SCHIZOPHRENIA & ANTIPSYCHOTIC DRUGS

Question 1

positive symptoms of schizophrenia

Answer 1

paranoid delusions
hallucinations
irrational thoughts
abnormal, aggressive, stereotypical behavior

Question 2

negative symptoms of schizophrenia

Answer 2

social withdrawal

blunted/flat affect (emotional response)

Question 3

other symptoms of schizophrenia

Answer 3

impaired cognitive function

defect in selective attention

Question 4

epidemiology of schizophrenia

Answer 4

1% of population affected
diagnosed ages 20-30
chronic - highly disabling

Question 5

causes of schizophrenia

Answer 5

runs in families // polygenic
mutations in genes that upregulate NMDA R expression = show strongest association
also mutations in genes encoding D2 R + MAOA
(A - breaks down NE + S // B - breaks down dopamine)

Question 6

risk factor of schizophrenia

Answer 6

maternal hypertension
virus infections
head injury during childhood
stress/child abuse

Question 7

what are the 3 theories of schizophrenia

Answer 7

1. Dopamine Theory (too much dopamine)
2. Glutamate Theory (decreased glutamate)
3. 5-HT Theory (increased activity)

Question 8

evidence supporting the Dopamine Theory

Answer 8

1. Amphetamines
   - cause dopamine release in the brain
   - induce stereotypy in mice/rats
   - produce schizophrenic behaviour in humans
2. Potent D2 R agonists
   - increase positive schizophrenic symptoms
3. Dopamine antagonists/ blockers of dopamine storage
   - suppress positive symptoms
   - prevent amphetamine-induced behavioural changes

Question 9

what did the Laurell study hypothesize

Answer 9

• more dopamine binds to D2 receptors in response to amphetamine in schizophrenics than non-schizophrenics
• PET study examined displacement of 123 I - D2 antagonist from D2 receptors in brain
  (lots of dopamine - decrease binding of 123 I)

Question 10

summary of Laurell study

Answer 10

schizophrenics = have D2 R which bind dopamine with HIGHER AFFINITY than non-schizophrenics

increased dopamine-D2 R binding = correlated with an increase in positive symptoms
decrease in negative symptoms

Question 11

how did they carry out the Laurell study

Answer 11

look at specific D2 receptor antagonist - radioactively label
look for displacement
increase affinity = greater displacement

Question 12

evidence supporting the Glutamate Theory

Answer 12

1. reduced glutamate + glutamate receptor concentrations seen in post-mortem schizophrenic brains
   (rapid brain deterioration after death)
2. Ketamine, Phencyclidine blocks NMDA R
   - induces schizophrenia symptoms in humans/rodents
3. emerging mGluR2/3 agonists
   - decrease positive symptoms
   (autoreceptors - inhibit glutamate release)
4. reduced NMDA R mice = stereotypy, less social interaction)

Question 13

evidence supporting Abnormal 5-HT Transmission

Answer 13

1. 5HT2A agonists induce schizophrenia symptoms

2. newer (atypical) antipsychotics also have affinity for 5HT2A

Question 14

TYPICAL classification of antipsychotic drugs

Answer 14

• dopamine D1/D2 receptor antagonists
• slow rate of drug dissociation from receptor = HIGH AFFINITY
• HALOPERIDOL

Question 15

ATYPICAL classification of antipsychotic drugs

Answer 15

• more selective D2 binding
• rapid rate of drug dissociation from receptor
  = fewer extrapyramidal side effects
• useful in treating negative symptoms
• CLOZAPINE

Question 16

HALOPERIDOL

Answer 16

• controls positive symptoms of schizophrenia
• dopamine D1/D2 receptor antagonist

side effects: weight gain, hypothermia, strong EPS
40% patients relapse after 1-year treatment

Question 17

CLOZAPINE

Answer 17

• controls positive + negative symptoms of schizophrenia
• no EPS
• D1/D2 receptor antagonist + high affinity for D4
• inverse agonist of 5-HT2 receptors
• NE antagonism
• Muscarinic receptor antagonist

side effects: weight gain, risk of diabetes, hypersalivation, intestinal hypomobility
25% patients relapse after 1-year treatment

Question 18

time course of action of antipsychotics

Answer 18

take days-weeks

transient increase, then decrease of activity of dopaminergic neurons - levels off after

Question 19

Extrapyramidal Motor Disturbances

Answer 19

Acute Dystonias (involuntary movements)
- muscle spasms, protruding tongue, Parkinson like
-occurs in first few weeks of drug therapy, then declines
= due to effects of typical antipsychotics on NIGOSTRIATAL pathways
REVERSIBLE

Question 20

Tardive Dyskinesia (EPS)

Answer 20

-over 50
-involuntary movements of face/limbs
- occurs after long term treatment
- depends on drug, dosage, age
- disabling + IRREVERSIBLE, may worsen after treatment
due to:
. gradual increase in D2 R in striatum
. chronic block of inhibitory dopamine R - enhance catecholamine (NE/E)/glutamate release in striatum = excitotoxic neurodegeneration

Question 21

Idiosyncratic Reactions to Antipsychotics

Answer 21

• jaundice
  -agranulocytosis (low WBC (clozapine)
• malignant syndrome:
  . muscle rigidity
  . rapid rise in body temp
  . mental confusion

Question 22

antipsychotics and how they work

Answer 22

treat schizophrenia - by blocking specific subtype of dopamine receptors = D2 R

Question 23

what is catalepsy

Answer 23

overdose of antipsychotic drugs = complete immobility due to complete block of dopamine regulated nigrostriatal pathways