 2 • The symptoms of schizophrenia, especially cognitive deficits, have been reported to be improved by… • Glycine, which facilitates NMDA receptor function by binding to a modulatory site on the receptor. • D-cycloserine, a selective partial agonist at the glycine modulatory site of the NMDA receptor.

  42. Classical APD High affinity D2 antagonists Reduces positive sx Limited against negative/cognitive High rates of EPS and TD Atypical APD Low affinity D2, high affinity 5HT2A antagonists Broader efficacy Blood dyscrasias, weight gain, glucose intolerance, $$$ Current Treatment of Schizophrenia

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