Understanding Schizophrenia by 9YTf8eJ

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									     Understanding
     Schizophrenia
    J. Daniel Ragland PhD
Associate Professor of Psychiatry
                 Clinical Features
                                  perceive, understand and
 Brain disorder - impairs ability to
  interpret the environment. 1% worldwide.

 Impaired function - social and   motivational

 Behavioral syndrome - positive and negative symptoms
- Onset in late teens to early 20s
- Unremitting course with later onset & better outcome for
  women

 Genetically complex - like heart disease
- Genetic & environmental factors
- Multiple genes with variable penetrance
                 Symptoms
At least 4 weeks of 2 of the following
• Hallucinations
• Delusions
• Negative symptoms
• Disorganization

Minimum duration of 6 months of continuous signs
  of illness
Functional decline!
               Clinical Course
                                         First
                                       episode Relapses
                            Prepsychotic                     Residual
                               phase                          phase
Premorbidphase
Age      10                  15                  20          25




                                  Prodrome
                                  onset          First
 Early development                               treatment
                                  Untreated illness
              Adolescence

                                                                   Keshavan
 Heterogeneity of Schizophrenia
• Symptom diversity
• DSM subtypes; paranoid, undifferentiated,
  disorganized, catatonic
• Other typologies; type I and type II (Crow),
  deficit and non deficit (Carpenter)
• People have increasingly tried to
  understand symptoms rather than the
  disorder itself
            Epidemiology
• 1% of population world wide
• Males and females equally affected but
  females have later onset and better
  functional outcome
• Onset in late adolescence, early adulthood
• Loss of function, inability to achieve
  expected function
• 10% SSI/SSDI, 2% GNP in direct care
  costs and lost productivity
                Genetics
• Highly heritable
• Risk increases with relationship e.g. 10%
  for first degree relative or fraternal twin,
  50% concordance for monozygotic twin
• Environmental factors certain but poorly
  characterized (intrauterine malnutrition,
  viral illnesses, perinatal insults, drug
  exposure)
Genetic Risk
Genetic Association
       (Endo)Phenotypes
Affectation status reflects an underlying quantitative
trait: liability, susceptibility, risk of developing disease.

             Discrete                Continuous
             (disease)                 (liability)




              0    1
                                                t
   Causes of Schizophrenia
• Risk gene/environment interactions
• Altered neurodevelopment leading to
  symptoms in early adolescence/young
  adulthood
• Gross structural changes in the brain
• Specific functional changes in the brain
• Alterations in local circuit architecture
• Alterations in dopamine neurotransmission
         Gross Pathology
n=63
Age 78.3 (SD=9.7, Range 67 - 99)
Brain Weight 1192 g (SD=143, Range 932 - 1520)
PMI 12.6 hrs (SD=4.9, Range 932 - 1520)

Diagnoses
  ‘Normal brain’                     45
  Alzheimer’s disease                5
  Lewy body variant AD               1
  Parkinson’s disease                2
  Cerebrovascular lesions            6
  Meningioma                         2
  Metastatic adenocarcinoma (lung)   1
  Adult polyglucosan body disease    1
    Neurodegenerative Lesions
                                    Control   Schiz     AD    FLD
           PHFtau NFTs         70

                               60

                               50

                               40

                               30

                               20

                               10

                                0
                                    EC        Sub/CA1        MFC     Calcarine

                                    Control   Schiz     AD     FLD
                      Ab SPs   10
                                9
                                8
                                7
                                6
                                5
                                4
                                3
                                2
                                1
Arnold et al., 1998             0
                                    EC        Sub/CA1        MFC     Calcarine
Neuron Density and Size




                  Arnold et al., 1995
        Entorhinal Cytoarchitecture
                         1.4



                         1.0




                         0.6
                                  N         S
                               Dispersion Index


                          40



                          20



                          0
                                  N        S
Arnold et al., 1997            Effective Radius
           Molecular Components
           of Structural Plasticity




Axons & Terminals          Dendrites & Spines                  LTP
Synapsin-1 Synaptophysin   Homer      MAP2           Homer     pGluR
SNAP25       VGluT-1       NFM/H-P-   Synaptopodin   pNMDAR1   N-cadherin
VGaT          GAP43        F-actin     Drebrin       pCamKII   Rim 1
NCAM           Dysbindin   EphA4
b-Dystrobrevin
 Specific functional changes in
            the brain
               Right BA 9                                                                                                                     Left BA 10/46
    2
                                                                                                                                    2
    1
    0                                                                                                                               1




                                                                           Activity (partial r)
   -1
                                                                                                                                    0
   -2
   -3                                                                                                                               -1
   -4
                                                                                                                                    -2
         Controls                            FE O Psych
                                                                                                                                             Controls            FE O Psych
                    FE Schiz                                                                                                                            FE Schiz
                    Diagnosis                                                                                                                           Diagnosis
Dis. Sx in Patients r=-.55, p<.005
                                                                                                                                  Dis. Sx in Patients r=-.40, p<.05
  10
                                                                                                                                         4
                                                                                                                                         2
   0
                                                           Neg. Sx in Patients r=-.46, p<.01
                                                                                        Activity (partial r)                             0

  -10
                                                                                                                                     -2
                                                             4
                                                                                                                                     -4
  -20                                                        2
                                                                                                                                     -6
     2     4    6                  8        10   12   14
                                                             0                                                                       -8
                     Activity (partial r)




               Disorganization                                                                                                         2         4      6    8     10   12   14
                                                             -2

    • FE Schiz                                               -4                                                                                      Disorganization

                                                             -6
    • FE Other Psych                                         -8
                                                               2   4   6                                       8   10   12   14

                                                                       Negative Sx
      Alterations in dopamine
         neurotransmission
• The classical dopamine hypothesis (too
  much dopamine in schizophrenia) rested
  on the observation that DA releasing drugs
  can cause psychosis, and the discovery
  that antipsychotics were dopamine
  antagonists.
      Alterations in dopamine
         neurotransmission
• C11 Racolpride displacement reflects DA
  release
Increased subcortical DA
   related to psychosis
      Alterations in dopamine
         neurotransmission
• Decreased prefrontal activity may lead to
  subcortical DA dysregulation and
  psychosis

               Decreased
              PFC function




       Increased    +
          DA                 VTA
Progressive Neuro-
developmental Model
     Cascade model of schizophrenia pathogenesis
                                                          Deficit state?


                            Untreated illness
                                                         Post-illness
                Hormones,                                Onset
                Psychosocial stress,                     Neurotoxicity?
                drugs

 Genes                                 Peri-adolescent
                                       mispruning         Schizophrenia
 viruses, Obstetric
 malnutrition


                                              Schizotypal PD
           Early developmental
           “miswiring”
                                                                           Keshavan
  Management of Schizophrenia
• Early intervention important for improving
  functional outcome
• Medication treatments
• Psychosocial Treatments
 Future Directions in the Treatment
         of Schizophrenia
• More optimistic view of outcome
• Much stronger focus on early intervention and
  prevention e.g. early psychosis clinics and
  prodromal studies
• Specific treatments for cognition in
  schizophrenia
• As molecular pathways associated with neural
  phenotypes become understood new, non
  dopamine based therapies
• Renewed emphasis on rehabilitation, supported
  employment etc.

								
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