Lecture 22

Question 1

What is Psychosis

Answer 1

Loss of contact with reality
Schizophrenia is a disorder of thinking and cognition

Question 2

Positive (abnormal extra behaviour) symptoms of Schizophrenia

Answer 2

Delusions, hallucinations (auditory), thought disorders, agitation, grandiosity, suspiciousness/paranoia, hostility

Question 3

Negative (absence of normal behaviour) symptoms of Schizophrenia

Answer 3

Blunted emotions, emotional and social withdrawal, poor rapport (limited relationships), passive/apathetic, lack of spontaneity

Question 4

Cognitive symptoms of Schizophrenia

Answer 4

Poor attention, poor memory, poor abstract thinking

Question 5

Schizophrenia risk factors

Answer 5

Genes (controlling neural development), environmental factors (birth complications like anoxia, virus, stress like starvation), structural changes in the brain, disordered neurotransmission (dopamine)

Question 6

What is a neuroleptic

Answer 6

Ex. chlorpromazine (but only alleviated positive symptoms)
An antipsychotic drug that blocks dopamine and causes EPS (Parkinson like motor impairment)

Question 7

Problems with antipsychotics

Answer 7

1) Provide only symptomatic relief
2) Need to be taken long-term
3) Block dopamine receptors

Question 8

2 families of antipsychotic drugs

Answer 8

1) Older family (chlorpromazine)
2) Newer family (clozapine)

Question 9

Chlorpromazine effect of dopamine

Answer 9

Did NOT change tissue content of dopamine in striatum
Increased dopamine metabolite levels hence causing the dopamine cells to fire fast and release more dopamine

Question 10

Reserpine vs Chlorpromazine

Answer 10

Both are antipsychotics and produce EPS (Parkinson like motor symptoms)
BUT
Reserpine DECREASES dopamine activity
Chlorpromazine INCREASES dopamine activity

Question 11

Chlorpromazine vs Haloperidol

Answer 11

Both are equally effective antipsychotics
BUT
Chlorpromazine STRONGLY inhibited dopamine’s ability to increase cAMP, and POTENTLY inhibited binding (radioligand binding)
Haloperidol WEAKLY inhibited dopamine’s ability to increase cAMP, and WEAKLY inhibited binding (radioligand binding) BUT also binds to Dopamine receptors
H-DA was binding mostly to D1 receptors

Question 12

Types of Dopamine receptors

Answer 12

D1 (postsynaptic)–>increases tissue levels of cAMP
D2 (both pre and post-synaptic)–>decreases cAMP formation

Question 13

Overall Chlorpromazine vs Haloperidol

Answer 13

Chlorpromazine is a potent antagonist at D1 receptors, while haloperidol has a much lower affinity and binds primarily to D2 receptors

Question 14

D1 and D2 receptor affinity

Answer 14

Low IC50–>high affinity for receptor
Most neuroleptics block D1 less potently than D2
D1–>no correlation between dosage and therapeutic effect
D2–>higher affinity of drug for D2 the less you need for an antipsychotic/therapeutic effect

Question 15

Triggers of positive schizophrenic symptoms

Answer 15

Amphetamine, cocaine, PCP (somewhat positive and negative), and LSD (not really)

Question 16

Schizophrenia hypothesis

Answer 16

There is an excess of dopamine transmission in the brain

Question 17

Evidence for Schizophrenia hypothesis

Answer 17

1) DA receptor blockers can acutely block psychosis when induced by amphetamine or cocaine
2) Increase in dopamine release during acute psychosis

Question 18

Mechanism of antipsychotics

Answer 18

Block postsynaptic dopamine receptors in the mesolimbic system–>inhibit psychosis

Question 19

Atypical drug criteria

Answer 19

1) Produces no or very little acute EPS at any dose
2) Do NOT produce a surge in prolactin like classical drugs
3) Rare tardive dyskinesia (which is common in classical)

Question 20

EPS symptoms

Answer 20

Difficult to find a therapeutic dose that does not cause EPS as they have very similar dose-response curves
Atypical drug–>NO EPS at therapeutic concentrations

Question 21

What is a Prolactin surge

Answer 21

Dopamine inhibits the secretion of prolactin through D2 receptors–>blocking D2 receptors blocks the inhibitory effect –>promoting prolactin–>increase milk production
Not present in atypical drugs (sign that they don’t block D2 receptors to same extent)

Question 22

What is Tardive Dyskinesia

Answer 22

Involuntary movements of the face and mouth

Question 23

Main action of Clozapine

Answer 23

Alleviated Negative AND positive symptoms, works well in patients who are refractory to other drugs
Atypical antipsychotic
Does NOT produce EPS, prolactin surge, or tardive dyskinesia
NOT A FIRST LINE DRUG

Question 24

Side effect of Clozapine

Answer 24

1) Produce Agranulocytosis, a granulocyte deficiency leading to increased susceptibility to infection
2) Weight gain (can lead to type 2 diabetes)
3) Increases risk of seizures
NOT A FIRST LINE DRUG

Question 25

How is Clozapine unique

Answer 25

1) Alleviates negative symptoms
2) Improves treatment-resistant patients
3) Risk to agranulocytosis

Question 26

Why do the Catalepsy test

Answer 26

Because acute atypical antipsychotic administration produces little or no nigrostriatal dopamine blockage, nigrostriatal dopamine dysfunction is known to cause catalepsy

Question 27

What is the Catalepsy test

Answer 27

Immobility (tensed) with high enough dose of classical antipsychotic
Atypical drugs produce little to no catalepsy–>don’t block dopamine receptors in nigrostriatal system

Question 28

What does acute atypical administration cause

Answer 28

Mesolimbic dopamine blockade
Inject rat with amphetamine, arousal = locomotion
Acute amphetamine increases locomotor activity caused by increased mesolimbic dopamine release
Giving clozapine prior to amphetamine prevents effect of amphetamine

Question 29

Overall Classical vs atypical antipsychotics

Answer 29

Classical–> Inhibits dopamine transmission in BOTH nigrostriatal and mesolimbic pathways
Atypical–>ONLY effect MESOlimbic pathway, block fewer D2 receptors

Question 30

Dissociation constant (Ki)

Answer 30

Ki is inversely related to affinity

Question 31

Main action of Risperidone

Answer 31

Blocks D2 receptors and 5-HT2 receptors
Most atypicals have a higher affinity for 5-HT2 than D2 receptors

Question 32

Chronic effect of antipsychotics

Answer 32

Depolarization inactivation occurs selectively in mesolimbic DA system and chronic action is what counts for therapeutic effect

Question 33

Given acutely dopamine…

Answer 33

D2 agonists–>stimulates auto receptors–>hyperpolarize, slow rate of firing (at high enough dose can stop firing)
D2 antagonist–>blocks auto receptors, depolarize, greater firing rate

Question 34

Given chronically

Answer 34

D2 antagonists become SOO depolarized that ion channels generating action potentials become inactivated–>cell can no longer fire–>depolarization inactivation/block
Classical–>mesolimbic + nigrostriatal systems
Atypical–>mesolimbic system

Question 35

Overall effect of inactivating dopamine neurons

Answer 35

Depolarizing and inactivating dopamine neurons prevents them from firing and from releasing dopamine–>reducing dopamine concentration

Question 36

First line drug for Schizophrenia

Answer 36

Haloperidol