Schizophrenia

Question 1

Key symptoms of schizophrenia:

Answer 1

• abnormalities of association
• inappropriate or flattened affect
• ambivalence  distorted relationship to reality
• inattention
• learning/memory deficits (esp. working memory)
• inappropriate or a lack of movements
• weak or distorted sense of identity.
• delusions and hallucinations

THERE ARE NO DEFINING SYMPTOMS OF THE
DIASEASE; IT IS A SYNDROME, WITH AN EQUAL DIVERSE NUMBER OF UNDERLYING NEUROPATHALOGICAL CORRELATES

Question 2

positive symptoms

Answer 2

Positive Symptoms: (represent an addition to the person’s functions; respond well to traditional drug treatments)

• hallucinations, delusions, thought disorders, repeated instances of bizarre or disorganized behavior. May be due to excess dopamine function?

Question 3

Negative Symptoms

Answer 3

Negative Symptoms (represent a loss to the individual’s functions esp. emotion and motivation; respond poorly to traditional drug treatments)

• poverty of speech or speech content, affective flattening, inability to feel pleasure, apathy, difficulty sustaining attention. May be due to a diffuse and irreversible abnormalities, such as frontal lobe and/or hippocampal pathology.?

Question 4

incidence of schizophrenia in general population

Answer 4

roughly 1-2%

Question 5

schizophrenia “facts”

Answer 5

no gender difference, but men more likely to be diagnosed early

cuts across SES, culture, history

Schizophrenia has a significant genetic component

Question 6

THE DOPAMINE HYPOTHESIS OF SCHIZOPHRENIA

Answer 6

Key: schizophrenia is the result of increased activity of dopaminergic neurons; antipsychotics decrease this activity (remember, these are most effective against positive symptoms).

supported by fact that reserpine (blocks storage of NT into vesicles) and AMPT (blocks conversion of tyrosine to l-dopa) reduce symptoms.

• supported by psycho-stimulant psychosis (schizophrenic-like symptoms such as compulsive pacing, compulsive repetition of behavior, hallucinations and paranoia; note that these are all positive symptoms of schizophrenia); small doses of stimulants can trigger schizophrenic episodes in schizophrenic patients.
• KEY DA PROJECTIONS: are from the VTA into both limbic regions and frontal lobes.
• All clinical antipsychotics decrease D-2 binding…

Question 7

KEY DA PROJECTIONS:

Answer 7

are from the VTA into both limbic regions and frontal lobes.

Question 8

Test for D-2 Binding…

Answer 8

All clinical antipsychotics decrease D-2 binding…

• All subjects given a radioactively labelled ligand that binds to D-2 receptors, and then a variety of antipsychotic medications
• All medications displace the radioactive label, revealing their affinity for D-2 receptors

Question 9

DA receptors always involve….

Answer 9

DA receptors always involve….

2nd messenger signaling;

• D-2 receptors generally decrease the production of cAMP
• are inhibitory on cell activity (DA autoreceptors are D-2)

Question 10

_________ is a cardinal symptom of schizophrenia…

Answer 10

Hypofrontality is a cardinal symptom of schizophrenia…

Pathways….

Mesostriatal DA – SNr to Dorsal Striatum

Mesocortical DA – VTA to neocortex

Mesoaccumbens DA – VTA to Nacc (ventral striatum)

Question 11

________ of cells in the ________

is frequently observed in schizophrenia…

Answer 11

Disorganization of cells in the hippocampus

is frequently observed in schizophrenia…

Question 12

Pharmacology of Antipsychotics:

Answer 12

2 families; typical (includes chlorpromazine, haloperidol) and atypical (includes clozapine and respiridone

Question 13

Typicals Pharmacology of Antipsychotics:

Answer 13

haloperidol is absorbed better; remains the gold standard for antipsychotic effectiveness.

• metabolized very slowly; half-life of 48-96 hours w/ oral administration, weeks w/ IM administration; stored in other tissues (lots of depot binding) such as liver, lungs and spleen (sometimes for months).
• ED50 = 2mg; LD50 = unknown; TI = estimated to be 100-500
• metabolized in liver by CYP, excreted in urine.
• therapeutic effect comes from blocking mesolimbic D-2 receptors.
• side effects include

Parkinson-like state (block of nigrostriatal DA);

tardive dyskinesia (uncontrolled movements due to hypersensitivity of nigrostrial DA);

neuroleptic malignant syndrome (due to hypsensitivity of hypothalamic DA);

and sometimes increased negative symptoms (due to block of mesocortical dopamine??)

Question 14

Atypical antipsychotics

Answer 14

Clozapine is the best known example

sometimes preferred due to decreased EPS/tardive dyskinesia (preferential mesolimbic effect?) and ability to reduce negative symptoms (due to 5HT effect? or to lack of effect on mesocortical DA pathways?).

slightly water soluble; quite fat soluble; well absorbed, but can be metabolized by enzymes in blood; metabolized in liver by CYP (same enzyme as nicotine); half life of just 9-24 hours (leading to compliance problems)

-ED50 = 12 mg; LD50 = 2400mg; TI = ~ 200

key side effect: agranulocytosis. (a deficiency of granulocytes in the blood, causing increased vulnerability to infection.)

• Patients must be monitored; very expensive, so clozapine generally reserved for patients resistant to other drugs.
• Atypical antipsychotics have more effect on 5HT-2a binding than Haloperidol

Question 15

Test for effect on 5HT-2a binding

Answer 15

• All subjects given a radioactively labelled ligand that binds to 5-HT2A receptors, and then a variety of antipsychotic medications
• Atypical medications, but not haloperidol, displace the radioactive label, revealing their affinity for 5HT-2A receptors