SCHIZOPHRENIA & ANTIPSYCHOTIC DRUGS Flashcards
positive symptoms of schizophrenia
paranoid delusions
hallucinations
irrational thoughts
abnormal, aggressive, stereotypical behavior
negative symptoms of schizophrenia
social withdrawal
blunted/flat affect (emotional response)
other symptoms of schizophrenia
impaired cognitive function
defect in selective attention
epidemiology of schizophrenia
1% of population affected
diagnosed ages 20-30
chronic - highly disabling
causes of schizophrenia
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)
risk factor of schizophrenia
maternal hypertension
virus infections
head injury during childhood
stress/child abuse
what are the 3 theories of schizophrenia
- Dopamine Theory (too much dopamine)
- Glutamate Theory (decreased glutamate)
- 5-HT Theory (increased activity)
evidence supporting the Dopamine Theory
- Amphetamines
- cause dopamine release in the brain
- induce stereotypy in mice/rats
- produce schizophrenic behaviour in humans - Potent D2 R agonists
- increase positive schizophrenic symptoms - Dopamine antagonists/ blockers of dopamine storage
- suppress positive symptoms
- prevent amphetamine-induced behavioural changes
what did the Laurell study hypothesize
- 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)
summary of Laurell study
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
how did they carry out the Laurell study
look at specific D2 receptor antagonist - radioactively label
look for displacement
increase affinity = greater displacement
evidence supporting the Glutamate Theory
- reduced glutamate + glutamate receptor concentrations seen in post-mortem schizophrenic brains
(rapid brain deterioration after death) - Ketamine, Phencyclidine blocks NMDA R
- induces schizophrenia symptoms in humans/rodents - emerging mGluR2/3 agonists
- decrease positive symptoms
(autoreceptors - inhibit glutamate release) - reduced NMDA R mice = stereotypy, less social interaction)
evidence supporting Abnormal 5-HT Transmission
- 5HT2A agonists induce schizophrenia symptoms
2. newer (atypical) antipsychotics also have affinity for 5HT2A
TYPICAL classification of antipsychotic drugs
- dopamine D1/D2 receptor antagonists
- slow rate of drug dissociation from receptor = HIGH AFFINITY
- HALOPERIDOL
ATYPICAL classification of antipsychotic drugs
- more selective D2 binding
- rapid rate of drug dissociation from receptor
= fewer extrapyramidal side effects - useful in treating negative symptoms
- CLOZAPINE
HALOPERIDOL
- controls positive symptoms of schizophrenia
- dopamine D1/D2 receptor antagonist
side effects: weight gain, hypothermia, strong EPS
40% patients relapse after 1-year treatment
CLOZAPINE
- 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
time course of action of antipsychotics
take days-weeks
transient increase, then decrease of activity of dopaminergic neurons - levels off after
Extrapyramidal Motor Disturbances
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
Tardive Dyskinesia (EPS)
-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
Idiosyncratic Reactions to Antipsychotics
- jaundice
-agranulocytosis (low WBC (clozapine) - malignant syndrome:
. muscle rigidity
. rapid rise in body temp
. mental confusion
antipsychotics and how they work
treat schizophrenia - by blocking specific subtype of dopamine receptors = D2 R
what is catalepsy
overdose of antipsychotic drugs = complete immobility due to complete block of dopamine regulated nigrostriatal pathways
