Patho of Schizophrenia/ Psychotic disorders

Psychosis is defined as this:

Altered state of mind

What are causes of psychosis?

drugs, toxins, or CNS disease or injury

What are the clinical features of schizophrenia?

Chronic, severe illness. Core symptom of cognitive dysfunction. Vocational and social disability. Likely a spectrum or syndrome

What are postive symptoms of schizophrenia? How do they respond to drugs?

Hallucinations, delusions, bizarre behavior, and disorganized thoughts/ speech respond well to drugs

What are negative symptoms of schizophrenia? How do they respond to drugs?

Social withdrawal, poor self care, reduced speech or interest/drive, blunted emotions, lack of pleasure typically respond poorly to drugs

Concordant rates of schizophrenia are higher in what twins?

Monozygotic

What genes have an increased schizophrenia risk? What are the specific genes?

Dopaminergic, glutamatergic or Gaba-ergic, and neuron development. COMT, DISC1, DTNBP1, GABRB2, and NRG1

What is the function of DISC1?

Cell morphology and migration

What is the function of DTNBP1?

Axon stablity

What is the function of GABRB2?

GABA system

What is the function of NRG1?

Cell growth and differentiation

What is the function of COMT?

Catecholamine metabolism

What are environmental factors that may increase risk of schizophrenia?

Obsterical complications (hemorrhage, pre-term labor, nutrition, maternal stress), infections and/or inflammations (winter pregnancies, flu epidemics), and marijuana use in pts with COMT polymorphism

Marijuana use in patients with COMT polymorphisms having a higher risk of schizophrenia is an example of what?

Gene-environment interaction

Gene-environment interactions during _______ have a substanitla impact on schizophrenia risk.

Neurodevelopment

Gene-environment interactions can lead to _________ which leads to _______ and ______.

changes in brain structure which leads to altered neuron activity and neurocircuitry function

What is the supporting evidence for the dopamine hypothesis of schizophrenia?

D2 antagonist binding correlate with clinical effectiveness, Increased D2 receptor density and DA release in patient imaging, dopaminergic agnets (L-DOPA, amphetamine) worsen schizo symptoms, COMT and DRD4 increase risk of schizo, smoking

What is th evidence against the dopamine hypothesis?

D2 antagonists aren’t universally effective, atypical antipsychotic drugs work via dopamine and serotonin, NMDA bloclers (ketamine) induce psychosis, and brain abnormalities extend beyond dopamine circuits

For D2 receptor antagonits to be able to treat schizophrenia, how many recpetors must be occupied for therapeutic effect?

60-70%

How do you solve for selectivity?

KD (off target) / KD (target)

How do you solve for Therapeutic Index?

Toxic Dose 50% / Effective Dose 50%

What are the major neurotransmitter targets for treatment in schizophrenia?

Dopamine (D1-D5), serotonin

What neurotransmitter does ketamine work on and therefore what hypothesis?

glutamate inhibitor so glutamate hypothesis

What neurotransmitter does LSD work on and therefore what hypothesis?

5HT2A agonist so serotonin hypothesis

What neurotransmitter does pramipexole work on and therefore what hypothesis?

D2/D3 agonist so against the dopamine hypothesis

What neurotransmitter does Olanzapine work on and therefore what hypothesis?

Blocks D2 and 5HT2a so in support of the dopamine hypothesis